Microalgae, seaweeds and aquatic bacteria, archaea, and yeasts: sources of carotenoids with potential antioxidant and anti-inflammatory health-promoting actions in the sustainability era.

Citation: Mapelli-Brahm, P.; Gómez-Villegas, P.; Gonda, M.L.; León-Vaz, A.; León, R.; Mildenberger, J.; Rebours, C.; Saravia, V.; Vero, S.; Vila, E.; et al. Microalgae, Seaweeds and Aquatic Bacteria, Archaea, and Yeasts: Sources of Carotenoids with Potential Antioxidant and Anti-Inflammatory Health-Promoting Actions in the Sustainability Era. Mar. Drugs 2023,21, 340. https://doi.org/ 10.3390/md21060340 Academic Editor: João Carlos Serafim Varela Received: 8 May 2023 Revised: 25 May 2023 Accepted: 27 May 2023 Published: 1 June 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). marine drugs Review Microalgae, Seaweeds and Aquatic Bacteria, Archaea, and Yeasts: Sources of Carotenoids with Potential Antioxidant and Anti-Inflammatory Health-Promoting Actions in the Sustainability Era Paula Mapelli-Brahm 1,* , Patricia Gómez-Villegas 2, Mariana Lourdes Gonda 3, Antonio León-Vaz 2, Rosa León2, Jennifer Mildenberger 4, Céline Rebours 4, Verónica Saravia 5, Silvana Vero 3, Eugenia Vila 5 and Antonio J. Meléndez-Martínez 1,* 1Food Colour and Quality Laboratory, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain 2 Laboratory of Biochemistry, Faculty of Experimental Sciences, Marine International Campus of Excellence and REMSMA, University of Huelva, 21071 Huelva, Spain; [email protected] (P.G.-V.); [email protected] (A.L.-V.); [email protected] (R.L.) 3Área Microbiología, Departamento de Biociencias, Facultad de Química, Universidad de la República, Gral Flores 2124, Montevideo 11800, Uruguay; [email protected] (M.L.G.); [email protected] (S.V.) 4 Møreforsking AS, Borgundveien 340, 6009 Ålesund, Norway; jennifer[email protected] (J.M.); [email protected] (C.R.) 5Departamento de Bioingeniería, Facultad de Ingeniería, Instituto de Ingeniería Química, Universidad de la República, Montevideo 11300, Uruguay; [email protected] (V.S.); [email protected] (E.V.) *Correspondence: [email protected] (P.M.-B.); [email protected] (A.J.M.-M.) Abstract: Carotenoids are a large group of health-promoting compounds used in many industrial sectors, such as foods, feeds, pharmaceuticals, cosmetics, nutraceuticals, and colorants. Considering the global population growth and environmental challenges, it is essential to find new sustainable sources of carotenoids beyond those obtained from agriculture. This review focuses on the potential use of marine archaea, bacteria, algae, and yeast as biological factories of carotenoids. A wide variety of carotenoids, including novel ones, were identified in these organisms. The role of carotenoids in marine organisms and their potential health-promoting actions have also been discussed. Marine organisms have a great capacity to synthesize a wide variety of carotenoids, which can be obtained in a renewable manner without depleting natural resources. Thus, it is concluded that they represent a key sustainable source of carotenoids that could help Europe achieve its Green Deal and Recovery Plan. Additionally, the lack of standards, clinical studies, and toxicity analysis reduces the use of marine organisms as sources of traditional and novel carotenoids. Therefore, further research on the processing of marine organisms, the biosynthetic pathways, extraction procedures, and examination of their content is needed to increase carotenoid productivity, document their safety, and decrease costs for their industrial implementation. Keywords: bioactives; natural pigments; antioxidant activity; marine organisms; human health; blue economy; agro-food; functional foods; marine resources; cosmetics 1. Introduction: Sustainability, the Blue Economy, and the Versatility of Carotenoids in Agro-Food and Health It is estimated that 40% of the global land surface is used by agriculture and that 30% of global greenhouse gas emissions and 70% of freshwater use are related to food production. Besides, 820 million people have insufficient food, 2000 million adults are overweight or obese, and the global prevalence of diabetes has doubled since 1990 [ 1 ]. Thus, research on food science, technology, and related fields such as agriculture, aquaculture, and nutrition must be directed toward the sustainable production of health-promoting foods to combat Mar. Drugs 2023,21, 340. https://doi.org/10.3390/md21060340 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2023,21, 340 2 of 45 diet-related diseases and preserve key resources for future generations. The synergistic work carried out in large related networks (CYTED-IBERCAROT, CYTED-MICROAGRO, COST-EUROCAROTEN, COST-SEAWHEAT, COST-OCEAN4BIOTECH, CaRed, etc.) is important to orchestrate efforts and produce breakthroughs. The rapid growth of the global population requires new solutions to ensure food security, which cannot rely exclusively on land-based agriculture; hence, the importance of tapping further into the vast aquatic biodiversity. The blue economy of the EU is fundamental for the European Green Deal and the Recovery Plan for Europe, which will define the European economy for many years, as the ocean is the main climate regulator, offers clean energy, and provides us with oxygen and food, among other resources. The Blue Economy includes all those activities that are marine-based or marine-related and encompasses sectors including living and non-living resources or renewable energy, among others. Important marine species featured in the blue bioeconomy are algae (microalgae and seaweeds), bacteria, fungi, and invertebrates. Each year, hundreds of untapped new compounds derived from these organisms are discovered, including carotenoids and their derivatives. The applications of their biomasses in agro-food health range from foods, supplements, cosmetics, and feeds to biostimulants and fertilizers. They can also be used for biomaterials, bioremediation, or biofuels [ 2 ]. Regarding the carotenoids, the Action COST EUROCAROTEN (www.eurocaroten.eu (accessed on 30 May 2023)) highlighted that apart from marine sources, understudied carotenoids (the great majority, as only 10–20 carotenoids are being studied in depth) offer many possibilities for innovation in agro-food, health, cosmetics, or biomaterials [3]. Algae and microbes (as well as insects) are highlighted as matrices that can be further harnessed to produce innovations in the context of healthy diets from sustainable food systems in the EAT-Lancet Commission report [ 1 ]. Microalgae and macroalgae received much interest as biofuel feedstocks in response to the uprising energy crisis, climate change, and the depletion of natural sources. Concomitantly, high-value co-products, including carotenoids, have been produced through the extraction of a fraction of algae to improve the economics of a microalgae biorefinery. This is the process of obtaining biofuels, energy, and diverse high-value products through biomass transformation and process equipment [ 4 , 5 ]. The advantages of using algae biomass as feedstock to produce biofuels and co-products compared to higher plants are several: higher growth and productivity due to their all-year production capability; growth under stress conditions and lower nutritional and water requirements; no requirements of herbicides or pesticides; contribution to CO 2 sequestration and wastewater bioremediation; easier modulation of the biosynthesis of valuable co-products by modifying growth conditions [ 5 – 7 ]. It is no wonder that the importance of algae (either as whole cells or for the extraction of high-value components) for innovation in agro-food was highlighted in recent reports from the European Commission and the Food and Agriculture Organization (FAO) [ 8 , 9 ]. More than 20 genera of cyanobacteria and microalgae are currently used for food or feed applications. This number is expected to increase considerably over the next few years as research on such microalgal applications grows incessantly [ 8 ]. Regarding macroalgae, some species are exploited and used for human consumption in Europe, particularly in France, Spain, and Ireland, where several companies harvest edible seaweed. These new types of industries have recently been developed following the increasing demand from European consumers [ 10 ]. Recent reviews highlight the incorporation of algae (either whole cells or extracts) into a wide variety of foods (emulsions, vegetarian gels, dairy products, cookies, bread, and pasta) with potential health-related and even technofunctional benefits [6,11]. Being microbes, bacteria share biotechnological and sustainability advantages with microalgae. Indeed, they are similarly important for alleviating the greenhouse effect, as they can also assimilate CO 2 [ 12 ]. Bacteria have long been used for food production in diverse types of fermentation to obtain food components (including carotenoids, as discussed later) [ 13 , 14 ] and in the last decades, they have attracted great interest in the context Mar. Drugs 2023,21, 340 3 of 45 of the development of probiotics and the role of the microbiome on human health [ 15 – 17 ]. Currently, there is a growing trend to look for innovative applications in aquaculture [18]. Marine archaea offer many opportunities for innovation as they produce unique metabolites as a result of their adaptation to extreme environments. Examples are the C45 carotenoid dihydroisopentenyldehydrorhodopin, the C50 carotenoid bacterioruberin, or the glycoside esters thermozeaxanthin and salinixanthin (Figure 1), whose structures (and therefore their physico-chemical properties) differ greatly relative to typical dietary carotenoids [19]. Mar. Drugs 2023, 21, x 3 of 49 diverse types of fermentation to obtain food components (including carotenoids, as discussed later) [13,14] and in the last decades, they have attracted great interest in the context of the development of probiotics and the role of the microbiome on human health [15–17]. Currently, there is a growing trend to look for innovative applications in aquaculture [18]. Marine archaea offer many opportunities for innovation as they produce unique metabolites as a result of their adaptation to extreme environments. Examples are the C45 carotenoid dihydroisopentenyldehydrorhodopin, the C50 carotenoid bacterioruberin, or the glycoside esters thermozeaxanthin and salinixanthin (Figure 1), whose structures (and therefore their physico-chemical properties) differ greatly relative to typical dietary carotenoids [19]. Figure 1. Chemical structures of the main carotenoids present in marine organisms. Figure 1. Chemical structures of the main carotenoids present in marine organisms. Mar. Drugs 2023,21, 340 4 of 45 Yeasts are ubiquitous. Marine yeasts were first discovered in the Atlantic Ocean, and since then they have been isolated from seawater, marine deposits, seaweed, fish, marine mammals, and sea birds. They have also been found in benthic animals and seafloor sediment at depths up to 11,000 m. They are more abundant in nearshore habitats ( 10–1000 cells/L of water), whereas in low organic surface to deep-sea oceanic regions, they are found at densities <10 cells/L [ 20 ]. Some of the many marine yeast genera are Rhodotorula,Rhodosporidium,Candida,Cryptococcus,Torulopsis, and Saccharomyces [21]. The ability of algae, bacteria, and yeasts to use diverse products for growing (especially agriculture and aquaculture wastes or even flue gases in the case of algae) makes them very attractive in the context of the circular economy [22–31]. Carotenoids are unsaturated compounds that can be classified into two types: carotenes, which are hydrocarbons, and xanthophylls, which present one or more functional groups containing oxygen [ 32 ]. Beyond their long-known roles as natural colorants and (some of them) precursors of vitamin A, a large body of evidence indicates that they (or their derivatives, commonly known as apocarotenoids) may be involved in health-promoting biological actions, contributing to reducing the risk of non-communicable diseases as well as attracting renewed interest in cosmetic products [ 33 – 35 ]. According to the last update of the carotenoid database on 1 November 2020 (http://carotenoiddb.jp, accessed on 30 May 2023 ), 680 natural carotenoids from different eukaryotic organisms have been described, including animals, plants, algae, filamentous fungi, and yeasts. Various marine organisms can accumulate carotenoids and represent a route of entry for these compounds into the food chain (Figure 1, Tables 1–5). Thus, they can be considered a natural and renewable source for carotenoid production. However, to date, the industrial production of carotenoids has been based primarily on chemical synthesis [ 29 ]. Their extraction from marine organisms cannot compete economically with chemical synthesis, due to the high costs associated with their production and with downstream extraction and purification processes. However, it should be taken into account that obtaining the same isomeric mixtures as those found in natural sources could increase the cost of the production process. For example, in the case of astaxanthin, a mixture of stereoisomers is generally obtained by chemical synthesis, while astaxanthin from natural sources is mainly represented by a single isomer and has higher antioxidant activity and stability [ 36 ]. In any case, current trends in natural products have renewed interest in the use of microbial carotenoids as an alternative to those chemically produced [ 37 ]. This preference is mainly based on safety concerns about the hazardous waste and intermediate products that could be produced in chemical synthesis. The obtention of carotenoids from marine organism cultures is considered a sustainable process by which carotenoids are produced by milder and more environmentally friendly procedures. The extraction of carotenoids from marine organisms also has advantages over the extraction from plants. They have higher growth rates than vegetables, and their production is for most of these organisms not as affected by seasons or geographic variabilities. Most of them are reasonably easy to cultivate and can be produced in large quantities within a limited space. Moreover, some marine organisms, as a source of carotenoids, can be cultivated on agro-industrial waste or by-products in processes supporting the concept of a circular economy. This review assesses the potential use of marine organisms as a sustainable source of carotenoids, including well-known and novel carotenoids, as a fundamental part of the European Green Deal and its Recovery Plan. In addition, the different challenges that need to be addressed to obtain new carotenoids on an industrial scale are discussed. The possible antioxidant and anti-inflammatory actions of marine carotenoids are also discussed. 2. Main Marine Organisms Containing Carotenoids 2.1. Archaea 2.1.1. Ecological Importance Archaea constitute a domain of prokaryotic organisms with riveting characteristics and high ecological importance. This domain was introduced by Carl Woese in 1990 [ 38 ] Mar. Drugs 2023,21, 340 5 of 45 and originally included only extremophilic microorganisms, concretely methanogens, thermophiles, and halophiles. However, members of the domain Archaea are now known to be widespread in non-extreme habitats, including aquatic and terrestrial environments. In marine ecosystems, planktonic archaea are classified into four distinct groups designated Marine Group (MG) from I to IV, with a growing number of phylum, class, order, and family designations [ 39 ]. Thaumarchaeota (MGI) have an important role in marine biogeochemistry as they perform the oxidation of ammonia to nitrite, the first step of nitrification. In addition, thaumarchaea are capable of synthesizing cobalamin, the precursor of vitamin B12, which is required by other planktonic members that are not capable of producing it [ 40 ]. The MGII archaea are a diverse group of uncultivated heterotrophic and photoheterotrophic microbes with a potential role in the ocean carbon cycle because they are able to break high-molecular-weight compounds. Finally, the MGIII and MGIV archaea are usually found in the deep sea, and so far, little information about them is available [41]. Archaeal communities are also present in freshwater environments, where their main biogeochemical role is related to methanogenesis and ammonium metabolism [ 42 ]. Methanogenic archaea, including Methanobacteriales,Methanosarcinales, and Methanomicrobiales, are usually found in anaerobic water and sediments, while ammonia-oxidizing archaea, such as Thaumarchaeota and Nitrosotalea-like, are often present in oligotrophic surface freshwaters. In addition, some potential genome-based roles, including fermentative metabolism or symbiosis, are being studied in Woesearchaeota, the main group found in boreal lakes [43]. The most studied archaea are extremophiles distributed in aquatic environments under severe conditions. Halophiles inhabit salt lakes, soda lakes, and salterns, while hyperthermophiles live in hot springs and shallow or deep hydrothermal systems. Among them, methanogens are represented in halophiles, thermophiles, psychrophiles, acidophiles, and alkaliphiles [ 44 ]. Many hyperthermophilic archaea are sulfur-chemolithoautotrophs (e.g., Sulfolobus), and complete denitrification is usual in some families of haloarchaea such as Haloarculaceae and Haloferacaceae [45]. 2.1.2. Sustainability Pros and Cons Archaea are relevant microorganisms for the sustainable production of carotenoids. Currently, bacterioruberin is one of the few products commercialized from archaea [ 46 ], and its bioprocess production ensures a low environmental footprint by re-using raw materials in the fermentation cycles [ 47 ]. From a biotechnological point of view, the extreme conditions in which haloarchaea proliferate reduce the risk of culture contamination by other microorganisms and allow their cultivation under non-sterile conditions with reduced cultivation costs. Additionally, given that haloarchaea undergo cell lysis at low concentrations of salt, carotenoids can be easily recovered under mild conditions with lower costs than from other microorganisms that require harsh cell disruption methods. Finally, haloarchaea show an advantage over other microorganisms as a source of bioactive products that can be used in personal care products, drugs, or foods, as they are non-pathogenic for animals and humans [19]. 2.1.3. Main Species (and Compounds) in the Context of Agro-Food and Health Archaea are a valuable source of unique carotenoids with promising applications in cosmetics, food, pharmaceuticals, and nutraceuticals. To date, 25 different carotenoids and apocarotenoids have been described in Archaea, 13 of which are only present in this domain. Most archaeal carotenoids are synthesized by haloarchaea, with bacterioruberin being the most abundant [19] (Table 1, Figure 1). Mar. Drugs 2023,21, 340 6 of 45 Table 1. Examples of carotenoid content in marine archaea. Species Carotenoids Collection Sites Experimental Conditions Quantification/ Identification Methodologies Contents References Halobacterium halobium Total carotenoids (mainly bacterioruberin) Saltern brine, Sfax, Tunisia Liquid culture (10 g/L yeast extract, 7.5 g/L casamino acids, 250 g/L NaCl, 20 g/L MgSO4.7H2O, 2 g/L KCl, and 3 g/L trisodium citrate), 37 ◦C, 240 rpm, 7 days Spectrophotometry 5.66–7.63 mg/L, FW [48] Haloarcula japonica Total carotenoids (mainly bacterioruberin) Saltern soil Liquid culture, 37 ◦C, 10 days HPLC-MS 335 µg/g, DW. Bacterioruberin was up to 68.1% of the total carotenoids (mol%) [49] Halorubrum sp. Total carotenoids (mainly bacterioruberin) Saltern brine Liquid culture, 37 ◦C Spectrophotometry 25 mg/L, FW [50] Haloterrigena turkmenica Total carotenoids (mainly bacterioruberin) Salt soil crust Liquid culture, 37 ◦C, 180 rpm Spectrophotometry 74.5 µg/g, DW [51] Halorubrum sp. Total carotenoids (mainly bacterioruberin) Seven distinct saline habitats, Algeria Liquid culture, 37 ◦C Spectrophotometry 3.68 mg/L, FW [52] Haloarcula sp. Total carotenoids (mainly bacterioruberin) Tebenquiche Lake of the Atacama Saltern, Chile Liquid culture (5 g/L proteose-peptone, 10 g/L yeast extract, 1 g/L glucose, with 25% (w/v) total salts), 40 ◦C, 120 rpm, 10 days HPLC-MS 488.88–871.53 mg/g, DW [53] Haloferax mediterranei strain R-4 (ATCC33500) Total carotenoids (mainly bacterioruberin) Salt pond Liquid culture, 36.5 ◦C Spectrophotometry 92.2 µg/mL, FW [54] DW, dry weight; FW, fresh weight; HPLC, high-performance liquid chromatography; MS, mass spectrometry. Bacterioruberin is an unusual C50 carotenoid whose function is related to UV protection and membrane stability. The complete biosynthetic pathway of bacterioruberin from lycopene was elucidated in Haloacula japonica by Yang et al. [ 55 ], and intermediates such as monoanhydrobacterioruberin and bisanhydrobacterioruberin are usually present in different proportions in haloarchaeal extracts [ 49 – 51 ]. Bacterioruberin possesses 13 carbon double bonds and 4 hydroxyl groups at the terminal ends that confer it a high antioxidant potential, even greater than the reference antioxidant β -carotene under certain conditions. Several studies have demonstrated the antioxidant activity of bacterioruberinrich extracts [ 51 , 56 ], and some others have also evaluated the different bioactivities of haloarchaeal pigments. In this context, carotenoids extracted from Halobacterium halobium, Halogeometricum limi, and Haloplanus vescus have shown antiproliferative activities in the human cancer cell line HepG2 (hepatocarcinoma) [ 48 , 57 ]. In addition, carotenoids from Natrialba have shown antiviral activity against viral hepatitis (HCV and HBV) and potent antiproliferative and apoptotic activities against colon, breast, liver, and cervical cancer cells, as well as being safer than the standard anticancer drug 5-FU for normal human cells under certain conditions [ 58 ]. Furthermore, bacterioruberin-rich extracts from various species of haloarchaea, including the genera Haloarcula,Halobacterium,Halorubrum, and Haloferax, have displayed diverse bioactive properties in vitro , such as antibacterial, neuroprotective, anti-inflammatory, antiglycemic, and antilipidemic activities [ 52 – 54 , 59 ]. Finally, bacterioruberin-enriched extracts from a genetically modified Haloferax volcanii strain were shown to improve the quality of cryopreserved ram sperm cells, suggesting their potential application to increase insemination yields [60]. 2.1.4. Production Approaches and Production Data in Different Continents The extreme growth conditions required for extremophilic archaea that synthesize carotenoids have made the development of laboratory strategies for their culture and the production of biocompounds difficult. Studies on the genus Haloferax revealed that the bacterioruberin synthesis can be enhanced by adding carbon sources (glucose or starch) to the medium [ 54 ] and also by using a culture medium with lower salt (less than 15% w/v ) [ 61 ]. Mar. Drugs 2023,21, 340 7 of 45 Thus, bacterioruberin production from Haloferax has been proposed in a two-step process, using a first step with a high salt concentration (20%, w/v) for biomass production and a second step with lower salt concentrations for the accumulation of carotenoids [ 62 ]. However, other species of the genera Halorubrum and Natriabla required a salt concentration of 20–25% w/v for the maximum production of carotenoids [ 50 , 52 , 58 ], and therefore the process could be performed in a single step. Moreover, many other physicochemical parameters have to be taken into account to optimize the carotenoids produced by haloarchaea. In this regard, diverse species of haloarchaea cultured with a nearly neutral pH, a temperature of 30 to 40 ◦ C, high light exposure, and high oxygen availability have experimented with an increase in growth rate and carotenoid productivity. It has also been demonstrated that the amount of MgSO 4 , KCl, and trace elements may influence the production of bacterioruberin [63]. 2.1.5. Current and Prospective Applications Archaeal carotenoids offer a wide range of potential applications in foods, health promotion, and cosmetics, for instance, as nutraceuticals, colorants, or food preservatives. Given the antioxidant and photoprotective properties of bacterioruberin, the possibility of using it as a natural additive for foods and personal care products is quite realistic. The haloarchaeal carotenoid bacterioruberin is commercially produced as “Halorubin” by the company Halotek (Leipzig, Germany) [46]. Despite the bioactive properties described for bacterioruberin, its chemical lability, poor water solubility, and low bioavailability limit many of its potential health-promoting uses. Therefore, the use of nanovesicles (archaeosomes or nanoarchaeosomes) and nanoparticles has been proposed to improve the stability and biological activities of bacterioruberin [ 64 ]. In the same way, the encapsulation of archaeal carotenoids into two oil-in- water dispersions has been reported as a useful system for the delivery and protection of carotenoids for food applications [65]. 2.1.6. Research Needs Carotenoids from Archaea have shown considerable potential for health-promoting effects. Nonetheless, the small number of studies on natural products from Archaea compared to Bacteria and Eukarya suggests that this field of research is still relatively underexplored. Considering the extreme environments in which extremophilic archaea reside, it can be assumed that they contain many new molecules of biotechnological interest whose identification is still pending. The biotechnological applications of bacterioruberin contribute to the increasing demand for this carotenoid. Nowadays, commercial bacterioruberin extracted from lab-scale cultivation of H. salinarum can be purchased at a price point of 553 EUR/mg (CAS: 53026- 44-1) [ 46 ]. Thus, more studies on the biosynthetic pathways of carotenoids and cultivation methods are needed to obtain the maximum yield of growth and pigment production, as well as the implementation of large-scale production systems with reduced costs. Genetic engineering offers an interesting way to enhance the biosynthesis of highvalue-added products. Increasing bacterioruberin biosynthesis through the genetic manipulation of haloarchaea is now possible due to recent advances in the knowledge of carotenogenesis and the sequencing of the genomes of haloarchaea belonging to different genera. However, this approach has only been tested in some species [ 60 ]. Genetic manipulation of the carotenoid biosynthetic pathway by overexpression, edition, or knockout of specific genes of the pathway should be explored in more depth to overcome the low carotenoid concentration observed in many species. Finally, it is worth mentioning that most studies testing the bioactive properties of bacterioruberin have been performed in vitro , so it is necessary to study whether these results can be extrapolated in vivo . Moreover, the toxicity of bacterioruberin should be thoroughly analyzed in animal and human models, and the development of efficient and stable transport systems must be achieved. Mar. Drugs 2023,21, 340 8 of 45 2.2. Bacteria 2.2.1. Ecological Importance The bacterial communities inhabiting marine environments vary from coastal to offshore areas, as in the water column, due to differences in physico-chemical and biological properties to which they are exposed. Depending on their energy and carbon sources, bacteria can be phototropic or non-phototropic. Carotenoids are produced in all phototrophic bacteria (Table 2), and their biological function is to support photosynthesis as accessory pigments, protect the photosynthetic machinery from excess light that induces photodamage, and quench reactive oxygen species (ROS) [ 66 – 68 ]. There are four main types of bacterial phototrophs in marine microbial communities: (i) Cyanobacteria, which are mainly represented in marine environments with the genera Synechococcus and Prochlorococcus as one of the main contributors to planktonic systems [ 69 ]; (ii) anaerobic anoxygenic phototrophic bacteria such as purple sulfur bacteria, purple non-sulfur bacteria, and green sulfur bacteria, which are generally restricted to oxygen-free habitats, such as sediments and mats [ 67 , 70 – 72 ]; (iii) aerobic anoxygenic phototrophic bacteria, which includes members belonging to either α -, β -, or γ -proteobacteria, and inhabit the upper layer of the ocean, representing up to 15% of the total bacterial community [ 72 ]; and (iv) proteorhodopsin-containing bacteria. It is estimated that as much as half of the surface ocean bacteria could be part of them, but functional evidence is still scarce [69,72–74]. On the other hand, the widespread presence of carotenoids in non-phototrophic bacteria indicates their importance for their viability (Table 2). α -proteobacteria and γ - proteobacteria, together with members of the Bacteroidetes phylum, are the most abundant groups of heterotrophic bacteria in the sea [ 73 ]. Due to the absence of photosynthetic apparatus, the role of carotenoids in organoheterotrophs lies mainly in protection from photooxidative damage and in the regulation of membrane fluidity [ 75 , 76 ]. The production of carotenoids is proposed to be an adaptive response to certain environmental and stressor conditions, such as freeze–thaw cycles and solar radiation [77]. 2.2.2. Sustainability Pros and Cons Marine bacteria could be a promising alternative for the development of sustainable processes to produce carotenoids. As with other microorganisms, the culture systems used to grow bacteria are independent of seasonal restrictions, have low utilization of space, and do not require the use of arable land. Even when more research is needed to improve bacteria as a carotenoid source, novel strategies aligned with the development of sustainable processes could be a niche for the use of marine bacteria diversity. Second- and third-generation feedstocks require the maximum utilization of resources with the generation of multiple products, as in a biorefinery, to favor the global economic balance of the process. Microorganisms are known for their ability to use a wide variety of substrates. Bacteria present certain advantages, such as a high growth rate, metabolic diversity, and easier genetic manipulation [ 78 ]. Even though up-to-date scare reports include marine bacteria, promising research is being carried out. Kristjansdottir et al. proposed that Rhodothermus marinus has potential for its application in biorefineries since it is a thermophile that produces various biomass-degrading enzymes and, among other interesting products, produces carotenoids [ 79 ]. Park et al. isolated Vibrio sp. SP1 from a starfish for its ability to grow from alginate, and after introducing genes encoding enzymes to produce lycopene and β -carotene, it could grow on brown macroalgae Sargassum and produce lycopene [ 80 ]. 2.2.3. Main Species (and Compounds) in the Context of Agro-Food and Health Overall, the carotenoids most demanded for their importance in agro-food and health that are produced by bacteria are β -carotene, β -cryptoxanthin, zeaxanthin, astaxanthin, and canthaxanthin (Figure 1). In Table 2, a list of the species and main carotenoids produced is presented. Mar. Drugs 2023,21, 340 9 of 45 Table 2. Examples of carotenoid content in marine bacteria and cyanobacteria. Organisms Species Carotenoids Collection Sites Experimental Conditions Quantification/Identification Methodologies Contents References Bacteria Rubritalea squalenifaciens (DSM 18772T) Diapolycopenedioc acid xylosylesters Miura Peninsula, Kanagawa, Japan Liquid culture (1.0% starch, 0.4% yeast extract, and 0.2% peptone in seawater), 30 ◦C, 120 rpm, 2 days Carotenoids purification by chromatography and identification of the structures by HRESI-MS and spectroscopic analyses 2.2–10.2 mg purified from cells in a 42 L culture [81] Planococcus maritimus strain iso-3 Methyl 5-glucosyl-5,6-dihydro- apo-4,40-lycopenoate Clyde estuary, UK Marine broth 2216), 30 ◦C, 120 rpm, 1 day Carotenoids purification by chromatography and identification of the structures by HRESI-MS and spectroscopic analyses 2.5 mg purified from cells in an 18 L culture [81] 04OKA-13-27 (MBIC08261) (3R)-saproxanthin Coast of Okinawa Prefecture, Japan Marine Broth 2216, 30 ◦C, 100 rpm, 1 day Carotenoids purification by chromatography and identification of the structures by MS, 1H-NMR, and CD analyses 0.3 mg purified from cells in a 2 L culture [81] YM6-073 (MBIC06409) (3R,20S)-myxol Coast of Okinawa Prefecture, Japan Marine broth, 30 ◦C, 100 rpm, 1 day Carotenoids purification by chromatography and identification of the structures by MS, 1H-NMR, and CD analyses 0.5 mg purified from cells in a 2 L culture [81] Erythrobacter rubeus sp. nov. Keto-spirilloxanthin Hamdeok Beach, Jeju Island, Republic of Korea Marine agar 2216, 25 ◦C - - [82] Flavobacterium sp. P8 Zeaxanthin King George Island, Antarctica 2 L medium (7 g/L peptone, 7 g/L yeast extract, and 15 g/L NaCl) in a 5 L-bioreactor, 20 ◦C, pH 7, 1 vvm airflow, 20% pO2, 72 h HPLC 2.15 ±0.15 mg/L, DW [83] Brevundimonas scallop Astaxanthin, 2,20-dihydroxy-astaxanthin, and 2-hydroxy-astaxanthin Nanao Island of Guangdong Province, China 100 mL LB medium, 25 ◦C, 150 rpm, 3 days Spectrophotometry 104.29 ±4.98 µg/g astaxanthin, 1068.46 ±52.42 µg/g 2,20-dihydroxy-astaxanthin, and 130.36 ±6.11 µg/g 2-hydroxy-astaxanthin, DW [84] Erythrobacter citreus LAMA 915 Adonixanthin, caloxanthin, canthaxanthin, erythroxanthin sulfate, nostoxanthin, and zeaxanthin Atlantic Ocean (30◦S, 36◦W) Soluble fish hydrolysate 0.5% Spectrophotometry 1.5 mg/L total carotenoids, FW [85] Erythrobacter flavus KJ5 Caloxanthin, caloxanthin sulfate, caloxanthin sulfate isomer, β-carotene, β-carotene cis isomer, β-cryptoxanthin, nostoxanthin sulfate, nostoxanthin isomer, zeaxanthin, zeaxanthin isomer, zeaxanthin sulfate, and zeaxanthin sulfate cis isomer Hard coral Acropora nasuta, Karimunjawa Islands, Indonesia Shioi broth, 28 ◦C, under dark conditions, 48 h - - [86] Planococcus sp. Eg-Natrun Astaxanthin and β-carotene Umm Risha Lake, Wadi El-Natrun, south of Al-Buhayrah province, Egypt E1 rich marine medium (C/N~3.95), 37 ◦C, 150 rpm, 3 days Spectrophotometry 1024 ±53 µg/g, DW [87] Mar. Drugs 2023,21, 340 16 of 45 In animal studies, the administration of fucoxanthin-rich algae extracts increased antioxidative enzymes and decreased ROS in two mouse models of diabetes and colitis, respectively, and in cisplatin-induced hamsters [161–163]. Fucoxanthin treatment ameliorated histological damage and inflammatory levels of PGE 2 in the colon of mice after induced colitis and downregulated the inflammation-related enzyme cyclooxygenase-2 (COX-2) and the transcription factor nuclear factor kappa B (NF- kB) [ 164 ]. Oral and percutaneous administration of fucoxanthin reduced ear swelling in mice and limited the induction and activity of COX-2, phospholipase A2 (PLA 2 ), and hyaluronidase (HA) [ 165 ]. Fucoxanthin administration also reduced inflammatory cytokines (IL-1 β , IL-6, and TNF- α ) in an obesity mouse model [ 166 ] and by lipopolysaccharide (LPS)-induction as well as depression-associated behavior in the LPS-stimulated mice [ 167 ]. These effects have also been reviewed in light of their potential protective role in several connected pathologies, such as liver and skin damage or cardiovascular and metabolic disease [ 159 ]. Miyashita and Hosokawa have also reviewed the potential uses of fucoxanthin in the management of obesity and diabetes, including a downregulation of inflammatory adipokines [ 158 , 168 ] and reduced body weight and abdominal fat in overweight Japanese subjects [169]. Yang et al. summarize the studies in cell models and mice, which show the potential of fucoxanthin for therapeutic efficacy in neurodegenerative disorders [ 164 ]. Of special interest, fucoxanthin had a neuroprotective effect against cerebral ischemic/reperfusion injury through activation of the antioxidative response pathway involving nuclear factor erythroid 2-like 2 (NFE2L2/Nrf2) and heme oxygenase 1 (HMOX-1) [ 170 ]. Fucoxanthin also reduced neuroinflammation in a mouse model of Parkinson’s disease [171]. Here, we only mention some in vivo studies illustrating the anti-inflammatory and antioxidative effects of fucoxanthin, as we understand these to be most relevant for its final application. An extensive body of work in vitro has been published to evaluate this and other seaweed-derived carotenoids, with some described in Section 5[ 139 , 172 , 173 ]. There are a few additional studies with whole seaweed and mixed extracts, which also provide valuable information on the effects of dietary intake of seaweed [ 174 , 175 ]. During uptake, fucoxanthin is metabolized to fucoxanthinol and amarouciaxanthin A, which were found in the adipose tissue, kidney, heart, lung, and spleen of mice [ 176 , 177 ]. In humans, fucoxanthin intake led to a peak of fucoxanthinol in plasma of 44.2 ± 14.9 nM after 4 h, gradually decreasing within 24 h [ 178 , 179 ]. Therefore, the bioavailability of fucoxanthin is lower and more transient than that of other dietary carotenoids such as β -carotene and lutein [ 178 , 180 ]. This underlines the importance of in vivo studies that take into account the limiting steps of metabolism and uptake. 2.3.6. Research Needs The anti-inflammatory and antioxidant effects are among the three most commonly published pharmacological properties of fucoxanthin in recent years. However, most studies are based on cell and mouse models, with only a minority focusing on clinical interventions [ 181 ]. Thus, more clinical studies are needed to confirm and fully exploit the described anti-inflammatory and antioxidant effects of this carotenoid. Compared to fucoxanthin, there is almost no literature on the potential health effects of other carotenoids derived from green or red seaweeds, including their metabolized or degradation products, which could also have beneficial effects. For example, a carotenoid degradation product, 3-hydroxy-4,7-megastigmadien-9-one, extracted from the green seaweed Ulva pertusa, was shown to limit the inflammatory response to microbial products in mouse innate immune cells [173]. In light of increasing interest in carotenoids from alternative sources, the production of seaweeds with a higher content of carotenoids could be one approach. Aquaculture technology would need to be optimized with a better understanding of how environmental parameters affect seaweed physiology and therefore their carotenoids content. Mar. Drugs 2023,21, 340 17 of 45 Finally, the economic and environmental sustainability as well as the safety of the whole value chain from seaweed to the carotenoid final product still need to be validated and documented according to the regulatory framework to ensure sustainable and safe use of this ingredient. 2.4. Microalgae 2.4.1. Ecological Importance Microalgae are a heterogeneous group of photosynthetic microorganisms of high ecological importance. They are responsible for approximately half of the global CO 2 fixation, which makes them “cell factories” capable of taking up the main greenhouse gas in the atmosphere [ 182 ]. Their cultivation does not require arable land, and microalgal biomass can be produced (between 40 and 100 t/ha year of dry weight) 10–50 times faster than higher plants [ 183 ]. Additionally, most microalgae show high robustness when exposed to different types of abiotic stress, such as extreme temperatures, nutrient depletion, high salinity, or the presence of pollutants. These characteristics make it possible for microalgae to inhabit almost all ecosystems on Earth, demonstrating an enormous range of ecological adaptation capacities [184]. In addition, microalgae are at the base of the marine food chain, being the most abundant primary producers in aquatic ecosystems [ 185 ]. They are widely used as a nutritional supplement in aquaculture due to their high nutritional qualities and their potential to produce a wide range of high-value compounds, such as polyunsaturated fatty acids (PUFAs), sterols, vitamins, polyphenols, or carotenoids [ 186 ]. Some of these compounds are also synthesized for the pharmaceutical or cosmetic industry and marked as food supplements. 2.4.2. Sustainability Pros and Cons There is an increasing interest in addressing the integral utilization of all microalgal components, following a biorefinery approach, and in integrating their production with the utilization of residual waste waters or the capture of CO 2 through a circular economy perspective to reduce the costs of microalgal biomass culturing and harvesting [ 187 , 188 ]. These studies are mainly focused on the removal of pollutants and the production of low-value compounds, such as biofuel, bioethanol, or animal feed. An example of this is the cultivation of Chlorella vulgaris and Chlorella sorokiniana in wastewater from milk processing, dairy wastewater, or wastewater from the wine industry that obtains large amounts of lipids, mainly palmitic, oleic, and linoleic acids [ 189 – 191 ]. Arthrospira platensis (Spirulina) was also grown in an anaerobic digestion effluent containing Cu 2+ and Zn 2+ , and the obtained biomass was used as feed for animals [ 192 ]. Moreover, there are some studies that describe the culture of the microalgae Dunaliella sp. and Haematococcus pluvialis in digested poultry litter or treated primary wastewater for the production of β -carotene and astaxanthin, respectively. These microalgal species are the first natural source of these highly demanded carotenoids, and their culture in wastewater can improve their feasibility [193,194]. 2.4.3. Main Species (and Compounds) in the Context of Agro-Food and Health Carotenoids are among the high-value compounds produced from microalgae, with several applications and high commercial interest. Some carotenoids, such as β -carotene, astaxanthin, lutein, or fucoxanthin, obtained from different microalgae are widely commercialized for cosmetic and pharmaceutical applications [ 186 ]. Although many species of microalgae are able to produce these compounds, only a few of them synthesize enough amounts of carotenoids to make industrial processes economically feasible (Table 4). Dunaliella salina is one of the main producers of β -carotene and is considered the best commercial source of this naturally produced compound. This green microalga can accumulate up to 13% of its total biomass in β -carotene, making it a much better producer than other species such as Chromochloris zofingiensis or Arthrospira platensis (Spirulina), Mar. Drugs 2023,21, 340 18 of 45 which yield up to 1–2% of their dry biomass [ 145 ]. The β -carotene synthesized by Dunaliella salina has exhibited health-promoting actions in experiments of different nature, such as protective effects against atherosclerosis, protection against UV-induced erythema, and oxidative damage in humans [195]. Another microalga able to produce high amounts of carotenoids in industrial processes is Haematococcus pluvialis. This microalga belongs, as Dunaliella salina, to the chlorophyte phylum and is the main producer of astaxanthin, a keto-carotenoid with high antioxidant capacity in vitro .Haematococcus pluvialis can produce up to 4–5% of its dry biomass as astaxanthin, obtaining higher yields than other strains capable of producing this compound, such as Chromochloris zofingiensis or Chlorococcum sp. [ 196 ]. Natural astaxanthin produced by Haematococcus pluvialis has previously been reported to have 10 times the in vitro antioxidative capacity of other carotenoids, such as zeaxanthin, lutein, canthaxanthin, or β -carotene, as well as anti-aging, anti-inflammatory, and anti-atherosclerotic properties [196]. Other green microalgae belonging to the Chlorella,Muriellopsis, or Scenedesmus genera are able to produce considerable amounts of lutein. However, its lutein content ( 0.5–1.2% of dry biomass) is much lower than the β -carotene or astaxanthin content in Dunaliella or Haematococcus, respectively [ 197 ]. This low productivity has restricted the industrial production of lutein from microalgae, whose main industrial source continues to be the petals of higher plants, such as marigolds [ 145 ]. However, microalgae can produce lutein in its free form, while in marigolds, lutein is mainly esterified with fatty acids [ 145 ]. One of the most promising species for the production of lutein is Chlorella vulgaris. This microalga can accumulate around 0.8% of the total dry weight in lutein and is one of the microalgae species allowed for human consumption [ 198 , 199 ]. However, further studies are necessary for the industrial production of Chlorella vulgaris as a producer of this health-promoting carotenoid [195]. Some marine microalgal species are also able to produce carotenoids. Diatoms, including Phaedoactylum tricornutum,Cylindroteca closterium,Nitzschia laevis, and Odontella aurita, among others, can produce outstanding amounts of fucoxanthin, up to 2.6% of dry biomass [200]. Table 4. Examples of carotenoid content in marine microalgae. Species Carotenoids Collection Sites Experimental Conditions Quantification/ Identification Methodologies Contents References Chlorella vulgaris 211/52 β-carotene, lutein Grüental campus of the Zurich University of Applied Sciences, Wädenswil, Switzerland Open thin-layer bioreactor HPLC 50 µg/g β-carotene, 90 µg/g lutein, DW [201] Dunaliella sp. FACHB-558 β-carotene Institute of Hydrobiology, Chinese Academy of Sciences, China Two-step cultivation in anaerobically digested poultry litter wastewater Spectrophotometry 7.26 mg/L, FW [193] Isochrysis zhangjiangensis Fucoxanthin Chinese Academy of Sciences, China Photo-autotrophically cultured at 23 ◦C in a bubble column photobioreactors, supplemented with f/2 medium (nutrient, trace metal, and vitamin solutions) HPLC 23 µg/g, DW [202] Haematococcus plivualis Astaxanthin Umeå University, Sweden First step: inoculum in Bold’s basal medium, OD750 of 0.1, 20 ◦C, cool white LED, 1 L/min of air, 7 days. Second step: grown in a multi-cultivator with cool white LED HPLC 19.1 mg/g, DW [203] Desmodesmus sp. Lutein and zeaxanthin Isolated from a wastewater treatment system, Kalundborg Kommune, Copenhagen, Denmark Industrial wastewater in Schott bottles, stirred, aerated (2% CO2), and with fluorescent lights (200 µmol photon/m2·s) HPLC 5.11 mg/g lutein and 0.28 mg/g zeaxanthin, DW [204] Mar. Drugs 2023,21, 340 19 of 45 Table 4. Cont. Species Carotenoids Collection Sites Experimental Conditions Quantification/ Identification Methodologies Contents References Nannochloropsis salina 40.85 β-carotene and violaxanthin Algae culture collection (SAG), University of Gottingen, Germany Industrial wastewater in Schott bottles, stirred, aerated (2% CO2), and with fluorescent lights (200 µmol photon/m2·s) HPLC 2.22 mg/g β-carotene and 1.68 mg/g violaxanthin, DW [204] Phaeodactylum tricornutum Diadinoxanthin and diatoxanthin - Industrial wastewater in Schott bottles, stirred, aerated (2% CO2), and with fluorescent lights (300 µmol photon/m2·s) HPLC 2.17 µg/g diadinoxanthin and 1.55 µg/g diatoxanthin, DW [204] Chlorella C.S1 β-carotene and lutein - Industrial wastewater in flat panel reactors with fluorescent lights (2000 µmol photon/m2·s) HPLC 1.4 mg/g β-carotene and 3.22 mg/g lutein, DW [204] Nannochloropsis limnetica 18.99 Neoxanthin and violaxanthin Algal culture collection (SAG), University of Gottingen, Germany Industrial wastewater in Schott bottles, stirred, aerated (2% CO2), and with fluorescent lights (200 µmol photon/m2·s) HPLC 0.42 mg/g neoxanthin and 1.22 mg/g violaxanthin, DW [204] Chlorococcum sp. Lutein Umeå University, Sweden Multi-cultivator with high light/cold stress in BG11 HPLC 15.5 mg/g, DW [205] Scenedesmus sp. Lutein Umeå University, Sweden Multi-cultivator with high light/cold stress in BG11 HPLC 10.7 mg/g, DW [205] DW, dry weight; HPLC, high-performance liquid chromatography. 2.4.4. Production Approaches and Production Data in Different Continents The industrial production of microalgae throughout the world is under development. The microalgal global market was estimated at between USD 3.4 and USD 3.9 billion in the period 2018–2020, and it is expected to increase to USD 4.6–5.1 billion by 2027 [ 206 , 207 ]. Although the values of global markets will reach USD 800 million for astaxanthin, USD 620 million for β -carotene, or USD 358 million for lutein by the end of 2026 [ 145 ], around 95% of the industrial production of carotenoids is performed by chemical synthesis due to its lower cost. For astaxanthin, while synthetic production is about USD 1000–2000 per kg; production from Haematococcus (around 1% of total production) has a cost between USD 1800 and 7000 per kg, depending on the location [ 208 ]. However, naturally produced astaxanthin is thought to have a stronger antioxidant capacity, being over 50 times stronger in singlet oxygen quenching and 20 times stronger in free radical elimination [ 209 ]. Natural astaxanthin is mainly obtained from Haematococcus pluvialis. This microalga can have two different cell morphologies: a green vegetative form and a red cyst form. Astaxanthin production in H. pluvialis is usually performed based on these two different morphologies, with a first stage focusing on developing their green form, which includes the production of biomass, followed by a second red stage where the astaxanthin is produced [ 145 , 195 ]. The production of natural astaxanthin from H. pluvialis is mainly concentrated in the USA, Europe, and Asia-Pacific countries, which are the main manufacturers of the companies Algatechnologies Ltd. in Israel, BluebioTech International GmbH in Germany, Algalif in Iceland, Algae Health Sciences and Cyanotech Corporation in the USA, AstaReal AB in Japan, BGG (Beijing Ginko Group) in China, and Parry’s Pharmaceuticals in India [208]. In the case of β -carotene, which is the other pigment produced by microalgae on an industrial scale, the cost of its production from Dunaliella salina is still higher than the chemically synthesized one. Nevertheless, synthetic β -carotene is composed only of the all-trans isomer, whereas natural β -carotene, as found in this microalga, is a mixture of the all-trans and 9-cis isomers, which may exhibit more beneficial properties [ 210 ]. The main strategies to increase the production of β -carotene in D. salina are to subject them to salt stress, high light, and N depletion. However, these stress conditions can reduce the production of biomass and, as a consequence, the yield of this carotenoid. Different solutions have been exploited to balance biomass and β -carotene production being the most common of the two-stage processes [ 211 , 212 ]. In these systems, there is a first stage focused on biomass production and a second one that improves the production of β -carotene. The natural production of β -carotene from D. salina is mainly found in Asia-Pacific countries, followed by Europe and Australia. The main manufacturers of this compound are Seagrass Mar. Drugs 2023,21, 340 20 of 45 Tech Private Limited in India, Hangzhou OuQi Food Co. and Shaanxi Rebecca Bio-Tech Co. in China, Algalimento SL and Monzón Biotech SL in Spain, IBR Ltd. in Israel, and Plankton Australia Pty Ltd. in Australia. The industrial production of fucoxanthin by the above-mentioned diatoms ( Section 2.4.3 ) could be a more economically feasible approach if combined with the co-production of other high-value compounds. Diatoms are also able to produce large amounts of PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Thus, the extraction of these PUFAs in combination with fucoxanthin can be an excellent approach that has to be further studied in marine microalgae [200,202]. 2.4.5. Current and Prospective Applications Microalgal carotenoids have a wide range of applications, including in the cosmetic, pharmaceutical, food, and feed industries. Additionally, the development of aquaculture processes including microalgae as a nutritional supplement for fish can stimulate the production of microalgae in high-scale processes, with the reduction in cultivation and harvesting costs being one of the main objectives in microalgae biotechnology. Although the cost of producing synthetic carotenoids is lower than that of natural ones, the continuous increase in demand for natural products in the global market points to carotenoids produced by microalgae as highly demanded products in the following years. This, along with the sustainable production of microalgae, can make them outstanding candidates for the development of “green” biofactories in the near future [213]. 2.4.6. Research Needs Although microalgae have a high potential for carotenoid production, further research is needed relating to the isolation, cultivation, extraction, or processing of algal biomass in order to reduce the cost of their industrial implementation. For example, isolating species from different extreme environments, such as high/low temperatures, high/low pH values, or high salinity, could be an interesting approach to finding strains able to produce higher amounts of carotenoids, such as lutein, fucoxanthin, or zeaxanthin. Additionally, genetic engineering is another strategy to improve the productivity of these compounds and achieve their economically feasible production. Reducing the cultivation costs, both by using alternative nutrient sources and improving the cultivation system, could also help boost productivity. This low productivity is one of the main problems in the industrial production of microalgae, which makes its competition with synthetic systems difficult. On the other hand, although there is much research about the use of emerging technologies (pressurized liquid extraction, pulsed electric fields, moderate electric fields, high-voltage electric discharges, high-pressure homogenization, microwave-assisted extraction, subcritical fluid extraction, and supercritical fluid extraction, among others) for the extraction of microalgal carotenoids [ 214 , 215 ], their industrial scaling-up remains a bottleneck. These concerns are the main challenge for future research in microalgal biotechnology to produce a more efficient and sustainable industry for the natural production of carotenoids from microalgae. 2.5. Yeast 2.5.1. Ecological Importance Yeasts are single-celled eukaryotic microorganisms that are members of the fungi kingdom. Since they are organotrophic and heterotrophic microorganisms, they require organic compounds as energy and carbon sources, and their growth is always associated with the presence of organic matter. Yeasts are globally distributed. They have been found in diverse habitats, including aquatic environments such as marine water, freshwater, glacier meltwater, groundwater, and the deep sea [ 216 , 217 ]. The concentration and diversity of yeasts in different aquatic habitats vary depending on the amount and type of organic matter and other environmental parameters. It has been observed that yeast populations decrease as the distance from the land increases. In coastal waters, thousands of yeast cells Mar. Drugs 2023,21, 340 21 of 45 can be found per liter, while deep-sea regions can contain lower levels of yeast (10 cells/L, or even fewer) [ 20 ]. Despite the low numbers, the diversity is not low. For example, when studying the diversity of culturable yeasts in five locations in coastal waters on King George Island (maritime Antarctica), Garmendia et al. [ 218 ] identified eleven genera. The analysis by massive sequencing of the region ITS2 showed great diversity since 31 yeast genera were found. Kutty and Philip [ 20 ] reviewed studies on the diversity of marine yeasts around the world and found that the most frequently reported genera were Candida,Cryptococcus, Debaryomyces, and Rhodotorula. Of them, ascomycetous genera are predominant in shallow waters, and basidiomycetous yeasts predominate in the deep sea. In both terrestrial and aquatic environments, yeasts play an important role as organic matter decomposers, facilitating the mineralization and recycling of nutrients. They also actively participate in nitrogen, sulfur, and phosphorous cycles [ 219 ]. Their ability to produce hydrolytic enzymes such as proteases, glycosidases, esterases, and lipases allows them to break down many organic polymers, producing lower molecular weight molecules that can serve as carbon or energy sources for themselves and for other organisms. In this way, their ecological role is very important in oligotrophic habitats. They also contribute to the bioremediation of contaminated areas due to their ability to decompose organic pollutants such as alkanes, phenolic compounds, or dyes [ 220 , 221 ]. Most yeasts undergo aerobic respiration, but some of them are also capable of obtaining energy by fermentation or anaerobic respiration using nitrate or nitrite as electron acceptors that produce NO or N 2 O, which are released into the atmosphere. In these cases, yeast would act as denitrifying microorganisms, causing the depletion of fixed nitrogen forms. Some aquatic yeasts have evolved molecular and metabolic adaptations to survive or even grow under harsh conditions, such as low or high temperatures, high solar radiation, low nutrient availability, high salt concentrations, or even low or high pH [ 222 ]. In particular, in polar regions or at high altitudes, yeasts living in clear waters without natural shade are exposed to high UV radiation, which can influence diversity and population size [ 223 ]. UV radiation produces detrimental effects on living cells, causing direct or indirect damage to DNA, proteins, and lipids and accumulating ROS. To cope with such effects, some yeasts synthesize UV protectants and antioxidants such as carotenoids and accumulate them intracellularly [ 224 ]. The antioxidant properties of carotenoids may help extend the survival times of yeast in their natural habitats. Differences in growth between strains differing in carotenoid content showed a protective effect of those compounds [ 224 ]. 2.5.2. Sustainability Pros and Cons Many aquatic yeasts can accumulate intracellularly high levels of carotenoids [ 225 ]; thus, they can be considered a natural and renewable source for carotenoid production. As with other marine organisms, yeast, as a source of carotenoids, can be cultivated on agro-industrial waste or by-products in processes supporting the concept of a circular economy. As an example, the production of provitamin A carotenoids by Rhodotorula glutinis using goat cheese whey as a substrate has been recently described [ 226 ]. In addition, lycopene can also be obtained from yeasts by applying cheap agro-industrial waste such as flour extracts, whey, rice, and glycerol, among others [ 227 ]. In another interesting study, it was observed that the use of waste glycerol from the biodiesel production process in the yeast culture significantly increased the productivity and concentration of torularhodin compared to pure glycerol [228]. 2.5.3. Main Species (and Compounds) in the Context of Agro-Food and Health A great diversity of carotenoids from different yeast species has been reported (Table 5). In most cases, various carotenoids can be obtained from a single yeast species. For example, as shown in the carotenoid database (http://carotenoiddb.jp, accessed on 30 May 2023), Rhodotorula aurantiaca, a psychrophilic red yeast isolated from Antarctica, can produce ten different carotenoids. Some yeast carotenoids can be found in other organisms. This is the case for β -carotene, which can be extracted from vegetables and fruits, or astaxanthin, Mar. Drugs 2023,21, 340 22 of 45 which is also present in some microalgae, bacteria, crustaceans, or fish such as salmon and trout [ 229 ]. However, other yeast carotenoids, such as torulene and torularhodin, are specific fungal metabolites. Yeasts that accumulate remarkable levels of carotenoids are basidiomycetous yeasts belonging to the Cystofilobasidiales and Sporidiobolales orders. Among Cystofilobasidiales, only one species of Phaffia rodozyme (teleomorph X. dendrorhous) has been reported to be carotenogenic [ 230 ]. This species, which has been isolated from some tree exudates, leaves, fungal stromata, and freshwater [231], accumulates astaxanthin, a carotenoid with many biotechnological applications [ 230 ]. Among Sporidiobolales, yeasts that accumulate the highest levels of carotenoids belong to the genera Rhodotorula and Sporobolomyces and to their teleomorphs, Rhodosporidium and Sporidiobolus [ 37 ]. The carotenoid profile produced by these yeasts is mainly represented by γ -carotene, β -carotene, torulene, and torularhodin [ 232 ], but other compounds have also been described. Carotenogenic yeasts from Sporidiobolales have been isolated from diverse aquatic habitats. Ueno et al. [ 225 ] isolated 40 yeast strains from different aquatic environments in Japan. These yeasts accumulated carotenoids in amounts greater than 200 µ g/g of their dry cell mass. They were identified as Rhodotorula spp. and Rhodosporidium spp. and produced different amounts of intracellular β -carotene, torularhodin, γ -carotene, torulene, and β -zeacarotene, the first three compounds being the most abundant. Carotenogenic isolates from different species within the Rhodotorula genus have been isolated from the coastal waters of King George Island (maritime Antarctica) [ 218 ] and from oligotrophic lakes in Patagonia, Argentina [ 233 ]. Pigmented Rhodotorula spp. strains that accumulated intracellular carotenoids were also isolated from seawater near Chile [ 234 ]. One of the strains accumulated carotenoids, representing 19% of its dry weight, when cultured in glycerol as the only carbon source. The carotenoid profile was not very common and included β -carotene, adonirrubin, 3-hydroxyechinenone , and canthaxanthin. Strains from Sporidiobolales identified as R. mucilaginosa,R. toruloides,R. diobovata, and S. roseus recognized as species that accumulate significant amounts of carotenoids [ 235 ] were also found in oligotrophic hypersaline coastal waters of the Arabian Gulf [236]. Carotenoids are also produced in fewer amounts by basidiomycetous yeasts of the Sporidiobolales order. Strains belonging to different species from the genera Bullera,Cystobasidium,Cystofilobasidium, and Dioszegia, many of which have been isolated from aquatic environments, produce intracellular carotenoids [ 237 ]. Most of the compounds found in these yeasts are carotenes. However, two uncommon xanthophylls, 16-hydroxytorulene and torularhodinaldehyde, which were previously known only from chemical synthesis, have been found in certain Cystofilobasidium species [ 238 ]. Moreover, some isolates belonging to the genus Dioszegia produce almost exclusively plectaniaxanthin, a xanthophyll that is a dihydroxylated derivative of torulene [ 239 ]. These carotenoids represent a minor fraction of the carotenoids produced by yeast species but are illustrative of their chemical diversity. Undoubtedly, yeasts from aquatic environments throughout the world are a source of common and rare carotenoids that should be further explored. Many biological properties have been demonstrated for the main yeast carotenoids, which include carotenes such as β -carotene, γ -carotene, and torulene, and xanthophylls, including astaxanthin, canthaxanthin, and torularhodin [ 240 ]. Some of them, such as γ -carotene, β -carotene, torulene, and torularhodin, are vitamin A precursors [ 241 ]. Antibacterial and anti-fungal activity has been demonstrated for torularhodin, a specific fungal carotenoid [ 242 , 243 ]. Moreover, due to its important antimicrobial activity, it was successfully used to protect implanted medical devices against microbial contamination [ 244 , 245 ]. In the case of torulene and torularhodin, Du et al. [ 246 ] postulated that their action in the inhibition of prostate cancer in nude mice was associated with the apoptosis of tumor cells. Mar. Drugs 2023,21, 340 23 of 45 Table 5. Examples of carotenoid content in marine yeast. Species Carotenoids Collection Sites Experimental Conditions Quantification/ Identification Methodologies Contents References Sporidiobolus salmonicolor β-carotene, 2,3 dihydroxy-γ- carotene, 4-ketotorulene, and torulene Union Glacier, Antarctic 30 mL YM broth in 300-mL baffled flasks, 150 rpm, 20 ◦C, 5 days HPLC 2,3-dihydroxy-γ-carotene was the main carotenoid [247] Sporidiobolus metaroseus β-carotene, β-cryptoxanthin, 4-ketotorulene, and spirilloxanthin Union Glacier, Antarctic 30 mL YM broth in 300-mL baffled flasks, 150 rpm, 20 ◦C, 5 days HPLC β-carotene and 4-ketotorulene were the main carotenoids [247] Rhodotorula mucilaginosa Astaxanthin, β-carotene, and lycopene Chiloe, 30 km southeast of Puerto Montt, Chile 4 g yeast/L seaweed (25% v/v), 150 rpm, 25 ◦C, 6 days HPLC 1.84 ±0.03 mg/L total carotenoids. Carotenoids proportion: 1.8 ±0.3% astaxanthin, 21.8 ±1.5% β-carotene, and 38.4 ±9.4% lycopene [248] Rhodosporidium babjevae β-carotene, γ-carotene, torularhodin, and torulene Grøtsundet, Northern Norway 10 g/L Difco Marine broth 2216 (10 g/LDifco Bacto-peptone, 10 g/L glucose, 15 g/L NaCl, and 15 g/L agar), 6 ◦C, 140 h HPLC Torularhodin > torulene > β-carotene > γ-carotene [249] Rhodotorula mucilaginosa β-carotene, torularhodin, and torulene Escondido lake, North-western Patagonia, Argentina 20 mL of minimal medium salt broth (MMS), 25 ◦C, 250 rpm, 24 h TLC (for pigment profile), spectrophotometry, and HPLC 205 ±15 µg/g total carotenoids, DW. Carotenoid proportions: 10.8% β-carotene, 83.4% torularhodin, and 5.7% torulene [250] Rhodotorula dairenensis β-carotene, γ-carotene, torularhodin, and torulene Freshwater in the middle of the Sagamigawa River, Japan 20 mL of YPD liquid medium (2% glucose, 2% peptone, and 1% yeast extract), 25 ◦C, 120 rpm, 36 h HPLC 267 µg/g total carotenoids, DW [225] DW, dry weight; HPLC, high-performance liquid chromatography; TLC, thin-layer chromatography. 2.5.4. Production Approaches and Production Data in Different Continents The production of carotenoids by yeast cultures can be considered a sustainable process. Although the use of yeast for carotenoid production is not economically profitable yet, efforts to improve yields and reduce production costs have merged to meet global demands for the use of natural products. The biosynthesis of carotenoids by yeast is influenced by many factors that can modify yields and affect operating costs. The yeast strains, culture medium composition (type and concentration of nutrient sources), and growth conditions (temperature, pH, oxygen, and light) influence the amount and profile of carotenoids accumulated within the yeast cell [251,252] (Table 5). Carotenoid biosynthesis in yeast begins in the late logarithmic phase and continues in the stationary phase; thus, the optimal harvest time to obtain the maximum content of carotenoids should be determined precisely in each case. The type and concentration of the main nutrients, such as carbon and nitrogen sources, are also important factors that significantly regulate the carotenogenesis process. Many studies on carotenoid synthesis in yeast cultures have been conducted in synthetic media with pure carbon sources, such as glucose, sucrose, xylose, cellobiose, glycerol, or a combination of some of them [ 253 ]. To lower production costs and in the search for circular economy strategies, many by-products, wastes, and raw materials from agro-industries, such as raw glycerol, brewery effluents, molasses, grape must, and milk whey, have been proposed as alternative carbon sources for carotenoid production [226,254–256]. An important fact for obtaining high levels of intracellular carotenoids is to consider that carbon sources cannot be the limiting factor in yeast growth. However, high initial concentrations of sugars are detrimental to carotenoid accumulation in batch cultures of yeasts that exhibit the Crabtree effect, such as Phaffia rodozyma [ 257 ]. In these cases, at high concentrations of carbon sources, fermentation occurs even under aerobic conditions. In consequence, pyruvate from glycolysis is partially transformed in ethanol and not totally derived to acetyl-CoA, which is a precursor for the mevalonate pathway, the first step in the carotenoid biosynthesis pathway [ 256 ]. The best strategy to improve biomass and carotenoid production under such conditions is the implementation of fed-batch cultures [258]. Mar. Drugs 2023,21, 340 24 of 45 The C/N ratio is an important parameter to optimize carotenoid accumulation in yeast. Much work related to this topic has been published; however, there are no general rules to follow. Although it is fairly agreed that high C/N ratios improve carotenoid synthesis [ 257 ], there are some cases in which the results are different [ 259 ]. Differences in carotenoid profiles have also been observed with different C/N ratios [29]. In the case of R. glutinis, the effect of the C/S and C/P ratios on the accumulation of carotenoids has also been studied [ 252 , 260 ]. In both cases, an increase in the sulfur and phosphorus source concentrations improved the production of carotenoids. Light also influences the production of carotenoids by yeast. To avoid possible damage caused by light exposure, carotenogenesis is induced when yeasts grow in the presence of light. The effect of light depends on the yeast strain and is related to an increase in the activity of certain enzymes associated with the carotenoid biosynthetic pathway [261]. Light induction of carotenoid biosynthesis has been reported for different yeast species such as R. glutinis [262], Rhodosporidium toruloides [263], and P. rodozyma [264]. Another factor that influences the production of carotenoids by yeasts is temperature. Studies on the effect of temperature on carotenoid content in Rhodosporidiobolus colostri [ 265 ], Rhodotorula babjevae [ 249 ], R. mucilaginosa [ 266 ], and R. glutinis [ 267 ] coincide in that at higher growth temperatures an increase in torularhodin is obtained in detriment of the β -carotene content. The effect on torulene varied with the specific yeast strain. According to Zhao and Li [ 267 ], the enhancement in torularhodin production at higher temperatures might be due to its high antioxidant activity and the protection it would exert by scavenging ROS induced by high-temperature stress. Carotenogenic yeasts are mainly aerobic microorganisms. The oxygen supply is an essential factor to enhance their growth in culture conditions, and it influences the amount and profile of carotenoids accumulated inside the cells [ 268 ]. Oxygen levels influence the relative concentration of carotenes and xanthophylls since the latter are formed through the oxidation of the former [ 29 ]. The synthesis of astaxanthin by P. rodozyma is greatly stimulated by oxygen supply. In the presence of low oxygen levels, yellowish biomass is formed due to the accumulation of β-carotene [258]. The yeast P. rodozyma accumulates intracellular astaxanthin but in much lower amounts than the microalgae Haematococcus pluvialis, so its commercial production is not as extensive. At present, there is at least a commercial product called Astaferm based on astaxanthin obtained from P. rodozyma. It is produced for human consumption in various presentations by the company Nextferm (Israel) and is also sold in the USA. Information about these products can be found on the company website (https://www.nextferm.com/, accessed on 30 May 2023). 2.5.5. Current and Prospective Applications Currently, the carotenoids found in yeasts have many commercial applications. However, their production at the industrial level, in most cases, does not involve their extraction from yeasts. The main reasons for that are the low yields of the processes and the high costs associated with microbial production and product purification. Astaxanthin, a xanthophyll produced by P. rodozyma, is a clear example of it. Astaxanthin is a carotenoid extensively used in aquaculture as a feed additive for imparting reddish coloration to the flesh of salmon, trout, shrimp, and ornamental fish [ 229 ]. It is also used in poultry to enhance the color of egg yolks and the skin and meat tissue of broilers, resulting in better acceptance in the market [ 269 ]. Due to its various health benefits, astaxanthin has been incorporated into food and beverages, nutraceutical preparations, and cosmetics [ 229 ]. Its industrial production is mainly based on chemical synthesis, except for products devoted to human direct consumption, for which natural astaxanthin is preferred [36]. Other yeast carotenoids, such as torulene and torularhodin, are not currently produced or used in industry; however, they have many potential applications. They have a reddish color and could be used as pigments in animal feeding in aquaculture or poultry [ 270 ]. Due to their proven activities as antioxidants and vitamin A precursors, they could also Mar. Drugs 2023,21, 340 25 of 45 have applications as food and cosmetic additives. Moreover, both carotenoids have been associated with tumor prevention, so they could also be postulated as nutraceutical products [ 240 ]. These carotenoids are synthesized only by yeast and fungi, and their effect on humans and animals is still unknown. 2.5.6. Research Needs The carotenoids present in yeasts have the potential to be used as food and cosmetic ingredients, as well as pigments in aquaculture and poultry. However, much research is still needed so that the production of carotenoids in yeast is competitive in the market. Some yeast carotenoids, such as torulene and torularhodin, have not been used in animals yet due to fewer studies on their safety and effects on health [ 240 ]. Further research is also needed to determine the properties of other carotenoids produced by aquatic yeasts that have not been explored yet. On the other hand, the extraction of yeast carotenoids has been scarcely studied. 3. Roles of Carotenoids in Marine Organisms Carotenoids are biosynthesized by all photosynthetic organisms (plants, algae, and cyanobacteria), as well as some fungi, non-photosynthetic archaea, bacteria, and arthropods. The vast majority of animals obtain them through their diet [35]. 3.1. Photosynthesis Carotenoids are essential in photosynthesis, intervening in actions such as light harvesting, energy transfer, photoprotection, or the assembly of pigment-protein complexes in the photosynthetic apparatus. Some microalgae can biosynthesize large amounts of carotenoids in response to stress conditions. They are deposited in lipid globules that can be found outside the photosynthetic apparatus (for instance, astaxanthin produced by Haematococcus) or within it (as appears to be the case for the massive β -carotene accumulation observed in some Dunaliella species). Carotenoids are also thought to somehow intervene in photoreception and phototaxis in some flagellate microalgae, which have a photosensitive eyespot capable of sensing variations in light intensity. The photoreceptors are usually membrane-bound rhodopsins (consisting of an apoprotein bound to retinal, a carotenoid derivative) located close to layers of photoprotective/reflective carotenoid-rich globules. Photoreception and phototaxis are important in deciding where to go for optimal light or to prevent predation [271]. There is a diverse body of evidence that carotenoids can protect aquatic organisms from various stressors. As can be inferred from the information provided below, some of the possible mechanisms could be protection against oxidation and modulation of membrane properties. 3.2. Secondary Antenna in Retinal Proteins The important role that carotenoids can play as secondary antennas of type I rhodopsins has recently been demonstrated [ 272 ]. Many marine and freshwater bacteria, as well as some eukaryotes, are capable of obtaining energy using sunlight, thanks to type I rhodopsins. These proteins, evolutionary-divergent but structurally related to the rhodopsin II of animals, have retinal as their main chromophore. The retinal of the rhodopsin proteins and the chlorophylls of the photosystems are the only two types of pigments with the ability to convert solar energy into chemical energy that, to date, are known. Since the discovery of the first type I rhodopsin in the 1970s, bacterioruberin, which pumps H+thanks to the sunlight, generating a proton-motive force used by ATP synthase for the production of ATP, many other similar light-driven pumps have been discovered [273,274]. In 2005, it was announced for the first time that a carotenoid, the keto-carotenoid salinixanthin, could act as a secondary antenna for a retinal rhodopsin. The study showed that salinixanthin, found in the halophile bacteria Salinibacter ruber, is able to harvest light energy and transfer it to retinal [ 275 ]. The recent discovery that the hydroxylated Mar. Drugs 2023,21, 340 32 of 45 been officially registered for direct human use in any country by regulatory authorities and has been used predominantly for animal feed [209,320]. Another advantage of using marine organisms as sources of carotenoids is related to consumer acceptance. Consumers generally feel that synthetic compounds are less safe than those obtained from natural sources. For example, in a recent study, it was observed how chemicals of natural origin are considered to be healthier and safer than synthetic ones and how consumers frequently associated the word “synthetic” with “unnatural”, “health hazard”, and “environmental hazard” [ 327 ]. As a consequence, some consumers are willing to pay high prices for products of natural origin [ 320 ]. However, as mentioned earlier, one approach to enhancing the productivity of marine organisms as a carotenoid source is through genetic engineering. In this regard, it is important to note that a considerable portion of consumers who oppose the consumption of synthetically derived carotenoids are likely to hold similar reservations about consuming carotenoids obtained from genetically modified organisms. The increased demand for natural carotenoids as food additives has spurred advancements in technological innovations for the manufacturing of microbial carotenoids. Numerous research studies have emphasized sustainable and biocompatible methods for manufacturing carotenoids from natural sources, promoting the use of safer carotenoids obtained through alternative means rather than chemical synthesis. The retro-sustainable biotechnological pathway can be accomplished through the implementation of a circular economy approach. This approach not only enables carotenoid recovery but also the possibility of obtaining additional value-added substances such as lipids and proteins associated with the recycling of raw materials for bioproduction and solvents used in extraction procedures. On the other hand, it is frequently thought that the production of synthetic carotenoids does not follow the principles of the circular economy and is destructive to the ecosystem. Thus, synthesis using nonrenewable sources reveals a negative impact on the environment and consumers [320]. However, there are important hurdles to overcome in order to increase the use of marine organisms to extract carotenoids instead of obtaining carotenoids from chemical synthesis. The main barriers are the acceptability by some consumers of new sources, the low bioavailability of carotenoids from natural sources (which can result in low bioactivity), and, of course, the safety of the product as food ingredients. Several research studies are needed, in particular about the metabolization of carotenoids from natural sources by humans and their health benefits, although there are many others. Further, the extraction of carotenoids from natural origin cannot yet compete in price with the chemical synthesis of carotenoids and could still present some negative environmental impacts. Thus, strategies and technologies (e.g., genetic engineering, CRISPR, fine-tuned cultivation conditions, sustainable and scalable extraction methodologies, and green solvents for biorefineries) may therefore be required to increase the production and use of carotenoid-rich natural products. 7. Concluding Remarks Altogether, the organisms investigated in this review can accumulate both common dietary carotenoids ( β -carotene, lutein, zeaxanthin, astaxanthin, canthaxanthin, or fucoxanthin in some countries) and unusual ones (e.g., bacterioruberin, salinixanthin, myxoxanthophyll, and β -zeacarotene), some of which are unique to some taxa. The fact that some studies provide evidence that unusual “marine carotenoids” exhibit important properties such as distinctive colors, high in vitro antioxidant capacity, or even health-promoting biological actions in studies of diverse nature is encouraging. Some advantages of using marine organisms as a source of carotenoids over chemical synthesis are that, in some cases, chemical synthesis produces isomers with lower activity, bioavailability, and stability. In addition, marine organisms have a great capacity to synthesize a wide variety of carotenoids, which can be obtained in a renewable manner without depleting natural resources. Thus, marine organisms have the potential to be key Mar. Drugs 2023,21, 340 33 of 45 sustainable sources of these compounds, which could help Europe achieve its Green Deal and Recovery Plan. However, to consolidate the industrial production of carotenoids from marine organisms, more research is needed to increase productivity and reduce costs. In summary, the need to promote the blue economy to help produce sustainable and healthpromoting foods offers an exciting opportunity to tap into aquatic ecosystems and valorize carotenoid-rich organisms. Author Contributions: P.M.-B. and A.J.M.-M. conceptualization and design of the idea, literature research, writing—original draft preparation, prepared figures and tables, supervision, writing— review and editing; P.G.-V., M.L.G., A.L.-V., R.L., J.M., C.R., V.S., S.V. and E.V. literature research, writing—original draft preparation, prepared figures and tables, writing—review and editing. All authors have read and agreed to the published version of the manuscript. Funding: C.R. and J.M. contributions were financed by The Research Council of Norway (326803 SUSKELPFOOD; 319577 SAFER-IMTA, 294946 SBP-N) and Møreforsking AS. P.M.-B. and A.J.M.-M. acknowledge Grant PID2019-110438RB-C21 (NEWCARFOODS), funded by MCIN/AEI/10.13039/ 501100011033. P.G.-V., A.L.-V. and R.L. acknowledge FITORIBOPEP-P20_00728. PROY. I + D + I JUNTA ANDALUCIA 2020, AGL2019-110438RB-C22-AEI/FEDER, Fertinagro Biotech Foundation (Cátedra Fertinagro Biotech de la Universidad de Huelva). P.M.-B. was supported by a posdoc fellowship from Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucía (PAIDI 2020). P.G.-V. and A.L.-V. wants to thank also Next Generation European Funds and the Ministry of Universities of Spain for funding the Recualificación del Profesorado Universitario system. V.S. and E.V. acknowledge CSIC I + D 2018 250 UdelaR, ANII POS NAC 2014 1 102321, and Ph.D. grant CAP UdelaR 2017–2019. Acknowledgments: This article is based upon work from COST Actions SEAWHEAT and EUROCAROTEN (CA20106, https://seawheatcost.haifa.ac.il/ (accessed on 30 May 2023) & CA15136 www.eurocaroten.eu (accessed on 30 May 2023)), supported by COST (European Cooperation in Science and Technology). A.J.M.-M. and P.M.-B. acknowledge MICROAGRO network (Red 121RT0110, https://www.cyted.org/?q=es/detalle_proyecto&un=1013 (accessed on 30 May 2023)) funded by CYTED (http://www.cyted.org/ (accessed on 30 May 2023)) and are member of the Carotenoid Network: from microbia and plants to food and health (CaRed) (BIO2015-71703-REDT), funded by the Spanish Ministry of Economy and Competitiveness, and CaRed: Red española de carotenoides (BIO2017-90877-REDT), funded by the Spanish Ministry of Economy, Industry and Competitiveness. M.L.G. and S.V. acknowledge MICROAGRO network (Red 121RT0110, https://www.cyted.org/?q=es/detalle_proyecto&un=1013 (accessed on 30 May 2023)) funded by CYTED (http://www.cyted.org/ (accessed on 30 May 2023)). Conflicts of Interest: A.J.M.-M. carries out consultancy work for diverse companies. References 1. Willett, W.; Rockström, J.; Loken, B.; Springmann, M.; Lang, T.; Vermeulen, S.; Garnett, T.; Tilman, D.; DeClerck, F.; Wood, A.; et al. Food in the Anthropocene: The EAT—Lancet Commission on Healthy Diets from Sustainable Food Systems. Lancet 2019 , 393, 447–492. [CrossRef] 2. European Commission. Blue Economy Report 2022; European Union: Brussels, Belgium, 2022. 3. Meléndez-Martínez, A.J.; Mandi´c, A.I.; Bantis, F.; Böhm, V.; Borge, G.I.A.; Brnˇci´c, M.; Bysted, A.; Cano, M.P.; Dias, M.G.; Elgersma, A.; et al. A Comprehensive Review on Carotenoids in Foods and Feeds: Status Quo, Applications, Patents, and Research Needs. Crit. Rev. Food Sci. Nutr. 2021,62, 1999–2049. [CrossRef] 4. Sosa-Hernández, J.; Romero-Castillo, K.; Parra-Arroyo, L.; Aguilar-Aguila-Isaías, M.; García-Reyes, I.; Ahmed, I.; Parra-Saldivar, R.; Bilal, M.; Iqbal, H. Mexican Microalgae Biodiversity and State-Of-The-Art Extraction Strategies to Meet Sustainable Circular Economy Challenges: High-Value Compounds and Their Applied Perspectives. Mar. Drugs 2019,17, 174. [CrossRef] 5. Cotas, J.; Gomes, L.; Pacheco, D.; Pereira, L. Ecosystem Services Provided by Seaweeds. Hydrobiology 2023,2, 75–96. [CrossRef] 6. Caporgno, M.P.; Mathys, A. Trends in Microalgae Incorporation Into Innovative Food Products with Potential Health Benefits. Front. Nutr. 2018,5, 1–10. [CrossRef] 7. Krause-Jensen, D.; Duarte, C.M. Substantial Role of Macroalgae in Marine Carbon Sequestration. Nat. Geosci. 2016 ,9, 737–742. [CrossRef] 8. Enzing, C.; Ploeg, M.; Barbosa, M.; Sijtsma, L. Microalgae-Based Products for the Food and Feed Sector: An Outlook for Europe; Vigani, M., Parisi, C., Rodriguez Cerezo, E., Eds.; Publications Office of the European Union: Luxembourg, 2014; ISBN 9789279340376. 9. Ferdouse, F.; Løvstad Holdt, S.; Smith, R.; Murúa, P.; Yang, L. The Global Status of Seaweed Production. Trade and Utilization, Globefish Research Program. FAO 2018,124, 1–120. Mar. Drugs 2023,21, 340 34 of 45 10. European Market Observatory for Fisheries and Aquaculture (EUMOFA). Blue Bioeconomy: Situation Report and Perspectives; EUMOFA: Luxembourg, 2018. 11. Nova, P.; Martins, A.P.; Teixeira, C.; Abreu, H.; Silva, J.G.; Silva, A.M.; Freitas, A.C.; Gomes, A.M.Foods with Microalgae andSeaweeds Fostering Consumers Health: A Review on Scientific and Market Innovations. J. Appl. Phycol. 2020,32, 1789–1802. [CrossRef] 12. Venkata Mohan, S.; Nikhil, G.N.; Chiranjeevi, P.; Nagendranatha Reddy, C.; Rohit, M.V.; Kumar, A.N.; Sarkar, O. Waste Biorefinery Models towards Sustainable Circular Bioeconomy: Critical Review and Future Perspectives. Bioresour. Technol. 2016,215, 2–12. [CrossRef] [PubMed] 13. Venil, C.K.; Aruldass, C.A.; Dufossé, L.; Zakaria, Z.A.; Ahmad, W.A. Current Perspective on Bacterial Pigments: Emerging Sustainable Compounds with Coloring and Biological Properties for the Industry—An Incisive Evaluation. RSC Adv. 2014 , 4, 39523. [CrossRef] 14. Bourdichon, F.; Casaregola, S.; Farrokh, C.; Frisvad, J.C.; Gerds, M.L.; Hammes, W.P.; Harnett, J.; Huys, G.; Laulund, S.; Ouwehand, A.; et al. Food Fermentations: Microorganisms with Technological Beneficial Use. Int. J. Food Microbiol. 2012 , 154, 87–97. [CrossRef] 15. Gerhauser, C. Impact of Dietary Gut Microbial Metabolites on the Epigenome. Philos. Trans. R. Soc. B Biol. Sci. 2018 , 373, 20170359. [CrossRef] [PubMed] 16. Suez, J.; Zmora, N.; Segal, E.; Elinav, E. The Pros, Cons, and Many Unknowns of Probiotics. Nat. Med. 2019 ,25, 716–729. [CrossRef] [PubMed] 17. Hadrich, D. Microbiome Research Is Becoming the Key to Better Understanding Health and Nutrition. Front. Genet. 2018 ,9, 212. [CrossRef] 18. Nevejan, N.; De Schryver, P.; Wille, M.; Dierckens, K.; Baruah, K.; Van Stappen, G. Bacteria as Food in Aquaculture: Do They Make a Difference? Rev. Aquac. 2018,10, 180–212. [CrossRef] 19. Grivard, A.; Goubet, I.; de Souza Duarte Filho, L.M.; Thiéry, V.; Chevalier, S.; de Oliveira-Junior, R.G.; El Aouad, N.; Guedes da Silva Almeida, J.R.; Sitarek, P.; Quintans-Junior, L.J.; et al. Archaea Carotenoids: Natural Pigments with Unexplored Innovative Potential. Mar. Drugs 2022,20, 524. [CrossRef] [PubMed] 20. Kutty, S.N.; Philip, R. Marine Yeasts-a Review. Yeast 2008,25, 465–483. [CrossRef] [PubMed] 21. Chi, Z.; Liu, G.-L.; Lu, Y.; Jiang, H.; Chi, Z.-M. Bio-Products Produced by Marine Yeasts and Their Potential Applications. Bioresour. Technol. 2016,202, 244–252. [CrossRef] 22. Carlozzi, P.; Touloupakis, E.; Di Lorenzo, T.; Giovannelli, A.; Seggiani, M.; Cinelli, P.; Lazzeri, A. Whey and Molasses as Inexpensive Raw Materials for Parallel Production of Biohydrogen and Polyesters via a Two-Stage Bioprocess: New Routes towards a Circular Bioeconomy. J. Biotechnol. 2019,303, 37–45. [CrossRef] 23. Gupta, V.; Goel, R. Managing Dissolved Methane Gas in Anaerobic Effluents Using Microbial Resource Management-Based Strategies. Bioresour. Technol. 2019,289, 121601. [CrossRef] 24. Sarsaiya, S.; Jain, A.; Kumar Awasthi, S.; Duan, Y.; Kumar Awasthi, M.; Shi, J. Microbial Dynamics for Lignocellulosic Waste Bioconversion and Its Importance with Modern Circular Economy, Challenges and Future Perspectives. Bioresour. Technol. 2019 , 291, 121905. [CrossRef] 25. Tao, Y.; Ersahin, M.E.; Ghasimi, D.S.M.; Ozgun, H.; Wang, H.; Zhang, X.; Guo, M.; Yang, Y.; Stuckey, D.C.; van Lier, J.B. Biogas Productivity of Anaerobic Digestion Process Is Governed by a Core Bacterial Microbiota. Chem. Eng. J. 2020 ,380, 122425. [CrossRef] 26. López, A.R.; Rodríguez, S.B.; Vallejo, R.A.; García, P.G.; Macías-Sánchez, M.D.; Díaz, M.G.; Librán, R.G.; Acero, F.J.F. Sustainable Cultivation of Nannochloropsis gaditana Microalgae in Outdoor Raceways Using Flue Gases for a Complete 2-Year Cycle: A Circular Economy Challenge. J. Appl. Phycol. 2019,31, 1515–1523. [CrossRef] 27. Stiles, W.A.V.; Styles, D.; Chapman, S.P.; Esteves, S.; Bywater, A.; Melville, L.; Silkina, A.; Lupatsch, I.; Fuentes Grünewald, C.; Lovitt, R.; et al. Using Microalgae in the Circular Economy to Valorise Anaerobic Digestate: Challenges and Opportunities. Bioresour. Technol. 2018,267, 732–742. [CrossRef] 28. Rodríguez, P.D.; Arce Bastias, F.; Arena, A.P. Modeling and Environmental Evaluation of a System Linking a Fishmeal Facility with a Microalgae Plant within a Circular Economy Context. Sustain. Prod. Consum. 2019,20, 356–364. [CrossRef] 29. Mata-Gómez, L.C.; Montañez, J.C.; Méndez-Zavala, A.; Aguilar, C.N. Biotechnological Production of Carotenoids by Yeasts: An Overview. Microb. Cell Fact. 2014,13, 1–11. [CrossRef] [PubMed] 30. Ding, S.; Liu, Y. Adsorption of CO 2 from Flue Gas by Novel Seaweed-Based KOH-Activated Porous Biochars. Fuel 2020 , 260, 116382. [CrossRef] 31. Israel, A.; Gavrieli, J.; Glazer, A.; Friedlander, M. Utilization of Flue Gas from a Power Plant for Tank Cultivation of the Red Seaweed Gracilaria cornea.Aquaculture 2005,249, 311–316. [CrossRef] 32. Batista, A.P.; Raymundo, A.; Sousa, I.; Empis, J. Rheological Characterization of Coloured Oil-in-Water Food Emulsions with Lutein and Phycocyanin Added to the Oil and Aqueous Phases. Food Hydrocoll. 2006,20, 44–52. [CrossRef] 33. Meléndez-Martínez, A.J. An Overview of Carotenoids, Apocarotenoids and Vitamin A in Agro-Food, Nutrition, Health and Disease. Mol. Nutr. Food Res. 2019,63, 1801045. [CrossRef] 34. Meléndez-Martínez, A.J.; Stinco, C.M.; Mapelli-Brahm, P. Skin Carotenoids in Public Health and Nutricosmetics: The Emerging Roles and Applications of the UV Radiation-Absorbing Colourless Carotenoids Phytoene and Phytofluene. Nutrients 2019 , 11, 1093. [CrossRef] [PubMed] 35. Rodriguez-Concepcion, M.; Avalos, J.; Bonet, M.L.; Boronat, A.; Gomez-Gomez, L.; Hornero-Mendez, D.; Carmen Limon, M.; Meléndez-Martínez, A.J.; Olmedilla-Alonso, B.; Palou, A.; et al. A Global Perspective on Carotenoids: Metabolism, Biotechnology, and Benefits for Nutrition and Health. Prog. Lipid Res. 2018,70, 62–93. [CrossRef] [PubMed] Mar. Drugs 2023,21, 340 35 of 45 36. Stachowiak, B.; Szulc, P. Astaxanthin for the Food Industry. Molecules 2021,26, 2666. [CrossRef] [PubMed] 37. Rapoport, A.; Guzhova, I.; Bernetti, L.; Buzzini, P.; Kieliszek, M.; Kot, A.M. Carotenoids and Some Other Pigments from Fungi and Yeasts. Metabolites 2021,11, 92. [CrossRef] 38. Woese, C.R.; Kandler, O.; Wheelis, M.L. Towards a Natural System of Organisms: Proposal for the Domains Archaea, Bacteria, and Eucarya. Proc. Natl. Acad. Sci. USA 1990,87, 4576–4579. [CrossRef] [PubMed] 39. DeLong, E.F. Exploring Marine Planktonic Archaea: Then and Now. Front. Microbiol. 2021,11, 616086. [CrossRef] 40. Heal, K.R.; Qin, W.; Ribalet, F.; Bertagnolli, A.D.; Coyote-Maestas, W.; Hmelo, L.R.; Moffett, J.W.; Devol, A.H.; Armbrust, E.V.; Stahl, D.A.; et al. Two Distinct Pools of B 12 Analogs Reveal Community Interdependencies in the Ocean. Proc. Natl. Acad. Sci. USA 2017,114, 364–369. [CrossRef] 41. Santoro, A.E.; Richter, R.A.; Dupont, C.L. Planktonic Marine Archaea. Ann. Rev. Mar. Sci. 2019,11, 131–158. [CrossRef] 42. Bomberg, M.; Montonen, L.; Münster, U.; Jurgens, G. Diversity and Function of Archaea in Freshwater Habitats. Curr. Trends Microbiol. 2008,4, 61–89. 43. Juottonen, H.; Fontaine, L.; Wurzbacher, C.; Drakare, S.; Peura, S.; Eiler, A. Archaea in Boreal Swedish Lakes Are Diverse, Dominated by Woesearchaeota and Follow Deterministic Community Assembly. Environ. Microbiol. 2020,22, 3158–3171. [CrossRef] 44. Chaban, B.; Ng, S.Y.M.; Jarrell, K.F. Archaeal Habitats—From the Extreme to the Ordinary. Can. J. Microbiol. 2006 ,52, 73–116. [CrossRef] 45. Miralles-Robledillo, J.M.; Bernabeu, E.; Giani, M.; Martínez-Serna, E.; Martínez-Espinosa, R.M.; Pire, C. Distribution of Denitrification among Haloarchaea: A Comprehensive Study. Microorganisms 2021,9, 1669. [CrossRef] [PubMed] 46. Pfeifer, K.; Ergal, ˙ I.; Koller, M.; Basen, M.; Schuster, B.; Rittmann, S.K.-M.R. Archaea Biotechnology. Biotechnol. Adv. 2021 , 47, 107668. [CrossRef] [PubMed] 47. Halorubin. Available online: https://cosmetics.specialchem.com/product/i-adeka-halorubin (accessed on 30 May 2023). 48. Abbes, M.; Baati, H.; Guermazi, S.; Messina, C.; Santulli, A.; Gharsallah, N.; Ammar, E. Biological Properties of Carotenoids Extracted from Halobacterium halobium Isolated from a Tunisian Solar Saltern. BMC Complement. Altern. Med. 2013,13, 255. [CrossRef] 49. Yatsunami, R.; Ando, A.; Yang, Y.; Takaichi, S.; Kohno, M.; Matsumura, Y.; Ikeda, H.; Fukui, T.; Nakasone, K.; Fujita, N.; et al. Identification of Carotenoids from the Extremely Halophilic Archaeon Haloarcula japonica.Front. Microbiol. 2014,5, 1–5. [CrossRef] [PubMed] 50. de la Vega, M.; Sayago, A.; Ariza, J.; Barneto, A.G.; León, R. Characterization of a Bacterioruberin-Producing Haloarchaea Isolated from the Marshlands of the Odiel River in the Southwest of Spain. Biotechnol. Prog. 2016,32, 592–600. [CrossRef] 51. Squillaci, G.; Parrella, R.; Carbone, V.; Minasi, P.; La Cara, F.; Morana, A. Carotenoids from the Extreme Halophilic Archaeon Haloterrigena turkmenica: Identification and Antioxidant Activity. Extremophiles 2017,21, 933–945. [CrossRef] 52. Sahli, K.; Gomri, M.A.; Esclapez, J.; Gómez-Villegas, P.; Ghennai, O.; Bonete, M.-J.; León, R.; Kharroub, K. Bioprospecting and Characterization of Pigmented Halophilic Archaeal Strains from Algerian Hypersaline Environments with Analysis of Carotenoids Produced by Halorubrum sp. BS2. J. Basic Microbiol. 2020,60, 624–638. [CrossRef] 53. Lizama, C.; Romero-Parra, J.; Andrade, D.; Riveros, F.; Bórquez, J.; Ahmed, S.; Venegas-Salas, L.; Cabalín, C.; Simirgiotis, M.J. Analysis of Carotenoids in Haloarchaea Species from Atacama Saline Lakes by High Resolution UHPLC-Q-Orbitrap-Mass Spectrometry: Antioxidant Potential and Biological Effect on Cell Viability. Antioxidants 2021,10, 1230. [CrossRef] 54. Giani, M.; Gervasi, L.; Loizzo, M.R.; Martínez-Espinosa, R.M. Carbon Source Influences Antioxidant, Antiglycemic, and Antilipidemic Activities of Haloferax Mediterranei Carotenoid Extracts. Mar. Drugs 2022,20, 659. [CrossRef] 55. Yang, Y.; Yatsunami, R.; Ando, A.; Miyoko, N.; Fukui, T.; Takaichi, S.; Nakamura, S. Complete Biosynthetic Pathway of the C 50 Carotenoid Bacterioruberin from Lycopene in the Extremely Halophilic Archaeon Haloarcula japonica.J. Bacteriol. 2015 , 197, 1614–1623. [CrossRef] 56. Alvares, J.J.; Furtado, I.J. Characterization of Multicomponent Antioxidants from Haloferax alexandrinus GUSF-1 (KF796625). 3 Biotech 2021,11, 1–12. [CrossRef] 57. Hou, J.; Cui, H.-L. In Vitro Antioxidant, Antihemolytic, and Anticancer Activity of the Carotenoids from Halophilic Archaea. Curr. Microbiol. 2018,75, 266–271. [CrossRef] [PubMed] 58. Hegazy, G.E.; Abu-Serie, M.M.; Abo-Elela, G.M.; Ghozlan, H.; Sabry, S.A.; Soliman, N.A.; Abdel-Fattah, Y.R. In Vitro Dual (Anticancer and Antiviral) Activity of the Carotenoids Produced by Haloalkaliphilic Archaeon Natrialba sp. M6. Sci. Rep. 2020 , 10, 5986. [CrossRef] [PubMed] 59. Gómez-Villegas, P.; Vigara, J.; Vila, M.; Varela, J.; Barreira, L.; Léon, R. Antioxidant, Antimicrobial, and Bioactive Potential of Two New Haloarchaeal Strains Isolated from Odiel Salterns (Southwest Spain). Biology 2020,9, 298. [CrossRef] 60. Zalazar, L.; Pagola, P.; Miró, M.V.; Churio, M.S.; Cerletti, M.; Martínez, C.; Iniesta-Cuerda, M.; Soler, A.J.; Cesari, A.; De Castro, R. Bacterioruberin Extracts from a Genetically Modified Hyperpigmented Haloferax volcanii Strain: Antioxidant Activity and Bioactive Properties on Sperm Cells. J. Appl. Microbiol. 2019,126, 796–810. [CrossRef] [PubMed] 61. D’Souza, S.E.; Altekar, W.; D’Souza, S.F. Adaptive Response of Haloferax Mediterranei to Low Concentrations of NaCl (<20%) in the Growth Medium. Arch. Microbiol. 1997,168, 68–71. [CrossRef] [PubMed] 62. Fang, C.-J.; Ku, K.-L.; Lee, M.-H.; Su, N.-W. Influence of Nutritive Factors on C50 Carotenoids Production by Haloferax Mediterranei ATCC 33500 with Two-Stage Cultivation. Bioresour. Technol. 2010,101, 6487–6493. [CrossRef] 63. Calegari-Santos, R.; Diogo, R.A.; Fontana, J.D.; Bonfim, T.M.B. Carotenoid Production by Halophilic Archaea under Different Culture Conditions. Curr. Microbiol. 2016,72, 641–651. [CrossRef] 64. Tatiana, A.; Yasynska, O.; Rivas, P.C.; Lilia, E.; Jose, M. Journal of Drug Delivery Science and Technology Improved Stability and Biological Activity of Bacterioruberin in Nanovesicles. J. Drug Deliv. Sci. Technol. 2022,77, 103896. [CrossRef] Mar. Drugs 2023,21, 340 36 of 45 65. Chaari, M.; Theochari, I.; Papadimitriou, V.; Xenakis, A.; Ammar, E. Encapsulation of Carotenoids Extracted from Halophilic Archaea in Oil-in-Water (O/W) Micro- and Nano-Emulsions. Colloids Surf. B Biointerfaces 2018,161, 219–227. [CrossRef] 66. Pagels, F.; Vasconcelos, V.; Guedes, A.C. Carotenoids from Cyanobacteria: Biotechnological Potential and Optimization Strategies. Biomolecules 2021,11, 735. [CrossRef] 67. George, D.M.; Vincent, A.S.; Mackey, H.R. An Overview of Anoxygenic Phototrophic Bacteria and Their Applications in Environmental Biotechnology for Sustainable Resource Recovery. Biotechnol. Rep. 2020,28, e00563. [CrossRef] 68. Sandmann, G. Diversity and Origin of Carotenoid Biosynthesis: Its History of Coevolution towards Plant Photosynthesis. N. Phytol. 2021,232, 479–493. [CrossRef] 69. Béjà, O.; Suzuki, M.T. Photoheterotrophic Marine Prokaryotes. In Microbial Ecology of the Oceans; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2008; pp. 131–157. 70. Imhoff, J. True Marine and Halophilic Anoxygenic Phototrophic Bacteria. Arch. Microbiol. 2001,176, 243–254. [CrossRef] [PubMed] 71. Hubas, C.; Jesus, B.; Passarelli, C.; Jeanthon, C. Tools Providing New Insight into Coastal Anoxygenic Purple Bacterial Mats: Review and Perspectives. Res. Microbiol. 2011,162, 858–868. [CrossRef] [PubMed] 72. Hess, W.R.; Garczarek, L.; Pfreundt, U.; Partensky, F. Phototrophic Microorganisms: The Basis of the Marine Food Web. In The Marine Microbiome; Springer International Publishing: Berlin, Germany, 2016; pp. 57–97. 73. Gómez-Consarnau, L.; Akram, N.; Lindell, K.; Pedersen, A.; Neutze, R.; Milton, D.L.; González, J.M.; Pinhassi, J. Proteorhodopsin Phototrophy Promotes Survival of Marine Bacteria during Starvation. PLoS Biol. 2010,8, e1000358. [CrossRef] 74. Béjà, O.; Spudich, E.N.; Spudich, J.L.; Leclerc, M.; DeLong, E.F. Proteorhodopsin Phototrophy in the Ocean. Nature 2001 , 411, 786–789. [CrossRef] 75. Armstrong, G.A. Genetics of Eubacterial Carotenoids Biosynthesis: A Colorful Tale. Annu. Rev. Microbiol. 1997 ,51, 629–659. [CrossRef] 76. Stafsnes, M.H.; Josefsen, K.D.; Kildahl-Andersen, G.; Valla, S.; Ellingsen, T.E.; Bruheim, P. Isolation and Characterization of Marine Pigmented Bacteria from Norwegian Coastal Waters and Screening for Carotenoids with UVA-Blue Light Absorbing Properties. J. Microbiol. 2010,48, 16–23. [CrossRef] [PubMed] 77. Dieser, M.; Greenwood, M.; Foreman, C.M. Carotenoid Pigmentation in Antarctic Heterotrophic Bacteria as a Strategy to Withstand Environmental Stresses. Arct. Antarct. Alp. Res. 2010,42, 396–405. [CrossRef] 78. Ram, S.; Mitra, M.; Shah, F.; Tirkey, S.R.; Mishra, S. Bacteria as an Alternate Biofactory for Carotenoid Production: A Review of Its Applications, Opportunities and Challenges. J. Funct. Foods 2020,67, 103867. [CrossRef] 79. Kristjansdottir, T.; Ron, E.Y.C.; Molins-Delgado, D.; Fridjonsson, O.H.; Turner, C.; Bjornsdottir, S.H.; Gudmundsson, S.; van Niel, E.W.J.; Karlsson, E.N.; Hreggvidsson, G.O. Engineering the Carotenoid Biosynthetic Pathway in Rhodothermus marinus for Lycopene Production. Metab. Eng. Commun. 2020,11, e00140. [CrossRef] 80. Park, S.; Cho, S.W.; Lee, Y.; Choi, M.; Yang, J.; Lee, H.; Seo, S.W. Engineering Vibrio sp. SP1 for the Production of Carotenoids Directly from Brown Macroalgae. Comput. Struct. Biotechnol. J. 2021,19, 1531–1540. [CrossRef] 81. Shindo, K.; Misawa, N. New and Rare Carotenoids Isolated from Marine Bacteria and Their Antioxidant Activities. Mar. Drugs 2014,12, 1690–1698. [CrossRef] [PubMed] 82. Yoon, J.; Lee, E.-Y.; Nam, S.-J. Erythrobacter Rubeus sp. Nov., a Carotenoid-Producing Alphaproteobacterium Isolated from Coastal Seawater. Arch. Microbiol. 2022,204, 125. [CrossRef] 83. Vila, E.; Hornero-Méndez, D.; Lareo, C.; Saravia, V. Biotechnological Production of Zeaxanthin by an Antarctic Flavobacterium: Evaluation of Culture Conditions. J. Biotechnol. 2020,319, 54–60. [CrossRef] 84. Liu, H.; Zhang, C.; Zhang, X.; Tan, K.; Zhang, H.; Cheng, D.; Ye, T.; Li, S.; Ma, H.; Zheng, H. A Novel Carotenoids-Producing Marine Bacterium from Noble Scallop Chlamys nobilis and Antioxidant Activities of Its Carotenoid Compositions. Food Chem. 2020,320, 126629. [CrossRef] 85. Niero, H.; da Silva, M.A.C.; de Felicio, R.; Trivella, D.B.B.; Lima, A.O.d.S. Carotenoids Produced by the Deep-Sea Bacterium Erythrobacter citreus LAMA 915: Detection and Proposal of Their Biosynthetic Pathway. Folia Microbiol. 2021 ,66, 441–456. [CrossRef] 86. Setiyono, E.; Heriyanto; Pringgenies, D.; Shioi, Y.; Kanesaki, Y.; Awai, K.; Brotosudarmo, T.H.P. Sulfur-Containing Carotenoids from A Marine Coral Symbiont Erythrobacter flavus Strain KJ5. Mar. Drugs 2019,17, 349. [CrossRef] 87. Sayed, A.; Elbalasy, I.; Mohamed, M.S. Novel β -Carotene and Astaxanthin-Producing Marine Planococcus sp.: Insights into Carotenogenesis Regulation and Genetic Aspects. Appl. Biochem. Biotechnol. 2022,195, 217–235. [CrossRef] [PubMed] 88. Asker, D. Isolation and Characterization of a Novel, Highly Selective Astaxanthin-Producing Marine Bacterium. J. Agric. Food Chem. 2017,65, 9101–9109. [CrossRef] 89. Ide, T.; Hoya, M.; Tanaka, T.; Harayama, S. Enhanced Production of Astaxanthin in Paracoccus sp. Strain N-81106 by Using Random Mutagenesis and Genetic Engineering. Biochem. Eng. J. 2012,65, 37–43. [CrossRef] 90. Sowmya, R.; Sachindra, N.M. Biochemical and Molecular Characterization of Carotenogenic Flavobacterial Isolates from Marine Waters. Pol. J. Microbiol. 2016,65, 77–88. [CrossRef] [PubMed] 91. Khomlaem, C.; Aloui, H.; Oh, W.-G.; Kim, B.S. High Cell Density Culture of Paracoccus sp. LL1 in Membrane Bioreactor for Enhanced Co-Production of Polyhydroxyalkanoates and Astaxanthin. Int. J. Biol. Macromol. 2021,192, 289–297. [CrossRef] 92. Choi, S.S.; Seo, Y.B.; Nam, S.-W.; Kim, G.-D. Enhanced Production of Astaxanthin by Co-Culture of Paracoccus haeundaensis and Lactic Acid Bacteria. Front. Mar. Sci. 2021,7, 597553. [CrossRef] 93. Joshi, C.; Singhal, R.S. Modelling and Optimization of Zeaxanthin Production by Paracoccus zeaxanthinifaciens ATCC 21588 Using Hybrid Genetic Algorithm Techniques. Biocatal. Agric. Biotechnol. 2016,8, 228–235. [CrossRef] Mar. Drugs 2023,21, 340 37 of 45 94. Joshi, C.; Singhal, R.S. Zeaxanthin Production by Paracoccus Zeaxanthinifaciens ATCC 21588 in a Lab-Scale Bubble Column Reactor: Artificial Intelligence Modelling for Determination of Optimal Operational Parameters and Energy Requirements. Korean J. Chem. Eng. 2018,35, 195–203. [CrossRef] 95. Takaichi, S.; Mochimaru, M.; Maoka, T.; Katoh, H. Myxol and 4-Ketomyxol 2 0 -Fucosides, Not Rhamnosides, from Anabaena sp. PCC 7120 and Nostoc Punctiforme PCC 73102, and Proposal for the Biosynthetic Pathway of Carotenoids. Plant Cell Physiol. 2005 , 46, 497–504. [CrossRef] 96. Takaichi, S.; Mochimaru, M.; Maoka, T. Presence of Free Myxol and 4-Hydroxymyxol and Absence of Myxol Glycosides in Anabaena variabilis ATCC 29413, and Proposal of a Biosynthetic Pathway of Carotenoids. Plant Cell Physiol. 2006,47, 211–216. [CrossRef] 97. Takaichi, S.; Maoka, T.; Masamoto, K. Myxoxanthophyll in Synechocystis sp. PCC 6803 Is Myxol 2 0 -Dimethyl-Fucoside, (3R,2 0 S)- Myxol 20-(2,4-Di-O-Methyl-α-l-Fucoside), Not Rhamnoside. Plant Cell Physiol. 2001,42, 756–762. [CrossRef] [PubMed] 98. Britton, G.; Brown, D.J.; Goodwin, T.W.; Leuenberger, F.J.; Schocher, A.J. The Carotenoids of Flavobacterium Strain R1560. Arch. Microbiol. 1977,113, 33–37. [CrossRef] [PubMed] 99. Sowmya, R.; Sachindra, N.M. Carotenoid Production by Formosa sp. KMW, a Marine Bacteria of Flavobacteriaceae Family: Influence of Culture Conditions and Nutrient Composition. Biocatal. Agric. Biotechnol. 2015,4, 559–567. [CrossRef] 100. Vila, E.; Hornero-Méndez, D.; Azziz, G.; Lareo, C.; Saravia, V. Carotenoids from Heterotrophic Bacteria Isolated from Fildes Peninsula, King George Island, Antarctica. Biotechnol. Rep. 2019,21, e00306. [CrossRef] [PubMed] 101. Lee, J.H.; Kim, Y.S.; Choi, T.-J.; Lee, W.J.; Kim, Y.T. Paracoccus Haeundaensis sp. Nov., a Gram-Negative, Halophilic, Astaxanthin- Producing Bacterium. Int. J. Syst. Evol. Microbiol. 2004,54, 1699–1702. [CrossRef] 102. Berry, A.; Janssens, D.; Hümbelin, M.; Jore, J.P.M.; Hoste, B.; Cleenwerck, I.; Vancanneyt, M.; Bretzel, W.; Mayer, A.F.; Lopez- Ulibarri, R.; et al. Paracoccus zeaxanthinifaciens sp. Nov., a Zeaxanthin-Producing Bacterium. Int. J. Syst. Evol. Microbiol. 2003 , 53, 231–238. [CrossRef] 103. Takaichi, S.; Mochimaru, M. Carotenoids and Carotenogenesis in Cyanobacteria: Unique Ketocarotenoids and Carotenoid Glycosides. Cell. Mol. Life Sci. 2007,64, 2607–2619. [CrossRef] 104. Sarnaik, A.; Nambissan, V.; Pandit, R.; Lali, A. Recombinant Synechococcus elongatus PCC 7942 for Improved Zeaxanthin Production under Natural Light Conditions. Algal Res. 2018,36, 139–151. [CrossRef] 105. Shimada, N.; Okuda, Y.; Maeda, K.; Umeno, D.; Takaichi, S.; Ikeuchi, M. Astaxanthin Production in a Model Cyanobacterium Synechocystis sp. PCC 6803. J. Gen. Appl. Microbiol. 2020,66, 116–120. [CrossRef] 106. Sandmann, G.; Albrecht, M.; Schnurr, G.; Knörzer, O.; Böger, P. The Biotechnological Potential and Design of Novel Carotenoids by Gene Combination in Escherichia coli.Trends Biotechnol. 1999,17, 233–237. [CrossRef] 107. Schmidt-Dannert, C. Engineering Novel Carotenoids in Microorganisms. Curr. Opin. Biotechnol. 2000,11, 255–261. [CrossRef] 108. Henke, N.; Heider, S.; Peters-Wendisch, P.; Wendisch, V. Production of the Marine Carotenoid Astaxanthin by Metabolically Engineered Corynebacterium glutamicum.Mar. Drugs 2016,14, 124. [CrossRef] [PubMed] 109. Buijs, Y.; Bech, P.K.; Vazquez-Albacete, D.; Bentzon-Tilia, M.; Sonnenschein, E.C.; Gram, L.; Zhang, S.-D. Marine Proteobacteria as a Source of Natural Products: Advances in Molecular Tools and Strategies. Nat. Prod. Rep. 2019,36, 1333–1350. [CrossRef] [PubMed] 110. Takemura, M.; Takagi, C.; Aikawa, M.; Araki, K.; Choi, S.-K.; Itaya, M.; Shindo, K.; Misawa, N. Heterologous Production of Novel and Rare C30-Carotenoids Using Planococcus Carotenoid Biosynthesis Genes. Microb. Cell Fact. 2021,20, 194. [CrossRef] 111. Bech, P.K.; Lysdal, K.L.; Gram, L.; Bentzon-Tilia, M.; Strube, M.L. Marine Sediments Hold an Untapped Potential for Novel Taxonomic and Bioactive Bacterial Diversity. mSystems 2020,5, e00782-20. [CrossRef] 112. Joint, I.; Mühling, M.; Querellou, J. Culturing Marine Bacteria—An Essential Prerequisite for Biodiscovery. Microb. Biotechnol. 2010,3, 564–575. [CrossRef] 113. Overmann, J.; Lepleux, C. Marine Bacteria and Archaea: Diversity, Adaptations, and Culturability. In The Marine Microbiome; Springer International Publishing: Berlin, Germany, 2016; pp. 21–55. 114. Matallana-Surget, S.; Joux, F.; Lebaron, P.; Cavicchioli, R. Isolement et Caractérisation de Bactéries Marines Oligotrophes. J. Soc. Biol. 2007,201, 41–50. [CrossRef] [PubMed] 115. Rygaard, A.M.; Thøgersen, M.S.; Nielsen, K.F.; Gram, L.; Bentzon-Tilia, M. Effects of Gelling Agent and Extracellular Signaling Molecules on the Culturability of Marine Bacteria. Appl. Environ. Microbiol. 2017,83, e00243-17. [CrossRef] 116. Stewart, E.J. Growing Unculturable Bacteria. J. Bacteriol. 2012,194, 4151–4160. [CrossRef] 117. Kato, S.; Yamagishi, A.; Daimon, S.; Kawasaki, K.; Tamaki, H.; Kitagawa, W.; Abe, A.; Tanaka, M.; Sone, T.; Asano, K.; et al. Isolation of Previously Uncultured Slow-Growing Bacteria by Using a Simple Modification in the Preparation of Agar Media. Appl. Environ. Microbiol. 2018,84, e00807-18. [CrossRef] 118. Ben-Dov, E.; Kramarsky-Winter, E.; Kushmaro, A. An in Situ Method for Cultivating Microorganisms Using a Double Encapsulation Technique. FEMS Microbiol. Ecol. 2009,68, 363–371. [CrossRef] [PubMed] 119. Manca, F.; Mulà, C.; Gustafsson, C.; Mauri, A.; Roslin, T.; Thomas, D.N.; Benedetti-Cecchi, L.; Norkko, A.; Strona, G. Unveiling the Complexity and Ecological Function of Aquatic Macrophyte—Animal Networks in Coastal Ecosystems. Biol. Rev. 2022 , 97, 1306–1324. [CrossRef] [PubMed] 120. Steneck, R.S.; Graham, M.H.; Bourque, B.J.; Corbett, D.; Erlandson, J.M.; Estes, J.A.; Tegner, M.J. Kelp Forest Ecosystems: Biodiversity, Stability, Resilience and Future. Environ. Conserv. 2002,29, 436–459. [CrossRef] 121. Singh, C.L.; Huggett, M.J.; Lavery, P.S.; Säwström, C.; Hyndes, G.A. Kelp-Associated Microbes Facilitate Spatial Subsidy in a Detrital-Based Food Web in a Shoreline Ecosystem. Front. Mar. Sci. 2021,8, 678222. [CrossRef] Mar. Drugs 2023,21, 340 38 of 45 122. Lotze, H.K.; Milewski, I.; Fast, J.; Kay, L.; Worm, B. Ecosystem-Based Management of Seaweed Harvesting. Bot. Mar. 2019 , 62, 395–409. [CrossRef] 123. Tano, S.A.; Eggertsen, M.; Wikström, S.A.; Berkström, C.; Buriyo, A.S.; Halling, C. Tropical Seaweed Beds as Important Habitats for Juvenile Fish. Mar. Freshw. Res. 2017,68, 1921. [CrossRef] 124. Yong, W.T.L.; Thien, V.Y.; Rupert, R.; Rodrigues, K.F. Seaweed: A Potential Climate Change Solution. Renew. Sustain. Energy Rev. 2022,159, 112222. [CrossRef] 125. Costanza, R.; de Groot, R.; Sutton, P.; van der Ploeg, S.; Anderson, S.J.; Kubiszewski, I.; Farber, S.; Turner, R.K. Changes in the Global Value of Ecosystem Services. Glob. Environ. Chang. 2014,26, 152–158. [CrossRef] 126. McGlathery, K.; Sundbäck, K.; Anderson, I. Eutrophication in Shallow Coastal Bays and Lagoons: The Role of Plants in the Coastal Filter. Mar. Ecol. Prog. Ser. 2007,348, 1–18. [CrossRef] 127. Watanabe, K.; Yoshida, G.; Hori, M.; Umezawa, Y.; Moki, H.; Kuwae, T. Macroalgal Metabolism and Lateral Carbon Flows Can Create Significant Carbon Sinks. Biogeosciences 2020,17, 2425–2440. [CrossRef] 128. Kim, S.-K.; Pangestuti, R. Biological Activities and Potential Health Benefits of Fucoxanthin Derived from Marine Brown Algae. Adv. Food Nutr. Res. 2011,64, 111–128. [CrossRef] 129. Larkum, A.W.D.; Kühl, M. Chlorophyll d: The Puzzle Resolved. Trends Plant Sci. 2005,10, 355–357. [CrossRef] [PubMed] 130. Clark, M.; Macdiarmid, J.; Jones, A.D.; Ranganathan, J.; Herrero, M.; Fanzo, J. The Role of Healthy Diets in Environmentally Sustainable Food Systems. Food Nutr. Bull. 2020,41, 31S–58S. [CrossRef] 131. WHO; FAO. Sustainable Healthy Diets: Guiding Principles; WHO: Geneva, Switzerland, 2019; ISBN 9789241516648. 132. Eismann, A.I.; Perpetuo Reis, R.; Ferreira da Silva, A.; Negrão Cavalcanti, D. Ulva spp. Carotenoids: Responses to Environmental Conditions. Algal Res. 2020,48, 101916. [CrossRef] 133. Xie, X.; Lu, X.; Wang, L.; He, L.; Wang, G. High Light Intensity Increases the Concentrations of β -Carotene and Zeaxanthin in Marine Red Macroalgae. Algal Res. 2020,47, 101852. [CrossRef] 134. Quitério, E.; Grosso, C.; Ferraz, R.; Delerue-Matos, C.; Soares, C. A Critical Comparison of the Advanced Extraction Techniques Applied to Obtain Health-Promoting Compounds from Seaweeds. Mar. Drugs 2022,20, 677. [CrossRef] 135. Hasselström, L.; Thomas, J.-B.E. A Critical Review of the Life Cycle Climate Impact in Seaweed Value Chains to Support Carbon Accounting and Blue Carbon Financing. Clean. Environ. Syst. 2022,6, 100093. [CrossRef] 136. Koesling, M.; Kvadsheim, N.P.; Halfdanarson, J.; Emblemsvåg, J.; Rebours, C. Environmental Impacts of Protein-Production from Farmed Seaweed: Comparison of Possible Scenarios in Norway. J. Clean. Prod. 2021,307, 127301. [CrossRef] 137. Hentati, F.; Tounsi, L.; Djomdi, D.; Pierre, G.; Delattre, C.; Ursu, A.V.; Fendri, I.; Abdelkafi, S.; Michaud, P. Bioactive Polysaccharides from Seaweeds. Molecules 2020,25, 3152. [CrossRef] 138. El-Beltagi, H.S.; Mohamed, A.A.; Mohamed, H.I.; Ramadan, K.M.A.; Barqawi, A.A.; Mansour, A.T. Phytochemical and Potential Properties of Seaweeds and Their Recent Applications: A Review. Mar. Drugs 2022,20, 342. [CrossRef] [PubMed] 139. Din, N.A.S.; Mohd Alayudin, ‘A.S.; Sofian-Seng, N.-S.; Rahman, H.A.; Mohd Razali, N.S.; Lim, S.J.; Wan Mustapha, W.A. Brown Algae as Functional Food Source of Fucoxanthin: A Review. Foods 2022,11, 2235. [CrossRef] [PubMed] 140. Mikami, K.; Hosokawa, M. Biosynthetic Pathway and Health Benefits of Fucoxanthin, an Algae-Specific Xanthophyll in Brown Seaweeds. Int. J. Mol. Sci. 2013,14, 13763–13781. [CrossRef] [PubMed] 141. Zarekarizi, A.; Hoffmann, L.; Burritt, D. Approaches for the Sustainable Production of Fucoxanthin, a Xanthophyll with Potential Health Benefits. J. Appl. Phycol. 2019,31, 281–299. [CrossRef] 142. Shen, Y.; Li, J.; Gu, R.; Yue, L.; Wang, H.; Zhan, X.; Xing, B. Carotenoid and Superoxide Dismutase Are the Most Effective Antioxidants Participating in ROS Scavenging in Phenanthrene Accumulated Wheat Leaf. Chemosphere 2018 , 197, 513–525. [CrossRef] [PubMed] 143. Van den Hoek, C.; Mann, D.G.; Jahns, H.M. Algae. An Introduction to Phycology; Guiry, M.D., Ed.; Issue 2; Cambridge University Press: Cambridge, UK, 1995; ISBN 0521304199. 144. Matsuno, T. Aquatic Animal Carotenoids. Fish. Sci. 2001,67, 771–783. [CrossRef] 145. Ren, Y.; Sun, H.; Deng, J.; Huang, J.; Chen, F. Carotenoid Production from Microalgae: Biosynthesis, Salinity Responses and Novel Biotechnologies. Mar. Drugs 2021,19, 713. [CrossRef] 146. Fukushima, Y.; Taguchi, C.; Kishimoto, Y.; Kondo, K. Japanese Carotenoid Database with α - and β -Carotene, β -Cryptoxanthin, Lutein, Zeaxanthin, Lycopene, and Fucoxanthin and Intake in Adult Women. Int. J. Vitam. Nutr. Res. 2023 ,93, 42–53. [CrossRef] 147. Nomura, M.; Kamogawa, H.; Susanto, E.; Kawagoe, C.; Yasui, H.; Saga, N.; Hosokawa, M.; Miyashita, K. Seasonal Variations of Total Lipids, Fatty Acid Composition, and Fucoxanthin Contents of Sargassum Horneri (Turner) and Cystoseira Hakodatensis (Yendo) from the Northern Seashore of Japan. J. Appl. Phycol. 2013,25, 1159–1169. [CrossRef] 148. Terasaki, M.; Hirose, A.; Narayan, B.; Baba, Y.; Kawagoe, C.; Yasui, H.; Saga, N.; Hosokawa, M.; Miyashita, K. Evaluation of Recoverable Functional Lipid Components of Several Brown Seaweeds (Phaeophyta) from Japan with Special Reference to Fucoxanthin and Fucosterol Content. J. Phycol. 2009,45, 974–980. [CrossRef] 149. Bhat, I.; Haripriya, G.; Jogi, N.; Mamatha, B.S. Carotenoid Composition of Locally Found Seaweeds of Dakshina Kannada District in India. Algal Res. 2021,53, 102154. [CrossRef] 150. Koizumi, J.; Takatani, N.; Kobayashi, N.; Mikami, K.; Miyashita, K.; Yamano, Y.; Wada, A.; Maoka, T.; Hosokawa, M. Carotenoid Profiling of a Red Seaweed Pyropia yezoensis: Insights into Biosynthetic Pathways in the Order Bangiales. Mar. Drugs 2018,16, 426. [CrossRef] [PubMed] Mar. Drugs 2023,21, 340 39 of 45 151. Duarte, C.M.; Holmer, M.; Olsen, Y.; Soto, D.; Marbà, N.; Guiu, J.; Black, K.; Karakassis, I. Will the Oceans Help Feed Humanity? Bioscience 2009,59, 967–976. [CrossRef] 152. Duarte, C.M.; Bruhn, A.; Krause-Jensen, D. A Seaweed Aquaculture Imperative to Meet Global Sustainability Targets. Nat. Sustain. 2022,5, 185–193. [CrossRef] 153. Rebours, C.; Marinho-Soriano, E.; Zertuche-González, J.A.; Hayashi, L.; Vásquez, J.A.; Kradolfer, P.; Soriano, G.; Ugarte, R.; Abreu, M.H.; Bay-Larsen, I.; et al. Seaweeds: An Opportunity for Wealth and Sustainable Livelihood for Coastal Communities. J. Appl. Phycol. 2014,26, 1939–1951. [CrossRef] [PubMed] 154. Barbier, M.; Araújo, R.; Rebours, C.; Jacquemin, B.; Holdt, S.L.; Charrier, B. Development and Objectives of the PHYCOMORPH European Guidelines for the Sustainable Aquaculture of Seaweeds (PEGASUS). Bot. Mar. 2020,63, 5–16. [CrossRef] 155. Smale, D.A.; Pessarrodona, A.; King, N.; Burrows, M.T.; Yunnie, A.; Vance, T.; Moore, P. Environmental Factors Influencing Primary Productivity of the Forest-Forming Kelp Laminaria Hyperborea in the Northeast Atlantic. Sci. Rep. 2020,10, 12161. [CrossRef] 156. White, L.; Loisel, S.; Sevin, L.; Davoult, D. In Situ Estimates of Kelp Forest Productivity in Macro-tidal Environments. Limnol. Oceanogr. 2021,66, 4227–4239. [CrossRef] 157. Bae, M.; Kim, M.-B.; Park, Y.-K.; Lee, J.-Y. Health Benefits of Fucoxanthin in the Prevention of Chronic Diseases. Biochim. Biophys. Acta–Mol. Cell Biol. Lipids 2020,1865, 158618. [CrossRef] 158. Hosokawa, M. Health-Promoting Functions of the Marine Carotenoid Fucoxanthin. Adv. Exp. Med. Biol. 2021 ,1261, 273–284. [CrossRef] 159. Liu, M.; Li, W.; Chen, Y.; Wan, X.; Wang, J. Fucoxanthin: A Promising Compound for Human Inflammation-Related Diseases. Life Sci. 2020,255, 117850. [CrossRef] 160. Olsthoorn, S.E.M.; Wang, X.; Tillema, B.; Vanmierlo, T.; Kraan, S.; Leenen, P.J.M.; Mulder, M.T. Brown Seaweed Food Supplementation: Effects on Allergy and Inflammation and Its Consequences. Nutrients 2021,13, 2613. [CrossRef] [PubMed] 161. Kong, Z.-L.; Sudirman, S.; Hsu, Y.-C.; Su, C.-Y.; Kuo, H.-P. Fucoxanthin-Rich Brown Algae Extract Improves Male Reproductive Function on Streptozotocin-Nicotinamide-Induced Diabetic Rat Model. Int. J. Mol. Sci. 2019,20, 4485. [CrossRef] 162. Kong, Z.-L.; Kao, N.-J.; Hu, J.-Y.; Wu, C.-S. Fucoxanthin-Rich Brown Algae Extract Decreases Inflammation and Attenuates Colitis-Associated Colon Cancer in Mice. J. Food Nutr. Res. 2016,4, 137–147. [CrossRef] 163. Wang, P.-T.; Sudirman, S.; Hsieh, M.-C.; Hu, J.-Y.; Kong, Z.-L. Oral Supplementation of Fucoxanthin-Rich Brown Algae Extract Ameliorates Cisplatin-Induced Testicular Damage in Hamsters. Biomed. Pharmacother. 2020,125, 109992. [CrossRef] [PubMed] 164. Yang, Y.-P.; Tong, Q.-Y.; Zheng, S.-H.; Zhou, M.-D.; Zeng, Y.-M.; Zhou, T.-T. Anti-Inflammatory Effect of Fucoxanthin on Dextran Sulfate Sodium-Induced Colitis in Mice. Nat. Prod. Res. 2020,34, 1791–1795. [CrossRef] [PubMed] 165. Sugiura, Y.; Kinoshita, Y.; Usui, M.; Tanaka, R.; Matsushita, T.; Miyata, M. The Suppressive Effect of a Marine Carotenoid, Fucoxanthin, on Mouse Ear Swelling through Regulation of Activities and MRNA Expression of Inflammation-Associated Enzymes. Food Sci. Technol. Res. 2016,22, 227–234. [CrossRef] 166. Tan, C.; Hou, Y. First Evidence for the Anti-Inflammatory Activity of Fucoxanthin in High-Fat-Diet-Induced Obesity in Mice and the Antioxidant Functions in PC12 Cells. Inflammation 2014,37, 443–450. [CrossRef] 167. Jiang, X.; Wang, G.; Lin, Q.; Tang, Z.; Yan, Q.; Yu, X. Fucoxanthin Prevents Lipopolysaccharide-Induced Depressive-like Behavior in Mice via AMPKNF-KB Pathway. Metab. Brain Dis. 2019,34, 431–442. [CrossRef] 168. Miyashita, K.; Hosokawa, M. Fucoxanthin in the Management of Obesity and Its Related Disorders. J. Funct. Foods 2017 , 36, 195–202. [CrossRef] 169. Hitoe, S.; Shimoda, H. Seaweed Fucoxanthin Supplementation Improves Obesity Parameters in Mild Obese Japanese Subjects. Funct. Foods Health Dis. 2017,7, 246. [CrossRef] 170. Hu, L.; Chen, W.; Tian, F.; Yuan, C.; Wang, H.; Yue, H. Neuroprotective Role of Fucoxanthin against Cerebral Ischemic/Reperfusion Injury through Activation of Nrf2/HO-1 Signaling. Biomed. Pharmacother. 2018,106, 1484–1489. [CrossRef] 171. Sun, G.; Xin, T.; Zhang, R.; Liu, C.; Pang, Q. Fucoxanthin Attenuates Behavior Deficits and Neuroinflammatory Response in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinson’s Disease in Mice. Pharmacogn. Mag. 2020,16, 51. [CrossRef] 172. Aziz, E.; Batool, R.; Khan, M.U.; Rauf, A.; Akhtar, W.; Heydari, M.; Rehman, S.; Shahzad, T.; Malik, A.; Mosavat, S.H.; et al. An Overview on Red Algae Bioactive Compounds and Their Pharmaceutical Applications. J. Complement. Integr. Med. 2020 ,17. [CrossRef] 173. Ali, I.; Manzoor, Z.; Koo, J.-E.; Kim, J.-E.; Byeon, S.-H.; Yoo, E.-S.; Kang, H.-K.; Hyun, J.-W.; Lee, N.-H.; Koh, Y.-S. 3-Hydroxy-4,7- Megastigmadien-9-One, Isolated from Ulva Pertusa, Attenuates TLR9-Mediated Inflammatory Response by down-Regulating Mitogen-Activated Protein Kinase and NF-KB Pathways. Pharm. Biol. 2017,55, 435–440. [CrossRef] 174. Young Park, S.; Su Seo, I.; Joo Lee, S.; Pyung Lee, S. Study on the Health Benefits of Brown Algae (Sargassum muticum) in Volunteers. J. Food Nutr. Res. 2015,3, 126–130. [CrossRef] 175. Shih, P.-H.; Shiue, S.-J.; Chen, C.-N.; Cheng, S.-W.; Lin, H.-Y.; Wu, L.-W.; Wu, M.-S. Fucoidan and Fucoxanthin Attenuate Hepatic Steatosis and Inflammation of NAFLD through Modulation of Leptin/Adiponectin Axis. Mar. Drugs 2021 ,19, 148. [CrossRef] [PubMed] 176. Asai, A.; Sugawara, T.; Ono, H.; Nagao, A. Biotransformation of Fucoxanthinol into Amarouciaxanthin A in Mice and HepG2 Cells: Formation and Cytotoxicity of Fucoxanthin Metabolites. Drug Metab. Dispos. 2004,32, 205–211. [CrossRef] 177. Hashimoto, T.; Ozaki, Y.; Taminato, M.; Das, S.K.; Mizuno, M.; Yoshimura, K.; Maoka, T.; Kanazawa, K. The Distribution and Accumulation of Fucoxanthin and Its Metabolites after Oral Administration in Mice. Br. J. Nutr. 2009,102, 242–248. [CrossRef] 178. Hashimoto, T.; Ozaki, Y.; Mizuno, M.; Yoshida, M.; Nishitani, Y.; Azuma, T.; Komoto, A.; Maoka, T.; Tanino, Y.; Kanazawa, K. Pharmacokinetics of Fucoxanthinol in Human Plasma after the Oral Administration of Kombu Extract. Br. J. Nutr. 2012 , 107, 1566–1569. [CrossRef] [PubMed] Mar. Drugs 2023,21, 340 40 of 45 179. Mikami, N. A Protocol for Human Serum Fucoxanthinol Quantitation Using LC-MS/MS System. J. Nutr. Med. Diet Care 2016 , 2, 019. [CrossRef] 180. Novotny, J.A.; Kurilich, A.C.; Britz, S.J.; Clevidence, B.A. Plasma Appearance of Labeled β -Carotene, Lutein, and Retinol in Humans after Consumption of Isotopically Labeled Kale. J. Lipid Res. 2005,46, 1896–1903. [CrossRef] 181. Mohibbullah, M.; Haque, M.N.; Sohag, A.A.M.; Hossain, M.T.; Zahan, M.S.; Uddin, M.J.; Hannan, M.A.; Moon, I.S.; Choi, J.-S. A Systematic Review on Marine Algae-Derived Fucoxanthin: An Update of Pharmacological Insights. Mar. Drugs 2022,20, 279. [CrossRef] [PubMed] 182. Irisson, J.-O.; Ayata, S.-D.; Lindsay, D.J.; Karp-Boss, L.; Stemmann, L. Machine Learning for the Study of Plankton and Marine Snow from Images. Ann. Rev. Mar. Sci. 2022,14, 277–301. [CrossRef] 183. Fernández, F.G.A.; Reis, A.; Wijffels, R.H.; Barbosa, M.; Verdelho, V.; Llamas, B. The Role of Microalgae in the Bioeconomy. N. Biotechnol. 2021,61, 99–107. [CrossRef] [PubMed] 184. Fabris, M.; Abbriano, R.M.; Pernice, M.; Sutherland, D.L.; Commault, A.S.; Hall, C.C.; Labeeuw, L.; McCauley, J.I.; Kuzhiuparambil, U.; Ray, P.; et al. Emerging Technologies in Algal Biotechnology: Toward the Establishment of a Sustainable, Algae-Based Bioeconomy. Front. Plant Sci. 2020,11, 279. [CrossRef] [PubMed] 185. Adarme-Vega, T.C.; Lim, D.K.Y.; Timmins, M.; Vernen, F.; Li, Y.; Schenk, P.M. Microalgal Biofactories: A Promising Approach towards Sustainable Omega-3 Fatty Acid Production. Microb. Cell Fact. 2012,11, 96. [CrossRef] 186. Russell, C.; Rodriguez, C.; Yaseen, M. High-Value Biochemical Products & Applications of Freshwater Eukaryotic Microalgae. Sci. Total Environ. 2022,809, 151111. [CrossRef] 187. López-Sánchez, A.; Silva-Gálvez, A.L.; Aguilar-Juárez, Ó.; Senés-Guerrero, C.; Orozco-Nunnelly, D.A.; Carrillo-Nieves, D.; Gradilla-Hernández, M.S. Microalgae-Based Livestock Wastewater Treatment (MbWT) as a Circular Bioeconomy Approach: Enhancement of Biomass Productivity, Pollutant Removal and High-Value Compound Production. J. Environ. Manag. 2022 , 308, 114612. [CrossRef] 188. Srimongkol, P.; Sangtanoo, P.; Songserm, P.; Watsuntorn, W.; Karnchanatat, A. Microalgae-Based Wastewater Treatment for Developing Economic and Environmental Sustainability: Current Status and Future Prospects. Front. Bioeng. Biotechnol. 2022 , 10, 904046. [CrossRef] 189. Verma, R.; Suthar, S.; Chand, N.; Mutiyar, P.K. Phycoremediation of Milk Processing Wastewater and Lipid-Rich Biomass Production Using Chlorella vulgaris under Continuous Batch System. Sci. Total Environ. 2022,833, 155110. [CrossRef] 190. Iliopoulou, A.; Zkeri, E.; Panara, A.; Dasenaki, M.; Fountoulakis, M.S.; Thomaidis, N.S.; Stasinakis, A.S. Treatment of Different Dairy Wastewater with Chlorella sorokiniana: Removal of Pollutants and Biomass Characterization. J. Chem. Technol. Biotechnol. 2022,97, 3193–3201. [CrossRef] 191. León-Vaz, A.; León, R.; Díaz-Santos, E.; Vigara, J.; Raposo, S. Using Agro-Industrial Wastes for Mixotrophic Growth and Lipids Production by the Green Microalga Chlorella sorokiniana.N. Biotechnol. 2019,51, 31–38. [CrossRef] [PubMed] 192. Zhou, T.; Li, X.; Zhang, Q.; Dong, S.; Liu, H.; Liu, Y.; Chaves, A.V.; Ralph, P.J.; Ruan, R.; Wang, Q. Ecotoxicological Response of Spirulina Platensis to Coexisted Copper and Zinc in Anaerobic Digestion Effluent. Sci. Total Environ. 2022,837, 155874. [CrossRef] [PubMed] 193. Han, T.; Lu, H.; Zhao, Y.; Xu, H.; Zhang, Y.; Li, B. Two-Step Strategy for Obtaining Dunaliella sp. Biomass and β -Carotene from Anaerobically Digested Poultry Litter Wastewater. Int. Biodeterior. Biodegradation 2019,143, 104714. [CrossRef] 194. Shah, M.M.R. Astaxanthin Production by Microalgae Haematococcus pluvialis through Wastewater Treatment: Waste to Resource. In Application of Microalgae in Wastewater Treatment; Springer International Publishing: Berlin, Germany, 2019; pp. 17–39. 195. Sathasivam, R.; Radhakrishnan, R.; Hashem, A.; Abd_Allah, E.F. Microalgae Metabolites: A Rich Source for Food and Medicine. Saudi J. Biol. Sci. 2019,26, 709–722. [CrossRef] [PubMed] 196. Patel, A.K.; Tambat, V.S.; Chen, C.-W.; Chauhan, A.S.; Kumar, P.; Vadrale, A.P.; Huang, C.-Y.; Dong, C.-D.; Singhania, R.R. Recent Advancements in Astaxanthin Production from Microalgae: A Review. Bioresour. Technol. 2022,364, 128030. [CrossRef] 197. Muhammad, G.; Butler, T.O.; Chen, B.; Lv, Y.; Xiong, W.; Zhao, X.; Solovchenko, A.E.; Zhao, A.; Mofijur, M.; Xu, J.; et al. Sustainable Production of Lutein-an Underexplored Commercially Relevant Pigment from Microalgae. Biomass Convers. Biorefinery 2022, 1–22. [CrossRef] 198. Gong, M.; Bassi, A. Investigation of Chlorella Vulgaris UTEX 265 Cultivation under Light and Low Temperature Stressed Conditions for Lutein Production in Flasks and the Coiled Tree Photo-Bioreactor (CTPBR). Appl. Biochem. Biotechnol. 2017 , 183, 652–671. [CrossRef] 199. Safafar, H.; Uldall Nørregaard, P.; Ljubic, A.; Møller, P.; Løvstad Holdt, S.; Jacobsen, C. Enhancement of Protein and Pigment Content in Two Chlorella Species Cultivated on Industrial Process Water. J. Mar. Sci. Eng. 2016,4, 84. [CrossRef] 200. Sun, H.; Yang, S.; Zhao, W.; Kong, Q.; Zhu, C.; Fu, X.; Zhang, F.; Liu, Z.; Zhan, Y.; Mou, H.; et al. Fucoxanthin from Marine Microalgae: A Promising Bioactive Compound for Industrial Production and Food Application. Crit. Rev. Food Sci. Nutr. 2022, 1–17. [CrossRef] 201. Damergi, E.; Schwitzguébel, J.-P.; Refardt, D.; Sharma, S.; Holliger, C.; Ludwig, C. Extraction of Carotenoids from Chlorella vulgaris Using Green Solvents and Syngas Production from Residual Biomass. Algal Res. 2017,25, 488–495. [CrossRef] 202. Li, Y.; Sun, H.; Wu, T.; Fu, Y.; He, Y.; Mao, X.; Chen, F. Storage Carbon Metabolism of Isochrysis Zhangjiangensis under Different Light Intensities and Its Application for Co-Production of Fucoxanthin and Stearidonic Acid. Bioresour. Technol. 2019,282, 94–102. [CrossRef] [PubMed] Mar. Drugs 2023,21, 340 41 of 45 203. Martínez, J.M.; Gojkovic, Z.; Ferro, L.; Maza, M.; Álvarez, I.; Raso, J.; Funk, C. Use of Pulsed Electric Field Permeabilization to Extract Astaxanthin from the Nordic Microalga Haematococcus pluvialis.Bioresour. Technol. 2019 ,289, 121694. [CrossRef] [PubMed] 204. Safafar, H.; Van Wagenen, J.; Møller, P.; Jacobsen, C. Carotenoids, Phenolic Compounds and Tocopherols Contribute to the Antioxidative Properties of Some Microalgae Species Grown on Industrial Wastewater. Mar. Drugs 2015,13, 7339–7356. [CrossRef] [PubMed] 205. León-Vaz, A.; León, R.; Vigara, J.; Funk, C. Exploring Nordic Microalgae as a Potential Novel Source of Antioxidant and Bioactive Compounds. N. Biotechnol. 2023,73, 1–8. [CrossRef] 206. Yusof, Z.; Khong, N.M.H.; Choo, W.S.; Foo, S.C. Opportunities for the Marine Carotenoid Value Chain from the Perspective of Fucoxanthin Degradation. Food Chem. 2022,383, 132394. [CrossRef] 207. Loke Show, P. Global Market and Economic Analysis of Microalgae Technology: Status and Perspectives. Bioresour. Technol. 2022 , 357, 127329. [CrossRef] 208. Jannel, S.; Caro, Y.; Bermudes, M.; Petit, T. Novel Insights into the Biotechnological Production of Haematococcus pluvialis-Derived Astaxanthin: Advances and Key Challenges to Allow Its Industrial Use as Novel Food Ingredient. J. Mar. Sci. Eng. 2020 ,8, 789. [CrossRef] 209. Capelli, B.; Bagchi, D.; Cysewski, G.R. Synthetic Astaxanthin Is Significantly Inferior to Algal-Based Astaxanthin as an Antioxidant and May Not Be Suitable as a Human Nutraceutical Supplement. Nutrafoods 2013,12, 145–152. [CrossRef] 210. Singh, R.V.; Sambyal, K. An Overview of β -Carotene Production: Current Status and Future Prospects. Food Biosci. 2022 , 47, 101717. [CrossRef] 211. Mohebi Najafabadi, M.; Naeimpoor, F. Boosting β -Carotene and Storage Materials Productivities by Two-Stage Mixed and Monochromatic Exposure Stresses on Dunaliella salina.Int. J. Phytoremediation 2022,25, 609–620. [CrossRef] [PubMed] 212. Prieto, A.; Pedro Cañavate, J.; García-González, M. Assessment of Carotenoid Production by Dunaliella salina in Different Culture Systems and Operation Regimes. J. Biotechnol. 2011,151, 180–185. [CrossRef] [PubMed] 213. Calijuri, M.L.; Silva, T.A.; Magalhães, I.B.; de Paula Pereira, A.S.A.; Marangon, B.B.; de Assis, L.R.; Lorentz, J.F. Bioproducts from Microalgae Biomass: Technology, Sustainability, Challenges and Opportunities. Chemosphere 2022,305, 135508. [CrossRef] 214. Poojary, M.; Barba, F.; Aliakbarian, B.; Donsì, F.; Pataro, G.; Dias, D.; Juliano, P. Innovative Alternative Technologies to Extract Carotenoids from Microalgae and Seaweeds. Mar. Drugs 2016,14, 214. [CrossRef] [PubMed] 215. Wang, M.; Morón-Ortiz, Á.; Zhou, J.; Benítez-González, A.; Mapelli-Brahm, P.; Meléndez-Martínez, A.J.; Barba, F.J. Effects of Pressurized Liquid Extraction with Dimethyl Sulfoxide on the Recovery of Carotenoids and Other Dietary Valuable Compounds from the Microalgae Spirulina, chlorella and Phaeodactylum tricornutum.Food Chem. 2022,405, 134885. [CrossRef] 216. Monapathi, M.E.; Bezuidenhout, C.C.; James Rhode, O.H. Aquatic Yeasts: Diversity, Characteristics and Potential Health Implications. J. Water Health 2020,18, 91–105. [CrossRef] [PubMed] 217. Nagahama, T. Yeast Biodiversity in Freshwater, Marine and Deep-Sea Environments BT–Biodiversity and Ecophysiology of Yeasts. In Biodiversity and Ecophysiology of Yeasts; Péter, G., Rosa, C., Eds.; Springer: Berlin/Heidelberg, Germany, 2006; pp. 241–262. ISBN 978-3-540-30985-7. 218. Garmendia, G.; Alvarez, A.; Villarreal, R.; Martínez-Silveira, A.; Wisniewski, M.; Vero, S. Fungal Diversity in the Coastal Waters of King George Island (Maritime Antarctica). World J. Microbiol. Biotechnol. 2021,37, 142. [CrossRef] 219. Vero, S.; Garmendia, G.; Martínez-Silveira, A.; Cavello, I.; Wisniewski, M. Yeast Activities Involved in Carbon and Nitrogen Cycles in Antarctica. In The Ecological Role of Micro-Organisms in the Antarctic Environment; Castro-Sowinski, S., Ed.; Springer Polar Sciences: Berlin/Heidelberg, Germany, 2019; pp. 45–64. ISBN 978-3-030-02785-8. 220. Jafari, N.; Soudi, M.R.; Kasra-Kermanshahi, R. Biodegradation Perspectives of Azo Dyes by Yeasts. Microbiology 2014 , 83, 484–497. [CrossRef] 221. Ruscasso, F.; Cavello, I.; Butler, M.; Loveira, E.L.; Curutchet, G.; Cavalitto, S. Biodegradation and Detoxification of Reactive Orange 16 by Candida Sake 41E. Bioresour. Technol. Rep. 2021,15, 100726. [CrossRef] 222. Segal-Kischinevzky, C.; Romero-Aguilar, L.; Alcaraz, L.D.; López-Ortiz, G.; Martínez-Castillo, B.; Torres-Ramírez, N.; Sandoval, G.; González, J. Yeasts Inhabiting Extreme Environments and Their Biotechnological Applications. Microorganisms 2022 ,10, 794. [CrossRef] 223. Libkind, D.; Moliné, M.; Sampaio, J.P.; Van Broock, M. Yeasts from High-Altitude Lakes: Influence of UV Radiation. FEMS Microbiol. Ecol. 2009,69, 353–362. [CrossRef] [PubMed] 224. Moliné, M.; Flores, M.R.; Libkind, D.; del Carmen Carmen Diéguez, M.; Farías, M.E.; van Broock, M. Photoprotection by Carotenoid Pigments in the Yeast Rhodotorula mucilaginosa: The Role of Torularhodin. Photochem. Photobiol. Sci. 2010,9, 1145–1151. [CrossRef] 225. Ueno, R.; Hamada-Sato, N.; Ishida, M.; Urano, N. Potential of Carotenoids in Aquatic Yeasts as a Phylogenetically Reliable Marker and Natural Colorant for Aquaculture. Biosci. Biotechnol. Biochem. 2011,75, 1654–1661. [CrossRef] 226. Mata-Gómez, L.C.; Mapelli-Brahm, P.; Meléndez-Martínez, A.J.; Méndez-Zavala, A.; Morales-Oyervides, L.; Montañez, J. Microbial Carotenoid Synthesis Optimization in Goat Cheese Whey Using the Robust Taguchi Method: A Sustainable Approach to Help Tackle Vitamin A Deficiency. Foods 2023,12, 658. [CrossRef] 227. Hernández-Almanza, A.; Montañez, J.; Martínez, G.; Aguilar-Jiménez, A.; Contreras-Esquivel, J.C.; Aguilar, C.N. Lycopene: Progress in Microbial Production. Trends Food Sci. Technol. 2016,56, 142–148. [CrossRef] 228. Cardoso, L.A.C.; Jäckel, S.; Karp, S.G.; Framboisier, X.; Chevalot, I.; Marc, I. Improvement of Sporobolomyces ruberrimus Carotenoids Production by the Use of Raw Glycerol. Bioresour. Technol. 2016,200, 374–379. [CrossRef] 229. Ambati, R.; Phang, S.-M.; Ravi, S.; Aswathanarayana, R. Astaxanthin: Sources, Extraction, Stability, Biological Activities and Its Commercial Applications—A Review. Mar. Drugs 2014,12, 128–152. [CrossRef] [PubMed]