Evaluating the anti-inflammatory and antioxidant efficacy of complementary andalternative medicines (CAM) used for management of inflammatory bowel disease:a comprehensive review

Redox Report Communications in Free Radical Research ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/yrer20 Evaluating the anti-inflammatory and antioxidant efficacy of complementary and alternative medicines (CAM) used for management of inflammatory bowel disease: a comprehensive review Sia Shin , Siqi Chen , Kangzhe Xie , Suehad Abou Duhun & Tamara OrtizCerda To cite this article: Sia Shin , Siqi Chen , Kangzhe Xie , Suehad Abou Duhun & Tamara OrtizCerda (2025) Evaluating the anti-inflammatory and antioxidant efficacy of complementary and alternative medicines (CAM) used for management of inflammatory bowel disease: a comprehensive review, Redox Report, 30:1, 2471737, DOI: 10.1080/13510002.2025.2471737 To link to this article: https://doi.org/10.1080/13510002.2025.2471737 © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Published online: 08 Mar 2025. Submit your article to this journal Article views: 962 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=yrer20 REVIEW ARTICLE Evaluating the anti-inflammatory and antioxidant efficacy of complementary and alternative medicines (CAM) used for management of inflammatory bowel disease: a comprehensive review Sia Shin a , Siqi Chen b , Kangzhe Xie b , Suehad Abou Duhun b and Tamara Ortiz-Cerda b,c a Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; b School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; c Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain ABSTRACT Inflammatory bowel disease (IBD) is a chronic autoimmune condition whose pathogenesis has not been fully elucidated, and current treatments are not definitive and often carry several side effects. The Complementary and Alternative Medicine (CAM) offers a new approach to conventional medicine. However, their clinical application and mechanisms remain limited. Objective: The aim of this review is to evaluate the anti-inflammatory, impact on microbiota and antioxidant efficacy of currently available CAM for IBD. Methods: The literature collection was obtained from Google Scholar, MEDLINE, PubMed and Web of Science (WOS). Studies in both human and animal models, published in English language between 2018 and 2024, were selected. Sixty-seven studies were included in the current review after inclusion and exclusion screening processes. Results: Mostly, studies showed significant anti-inflammatory, gut microbiota restoring, antioxidant effects of polyphenols, polysaccharides, emodin, short-chain fatty acids (SCFA; including butyrate, propionate and acetate), and probiotics although some contrasting results were noted. Current evidence shows that polyphenols exhibit the most consistent result in alleviating IBD pathophysiology, primarily due to their significant SCFA-elevating effect. Discussion: Future studies may focus on human studies, narrowing down on individual factors which may change natural product’s metabolism. Further research studies are also essential to obtain therapeutic recommendations. Abbreviations: 4HNE, 4-hydroxynonenal; 5-ASA, 5-aminosalicylates; ABX, antibiotic; ACAT1, acetylCoA acetyltransferase 1; AIEC, a strain of adherent-invasive E. coli; AKT, protein kinase B; AMP, atractylodes macrocephala Koidz polysaccharide; AOM, azoxymethane; AOS, alginate oligosaccharides; APS3a, non-honey-processed Astragalus polysaccharides; Arg-1, arginase 1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; ATB, antibiotic properties; BCFA, branched-chain fatty acids; BDH1, 3-hydroxybutyrate dehydrogenase I; BHB, Bhydroxybutyrate; BI, bilobalide; BMDMs, bone marrow-derived macrophages; CA, caffeic acid; CACC, colitis-associated colorectal cancer; CAM, complementary and alternative medicine; cAMP, cyclic AMP; CAT, catalase; CC, colorectal cancer; CCL2, chemokine ligand 2; CD, Crohn’s disease; CFU, colony-forming units; CGA, chlorogenic acid; Chil3, chiinase-like protein; CitH3, citrullinated H3; CLP, cecal ligation and puncture; COVID, coronavirus disease-2019; COX-2, cyclooxygenase-2; CP, calprotectin; CRP, C-reactive protein; CXCL-1, chemokine ligand 1; CXCR2, interleukin 8 receptor; Cy, cyclophosphamide; Dact3, dishevelled binding antagonist of beta catenin 3; DAI, disease activity index; DAMPs, damage associated molecular patterns; DAO, diamine oxidase; DAPP, dried apple peel powder; DCA, dichloroacetate; DCs, dendritic cells; DNBS, dinitrobenzene sulfonic acid; DO, Dendrobium officinaleon; DSS, dextran sodium sulfate; E. coli,Escherichia coli; EA, ellagic acid; EC, Eucheuma cottonii; EcN, Escherichia coli Nissle; EGCG, epigallocatechin-3-gallate; EGF, epidermal growth factor; EMO/PSM NPs, emodin-loaded poly (DL-lactide-co-glycolide)/ Eudragit S100/montmorillonite nanoparticles; Emodin, 1,3,8-trihidroxy-6-methyl-anthraquinone; EPS1-1, Rhizopus nigricans extracellular polysaccharide; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; F/B, Firmicute to Bacteroidete; F12, probiotic microparticles; FA, ferulic acid; FCP, fecal calprotectin; FFAR, free fatty acid receptors; FMT, fecal microbiota transplant; FOXO3, forkhead box O3; GM-CSF, granulocyte-macrophage colony-stimulating factor; GPCRs, G protein-coupled receptors; GSDMD, Gasdermin D; GSH-PX, glutathione-PX; GSH, glutathione; GSP, grape seed proanthocyanidin; GST, glutathione-S-transferase; H 2 O 2 , hydrogen peroxide; H 2 S, hydrogen sulfide; HAPS3a, honey-processed Astragalus polysaccharides; HAW1, Crataegis pinnatifida (Hawthorn); HC, healthy volunteers; HDAC, histone deacetylase; HE, Hericium erinaceus; HMGB1, high mobility group protein B; HMGCS2, 3-hydroxymethylglutaryl-CoA synthase 2; HO-1, heme oxygenase-1; hu-FMT, human fecal microbiota transplantation; i.v, intra-vascular; IBD, inflammatory bowel disease; IC, indeterminate colitis; IFN, interferon; IKK, inhibitory Kappa B kinase α; IL, interleukin; INCLD, international cohort on lifestyle determinants; iNOS, inducible nitric KEYWORDS Inflammatory bowel disease; polyphenols; polysaccharides; short-chain fatty acids; probiotics; microbiota; antioxidants; anti-inflammatory © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. CONTACT Tamara Ortiz-Cerda [email protected] Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain REDOX REPORT 2025, VOL. 30, NO. 1, 2471737 https://doi.org/10.1080/13510002.2025.2471737 oxide synthase; JAK2, janus kinase 2; JNK, c-Jun N-terminal kinase; LA-GOS, Lupinus albus α-galactooligosaccharides; Lac@HDP, Lactobacillus acdiphilus@Hyaluronic acid grafted with dopaine protected by phenylboric acid; LC3, microtubule-associated protein 1A/1B-light chain 3; LC3II/I, isoform II/I of microtubule-associated protein 1 light chain 3; LCN2, lipocalin-2; LPF, live P. freudenreichii KCTC 1063; LPO, lipid peroxidase level; MAPK, mitogen activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; Mip2, macrophage inflammatory protein 2; mix-sup, supernatant mixture; MPO, myeloperoxidase; Mt., mitochondria; MUC, mucin; MYD88, myeloid differentiation primary response 88; n/i, no information provided; NaB, sodium butyrate; NE, neutrophil elastase; NET, neutrophil extracellular trap; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; NFATC, nuclear factor of activated T cells; NK, natural killer; NKU556Fe, Lactobacillus alimentarius NKU556 iron-enriching from Chinese fermented food; NLRP3, nucleotide-binding domain, leucine-rich containing family, pyrin domain containing 3; NO, nitric oxide; NO 2 , nitrite; NO 3 , nitrate; Noni-PLS, isolated polysaccharide from Morinda citrifolia Linn; NPs, nanoparticles; NQO1, NADH-quinone reductase; Nrf-2, nuclear factor erythroid 2-related factor 2; Olfr78, olfactory receptor 78; ORY, food-derived oryzanol; OTUs, operational taxonomic units; p-IkB, phospho-I kappa B kinase; PCC, protein carbonyl compounds; PCNA, proliferating cell nuclear antigen; PDGF, platelet-derived growth factor; Poly P, long-chain polyphosphate; PPM, parts per million; PRISMA, preferred reporting items for systematic review and meta-analysis; PRR, pattern recognition receptors; Pt-Lipid@EcN, liposome-coated Escherichia coli Nissle (EcN) 1917; PYY, peptide YY; Redox, reduction–oxidation; RGal, Rhamnogalacturonan; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCFA, short-chain fatty acids; SDEA, Selaginella doederleinii Heiron etyl acetate; SFE, Sophora flavescens extract; sIgA, secretory immunoglobulin A; SIRT1, Sirtuin 1; SOD, superoxide dismutase; SPDEF, SAM pointed domain containing ETS transcription factor; SPFC, supernatant of the P. freudenreichii culture; SRB, sulfate-reducing bacteria; STAT3, signal transducer and activator of transcription 3; T-AOC, total antioxidant capacity; TED, transemodin dianthrones; TFF-3, trefoil factor 3; TFPS, Camellia sinensis L. pectic heteropolysaccharides; TGF-β:transforming growth factor-β; TLR: toll-like receptors; TNBS: trinitrobenzene sulfonic acid; TNF-α: tumor necrosis factor; Treg; T regulatory; UC: ulcerative colitis; UCDAI: UC disease activity index; UroA: Urolithin A; VEGF: vascular endothelial growth factor; W: week; ZAVE: Zhenjiang aromatic vinegar extract; ZO-1: zonula occludens 1 Introduction Inflammatory bowel disease (IBD) is a chronic and autoimmune condition which consists of Crohn’s Disease (CD) and Ulcerative Colitis (UC) representing the two main subtypes of clinical IBD. Indeterminate Colitis (IC) represents a third subtype of IBD, and this latter diagnosis is made when it is not possible to distinguish between UC and CD. The prevalence of IBD has been estimated in 653 per 100,000 patients, with the number of UC (334 per 100,000) being slightly higher than CD (306 per 100,000) [1]. Epidemiologic studies show that the prevalence of IBD is higher in Europe, North America, and Oceania. However, IBD has evolved into a global disease, with a rising incidence also documented in developing countries in Asia, Africa, and South America [2]. Overall, these subtypes of IBD often present with similar symptoms including abdominal pain, diarrhea, abdominal distension, hematochezia, tenesmus, and an extensive list of extraintestinal manifestations including gastrointestinal, mucocutaneous, musculoskeletal, ocular, pulmonary, vascular system, and generalized fatigue [3], significantly reducing an individual’s quality of life [4]. Contemporary biomarkers include C-reactive protein (CRP), fecal calprotectin (FCP), and lactoferrin, which are all routinely used for the detection of inflammatory activity [5]. However, given the nonspecific symptoms of CD and UC, a diffinitive diagnosis requires confirmation by endoscopy, radiology, and histological analysis of the intestinal tract. There is currently no cure, and the majority of contemporary therapies focus on symptoms management followed by maintenance of disease remission. Induction and maintenance therapy through the prescription of corticosteroids, 5-aminosalicylates (5-ASA), thiopurines, and biologic therapy trigger adverse effects and have significant impact on patient wellbeing [6]. A perspective population-based cohort study of a total of 330 patients demonstrated that almost 5% of patients with UC required surgery as primary intervention while the corresponding proportion for CD increased markedly to 21.4%. Additionally, the frequency of early postoperative clinical complications remained high in patients for both colon pathologies reaching 31% for UC and 36% for CD [6]. Currently, the pathogenic mechanism of IBD remains unclear [7]; however, factors including a combination of genetic, changes in gut microbiota, and environmental factors (such as diet and lifestyle), as well as individual variability have been well described, ultimately leading to a high reactive oxygen species (ROS) level and activity and an exacerbated colonic immune response in the gut [8]. The upregulation of both innate and adaptive immune responses contributes to colon inflammation and implicates in further tissue damage in patient with UC and CD. Intestinal innate system is made up of neutrophils, monocytes, macrophages, dendritic cells (DCs), and innate lymphoid and natural killer (NK) cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response [9] through the expression of pattern recognition receptors (PRR), such as toll-like receptors (TLR) to identify the molecular patterns of different microorganisms [10]. Moreover, innate cells, specially DCs are responsible to antigen presenting which are key to T-cell activation and the induction of adaptive immune response and in the developing of IBD [11]. Macrophages are also involved in the pathophysiological feature of IBD. For instance, a human study showed that inducible nitric oxide synthase (iNOS), a free radical producing enzyme and a marker of M1 macrophage inflammatory response, was primarily found in active UC, implying that in addition to inflammatory responses, elevated oxidative stress also involved in active state of the disease [12]. 2 S. SHIN ET AL. Additionally, Schroder et al. [13] have demonstrated a significant increase in inflammatory markers such as neutrophil elastase (NE) and myeloperoxidase (MPO)-indicative of neutrophil extracellular trap (NET) formation in specimens affected by CD compared to control. Similarly, other researchers have shown an overexpression of NET-associated proteins in inflamed colon of UC patients as compared to CD patients and normal control, where patients diagnosed with UC showed a higher capacity of neutrophils to produce NETs upon tumor necrosis factor (TNF)-α stimulation, which is reduced in patients receiving successful treatment with anti-TNF-α [14]. On the other hand, IBD is also characterized by an increase in colonic oxidative stress [15] that can manifest as oxidative damage to a range of biomolecules. In support of this notion, plasma levels of free thiols, a robust biomarker of systemic reduction–oxidation (redox) status, decrease significantly in CD when compared to healthy subjects [16]. Chronicity, unpredictable course of the disease, lack of definitive treatment, and several side effects from current treatment of IBD generate a great interest to study a new therapy with less side effect and higher treatment’s adherence. From this standpoint, Complementary and Alternative Medicine (CAM), a treatment approach that often utilizes natural compounds for pharmaceutical purposes, showcasing a promising complementary option to the conventional medicine, which allows reduced dosage of drugs, frequency or to maintain the remission phase. Have been widely reported the use of bioactive natural compound from plants for pharmaceutical propose. Precedents include aspirin, which is salicylic acid first used reporting back 4000 years by the Sumerians, who obtained it from Willow tree bark [17]. Digoxin, derived from Digitalis lanata plant for addressing cardiac issues [18], sterols, their derivative compounds, and plant stanol (phytosterols/phytostanols) for managing hypercholesterolemia [19] are other examples of natural compounds with current clinical use. However, there is yet to be a conventional plant derivative treatment in the field of IBD. Plants are commonly used by IBD patients to alleviate symptoms and most of evidence showed them only as complementary and alternative medicine. During the coronavirus disease 2019 (COVID) pandemic, an online survey study of IBD patients revealed that 5% of responders ceased or reduced dose of prescribed medications, 13% started supplements such as vitamin D, vitamin C, and other herbal supplements. 43% of responders used CAM and 34% used CAM frequently. Interesting, 59% of CAM users were satisfied and reported it to ‘work well’ or ‘work very well’ and their use was significantly associated with low medication adherence scores and major concern, higher perceived harm and lower score in ‘necessity’ from IBD medications [20]; however, any impact of work from home environment was not reviewed. Additionally, a recent study revealed that the frequency of herbal therapy use, combined with exercise, physical therapy, modified diet, as alternatives to contemporary drug treatments has increased in IBD patients from 2002 to 2019 [21]. Specifically, this study reported that patients experiencing resistance to contemporary treatment options, higher disease activity, or dealing with persistent and severe side effect from standard medications, corticosteroid or use of biologics, and lower quality of life were more likely to seek benefit from CAM [21]. Accordingly, studies examining the therapeutic effects of these plant derivatives in animals provide a versatile preclinical platform for evaluating treatment efficacy and elucidating mechanisms of actions. Experimental model of IBD using chemical stimulators such as dextran sodium sulfate (DSS) or di/trinitrobenzene sulfonic acid (DNBS/TNBS) is frequently studied as a preclinical experimental model, as they manifest clinical and histopathological changes such as irregular stool consistency or diarrhea, bloody stool, and mucosal damage, which are typically observed in IBD patients [22,23]. A complete holistic explanation which enables connection between IBD and potential therapeutic effect of CAM has not been established [24]. This is likely due to the complex nature of herbal mixtures that are available in market, where they are derived from multiple plants and each plant also has countless derivatives individually. Large amount of promising nutraceuticals and natural compounds have been reported for IBD treatment although rigorous evaluation of the benefits is often lacking. These nutraceuticals can be categorized broadly into the following five classes: (i) Polyphenols are a class of compounds consisting of one or more phenyl rings combined with one or more hydroxyl moieties and are commonly found in plant products recommended to alleviate gastrointestinal-related discomfort [25] with accumulative evidence supporting their positive effect on intestinal inflammation [26] gut microbiota [27], and redox imbalance that are linked to altered cellular function [28]. (ii) Polysaccharides are common natural macromolecules consisting of covalently linked monosaccharides (generally ≥10 monomer units) that form different polymeric structures [29] with documented biological activity of antitumor, antioxidant, and moisturizing activities, immune protein regulation, improving dendritic cell activity and cytokine release to potentially protect the colon [30]. (iii) The anthraquinone emodin (1, 3, 8-trihidroxy-6-methylanthraquinone) has gained particular interest on experimental models of IBD as recent studies have identified multiple biological actions for emodin with beneficial activities including anti-inflammation and gut-immunity symbiosis, which are all relevant pathophysiological actions central for disease progression in IBD pathogenesis [31,32]. (iv) Short-chain fatty acids (SCFA) represent a series of metabolites produced by gut microbiota commonly categorized by butyric acid, propionic acid and acetic acid, and has been widely recognized crucial to immune homeostasis [33]. Dietary fiber supplements are often incorporated to increase SCFA production, but types of dietary fiber and subsequent types of SCFA produced may lead to different effects on the microbial composition, diversity, and the immune system [34]. (v) Probiotics may be an essential therapeutic agent which can not only be used as a single agent but to aid conventional therapy as well, as probiotics with nanoenzyme coating therapy led to significant improvement in weight loss, apoptosis, mucin (MUC)-2 level, tight junction proteins, and Disease Activity Index (DAI) [35] and Mesalamine loaded with probiotics showed REDOX REPORT 3 significant restoration of weight, fecal consistency, fecal bleeding [36]. The aim of this comprehensive review is to evaluate the antiinflammatory and antioxidant efficacy of currently available CAM for IBD, as well as their role on gut microbiota, and to highlight the underlying molecular and cellular mechanisms of these treatments. Methods Keyword and search strategy This review utilized the Population, Intervention, Control, Outcome (PICO) search strategy to examine the anti-inflammatory and antioxidant effect of CAM in IBD. The keywords of ‘IBD patients’, ‘IBD model’, ‘Ulcerative Colitis’, ‘Crohn Disease’, ‘DSS model’, ‘TNBS model’, ‘DNBS model’ for Population and ‘polyphenol’, ‘polysaccharide’, ‘anthraquinone’ alternatively ‘emodin’, ‘SCFA’, ‘probiotics’, ‘Complementary and Alternative medicine’, ‘Herbal medicine’, and ‘Plant medicine’ for Intervention. Additionally, the keywords of ‘control’, ‘placebo’, ‘IBD therapy’ alternatively ‘mesalazine’ ‘5-ASA’ and ‘corticosteroids’ were used for Control strategy and the Outcome strategy includes the keywords of ‘anti-inflammation’, ‘gut microbiota’, and ‘anti-oxidation’. Article collection and study inclusion and exclusion criteria Published literature containing the keywords described above was collected from Google Scholar, MEDLINE, PubMed, and WOS and collated into a single file. The collected articles were screened against the following inclusion and exclusion criteria. All processes involving data collection (keyword and search strategy, article collection, study inclusion and exclusion and data extraction) were performed independently by two researches (S.S and T.O.C). Discrepancies in the processes described above were resolved through consultation and discussion with three other researchers (S.C, K.X, and S.A.D). Studies included based on the collected articles were screened against the following inclusion and exclusion criteria: (1) must involve animal models or human studies; (2) must focus on the gastrointestinal tract affections; (3) must examine the effect of herbal ingredients or natural product derivatives (polyphenols, polysaccharides, anthraquinone [emodin], SCFA, probiotics) on the pathophysiology of IBD, specifically regarding anti-inflammatory properties, antioxidant effects, and gut microbiota dysbiosis. All studies were filtered according to relevancy and date of publication, only including publication within the last 5 years. The studies included are a combination of preclinical animal experiment, randomized control trials, longitudinal cohort study, and observational studies. Studies that did not fall into the aforementioned criteria were excluded from the current review. During the screening process, studies that were published in English language that clearly established sample size, controls, and statistical analyses were included in this current review. Collected studies that did not satisfy the above-mentioned criteria were excluded and discarded from the current review. Journal impact factor or other journal metric were not one primary consideration for the inclusion and exclusion criteria. Data extraction The current review extracted the following information from the selected articles: experimental method, participants, CAM intervention, and CAM mode of action. Additionally, the active ingredients of the CAM intervention and changes in bioactivities, gut microbiota, and antioxidant capacity were also extracted from the selected articles. Results The database search began in January 2023 and concluded in August 2024. A total of 5251 articles were obtained. The study inclusion and exclusion screening process was highlighted in the article-screening flow diagram, where a total of 67 studies were included in the current review (Figure 1). The study characteristics were summarized in Table 1. Polyphenols and their bioactive metabolites Natural polyphenols are a class of compounds consisting of one or more phenyl rings combined with one or more hydroxyl moieties. These compounds are commonly found in plant products and are often recommended to alleviate gastrointestinal-related discomfort [25]. Accordingly, polyphenols are increasingly gaining attention as a potential therapeutic agent for IBD, with accumulated evidence supporting their positive effects on intestinal inflammation [26,28], gut microbiota [37,38], and redox imbalances that are linked to altered epithelial cell function [28]. Polyphenols as anti-inflammatory agents Studies with experimental animals consistently show that polyphenols administration significantly increased colon length, and alleviated inflammatory cell infiltration, weight loss, fecal bleeding, improved stool consistency, and colonic crypt depth in the IBD experimental animal model [26,28,39]. These gross observations were accompanied by significant decrease in proinflammatory biomarkers and inhibition of altered mitochondrial morphology in colon epithelia due to inflammation and provided the basis for the mechanism of action for this class of natural products. Importantly, these combined factors may be critical in determining severity of extraintestinal manifestations hence polyphenols may ameliorate these pathological changes to the colon. In addition, significant relative increases in populations of resolving macrophage phenotype (M2) cells and anti-apoptotic protein expression such as Bcl2, and lower level of pro-apoptotic protein expression, plasma inflammatory biomarkers and facilitators such as interleukin (IL)-6, IL-8, IL-1β, iNOS, cyclooxygenase-2 (COX-2), and TNFα are consistently reported in pre-clinical interventional studies with polyphenols in mice models of UC and CD-like colitis model [28,39,40]. As anti-inflammatory effects generally show a parallel link to the inhibition of oxidative stress in in-vitro studies, it may imply that the cumulative data obtained with pre-clinical models may also contribute to anti-ROS activity that leads to decreased oxidative damage [41], which will be further explored in the section below. In summary, the available evidence largely demonstrates that polyphenols protect against intestinal damage and alleviates both colonic signs and 4 S. SHIN ET AL. serum biomarkers of inflammation, implying its therapeutic potential for IBD. Polyphenols as scavengers of reactive oxygen species (antioxidant capacity) ROS are products of cell metabolism or environmental factors such as diet and smoking, which through excessive accumulation can induce host tissue damage [42]. Furthermore, cellular production of ROS is tightly related to inflammatory actions which is a crucial part of disease manifestation in IBD. Local production of ROS may disrupt intestinal permeability, damaging cells which form tight junctions along the colon epithelium [43]. For example, the free radical superoxide radical anion is chemically reduced to Figure 1. Flow diagram describing the screening strategy to identify the key references used in this systematic review. WOS, google scholar, PubMed, and MEDLINE were used to select all in vivo and human studies published in the last 5 years on CAM and IBD. 67 studies were eligible for critical in this review. REDOX REPORT 5 Table 1. Characteristics of screened studies with citations in the Far Left Column. 1 Ref. Method Participants Intervention Mode of action [26] Preclinical in vivo animal experiment n= 32 male ICR mice; 8/group Ethanol-induced inflammation ‘ZAVE’ rich in polyphenols (200 or 800 mg/kg/day), supplemented for 3 weeks Anti-inflammation, Restoration of gut microbiota [28] Preclinical in vivo animal experiment n= 48 male C57BL6 mice; 8/group DSS-induced colitis Apple peel (DAPP) rich in polyphenols (200 or 400 mg/ kg/day), for 10 days before and 10 days after induction Anti-inflammation, antioxidation [37] Preclinical in vivo animal experiment n= 15 male BALB/c mice; 5/group DSS-induced colitis Resveratrol (100 mg/kg/ day), supplemented for 10 days Anti-inflammation, restoration of gut microbiota [39] Preclinical in vivo animal experiment n= 24 male BALB/c mice; 6/group TNBS-induced CD Polyphenolic maqui extract (50 mg/kg/day) as a preventive (7 days prior TNBS) and therapeutic (4 days after TNBS) administration Anti-inflammation [40] Preclinical in vivo animal experiment n= 24 Female C57BL6 mice; 8/group. DSS-induced colitis EGCG from green tea (50 mg/kg body) supplemented for 3 days Anti-inflammation, restoration of gut microbiota, antioxidation [49] Preclinical in vivo Animal experiment n= 32 male C57BL/6 mice; 8/group DSS-induced colitis macrophage/ neutrophil depletion Phenolic acid (50mg/kg) 3 times per time of administration, once in 3 days Anti-inflammation, restoration of gut microbiota, antioxidation [51] Randomized Control Trial, Crossover n= 51 Intestinal permeability (↑zonulin serum level) patients Diet rich in polyphenols (1391 mg /day), supplemented for 8 weeks Anti-inflammation, restoration of gut microbiota [52] Longitudinal cohort on INCLD Health n= 96 Healthy adults Culinary herb rich in polyphenols (30,000 PPM, >50,000 PPM, >30,000 PPM/ATB or >50,000 PPM/ ATB), tested at 0, 6, and12 months Restoration of gut microbiota [106] Preclinical in vivo animal experiment n= 48 male CD-1 mice; 8/group AOM/DSS for CACC Moringa oleifera leaves (5%, 10%, or 20%), supplemented for 12 weeks Anti-inflammation, antioxidation [119] Preclinical in vivo animal experiment n= 30 male nude mice; 5/group Xenograft for CC ‘SDEA’ flavonoid (100, 200, or 300 mg/kg/day), supplemented for 25 days Anti-inflammation [163] Preclinical in vivo animal experiment n= 60 male Sprague-Dawley rats; 10/ group DSS-induced colitis SFE flavonoids (50, 100, or 150 mg/kg/day), supplemented for 1 week Anti-inflammation [171] Preclinical in vivo animal experiment n= 36 male & female Labrador Retrievers; 12/group IBD ‘GSP’ rich in proanthocyanidine (30 mg/kg), supplemented for 21 days Anti-inflammation, restoration of gut microbiota [172] Preclinical in vivo animal experiment n= 48 male C57BL/6 mice; 8/group DSS-induced colitis BI extract from Ginkgo biloba (2.5, 5, or 10 mg/kg/ day), supplemented for 4–10 days Anti-inflammation, restoration of gut microbiota [58] Preclinical in vivo animal experiment n= 55 female C57BL/6J mice; 7–8/group DSS-induced colitis ‘HAPS3a’ and ‘APD3a’ polysaccharides (200 mg/kg), days 2–5 over a total of 5 days Anti-inflammation, restoration of gut microbiota [59] Preclinical in vivo animal experiment n= n.i male C57BL/6 mice; n.i/ group DSS-induced colitis Noni (L.) polysaccharide (10 mg/kg/day), supplemented for 11 days Anti-inflammation [60] Preclinical in vivo animal experiment n= 48 male BALB/c mice; 8/group DSS-induced colitis ‘EC’ polysaccharide (0.35, 0.70, or 1.75g/kg/day), supplemented for 7 days Anti-inflammation [61] Preclinical in vivo animal experiment n= 60 male BALB/c mice; 12/group DSS-induced colitis ‘DO’ polysaccharide (50, 100, or 200mL/kg/day), supplemented for 7 days Anti-inflammation [62] Preclinical in vivo animal experiment n= 40 male & female Sprague Dawley (SD) rats; 10/group Acetic acid-induced colitis ‘HE’ polysaccharide (0.6 or 1.2 g/kg/day) for supplemented 10 days Anti-inflammation, restoration of gut microbiota, antioxidation [63] Preclinical in vivo animal experiment n= 40 female Swiss mice; 8/group DSS-induced colitis ‘RGal’ polysaccharide (3, 10, or 30 mg/kg/day), supplemented for 7 days Anti-inflammation [64] Preclinical in vivo animal experiment n= 15 male C57BL/6j mice; 5/group DSS-induced colitis ‘HAW1-2′polysaccharide (30 mg/kg/day), supplemented for 3 weeks Anti-inflammation, restoration of gut microbiota [65] Preclinical in vivo animal experiment n= 40 male C57BL/6J mice; 8/group DSS-induced colitis ‘AMP’ polysaccharide (10, 20, or 40 mg/kg), 3 days before induction and 7 days post-induction Anti-inflammation, restoration of gut microbiota [66] Preclinical in vivo animal experiment n= 36 male Swiss mice; 6/group Acetic acid-induced colitis Noni-PLS (0.1, 0.3, or 3.0 mg/kg), administered for 30 min before euthanasia Anti-inflammation, antioxidation [67] Preclinical in vivo animal experiment n= 60 male ICR mice; 20/group AOM/DSS colitis associated colorectal cancer Apple polysaccharide (10 mg/kg) supplemented for 15 weeks Anti-inflammation, restoration of gut microbiota [68] Preclinical in vivo animal experiment n= 50 male BALB/c mice; 10/group Cy-induced immunosuppression ‘TFPS’ heteropolysaccharide (50, 100, or 200 mg/kg/d) supplemented for 10 days Anti-inflammation, restoration of gut microbiota [69] Preclinical in vivo animal experiment n= 18 BALB/c mice, Sex n/i; 6/group AOM/DSS colitis associated colorectal cancer ‘EPS1-1’ polysaccharide (150 mg/kg) supplemented for 14 days Anti-inflammation, restoration of gut microbiota (Continued) 6 S. SHIN ET AL. Table 1. Continued. Ref. Method Participants Intervention Mode of action [70] Preclinical in vivo animal experiment n= 18 male Sprague-Dawley rats; 6/ group TNBS-induced colitis Polysaccharides (300 mg/kg/day), supplemented for 16 days Anti-inflammation, restoration of gut microbiota, Antioxidation [122] Preclinical in vivo animal experiment n= 24 Male & Female rats; Strain n/i;6/ group Healthy rats ‘AOS’ oligosaccharide (200 mg/kg), daily, supplemented orally for 28 days Anti-inflammation, restoration of gut microbiota [80] Preclinical in vivo animal experiment n= 80 male & female Kunming mice; 10/group E. coli -induced diarrhea Emodin (8.75, 17.5, or 35 mg/kg) for 6 h before euthanasia Anti-inflammation, restoration of gut microbiota [81] Preclinical in vivo animal experiment, in vitro n= 150 male BALB/c mice; 30/group CLP-induced sepsis Emodin (10, 20, or 40 mg/kg), supplemented for 7 days Anti-inflammation [82] Preclinical in vivo animal experiment, in vitro n= 49 male BALB/c mice; 7/group DSS-induced colitis Emodin/PSM NPs (5 or 20 mg/kg/d), supplemented for 5 days Anti-inflammation [83] Preclinical in vivo animal experiment, in vitro n= 48 male BALB/c mice; 8/group CLP-induced sepsis Emodin (20, 40, or 80 mg/kg/day), supplemented for 5 days Anti-oxidation [89] Human observational study n= 28 UC patients Butyrate (0–1.6 mM) on blood and intestinal T cells from patients Anti-inflammation [173] Human observational study; Preclinical in vivo animal experiment n= 187 IBD patients (CD and UC); n= 48 male C57BL/6 mice, 12/group DSS-induced colitis Butyrate (200 mM), supplemented for 10 days in animal model Anti-inflammation, antioxidation [12] Human observational study; Preclinical in vivo animal experiment n= 28, UC patients (active and inactive); n= 24 male BALB/c mice; 6/group DSS-induced colitis Butyrate (20 mg/kg), supplemented for 12 days in animal model Anti-inflammation, restoration of gut microbiota, antioxidation [109] Human observational study; Preclinical in vivo animal experiment n= 112; IBD patients (CD and UC); n= 20–40 male C57BL/6J mice; 7–10/ group, DSS-induced colitis ‘BHB’ ketone (15 mg/25g), single dose Anti-inflammation, restoration of gut microbiota [107] Preclinical in vivo animal experiment n= 44 male C57BL/6 mice; 8–12/group DSS-induced colitis Butyrate (NaB, 0.1 M or 500 g/kg/day), supplemented 12 days before induction and 10 days post-induction Anti-inflammation, antioxidation [113] Preclinical in vivo animal experiment n= 24 male C57BL/6 mice; 4/group Streptomycin or E. coli strains (LF82 or LF82lux)-induced infection Propionic acid (20 mM), 3 days before infection and 21 days after infection Restoration of gut microbiota [112] Preclinical in vivo animal experiment n= 40 male Sprague-Dawley rats; 8/ group Health rodent Cured chicken or beef product diet supplemented for 3 weeks Anti-inflammation, restoration of gut microbiota, antioxidation [116] Preclinical in vivo animal experiment n= 20 male BALB/c mice; 3–5/group Oxazolone-induced UC ‘DCA’ (100 mg/kg for 3 days), 1 h before induction and 3 days after induction Anti-inflammation, antioxidation [117] Preclinical in vivo animal experiment n= 10 male C57BL/6 mice; 5/group DSS-induced colitis Acetate enema (10 mM), provided daily for 7 days Anti-inflammation [120] Preclinical in vivo animal experiment n= 20 male C57BL/6J mice; 5/group Fiber-deficient and low DSS-induced colitis Sodium acetate (200 mM/day), supplemented for 7 days Anti-inflammation [35] Preclinical in vivo animal experiment n= 15 C57BL/6 mice Sex n/i; 3/group DSS-induced colitis Pt-Lipid@EcN probiotic, supplemented for 7 days Dose n/i Anti-inflammation, antioxidation [36] Preclinical in vivo animal experiment n= 30 female and male Wistar rats; 6/ group DSS-induced colitis Mesalamine and ‘F12’ probiotic (23 mg/kg/day), supplemented for 15 days Anti-inflammation [96] Human observational study; Preclinical in vivo animal experiment n= 37 UC patients; n = 30 male BALB/c mice; 6/group DSS-induced colitis Human FMT, supernant mixture and 7 mix probiotics strains: E. hirae, L. casei, S. salivarius, F. prausnitzii, A. muciniphila, C. butyricum, L. salivarius (1 × 10 8 CFU per strain), administered for 7 days Anti-inflammation, restoration of gut microbiota [100] Preclinical in vivo animal experiment n= 60 male C57BL/6 mice; 12/group DSS-induced colitis Butyrate-producing Veillonella and lactobacillus (1 × 10 9 CFU mL −1 each, 200 μL per day), supplemented for 14 days Anti-inflammation, restoration of gut microbiota, antioxidation [102] Preclinical in vivo animal experiment n= 25 male BALB/c mice; 5/group Lactobacillus plantarum ZJ31 (400 uL oral administration, 2.5 × 10 9 CFU mL –1 ), supplemented for 56 days Anti-inflammation, Restoration of gut microbiota [108] Preclinical in vivo animal experiment n= 24 male C57BL/6 mice; 8/group DNBS-induced colitis Butyrate-producing Faecalibacterium prausnitzii strain A2-165 probiotic (1 × 10 9 CFU), for 10 days after first induction and 3 days after second induction Anti-inflammation [111] Preclinical in vivo animal experiment n= 30 male Sprague-Dawley rats; 6/ group DSS-induced colitis Propionibacterium freudenreichii ‘LPF’(1 × 10 8 CFU) and ‘SPFC’ (1 mL), supplemented for 22 days Anti-inflammation [121] Preclinical in vivo animal experiment n= 40 male C57BL/6J mice; 10/group DNBS-induced colitis Acetate-producing bacteria Christensenella minuta (1 × 10 9 CFU/mL), supplemented for 2 weeks Anti-inflammation (Continued) REDOX REPORT 7 hydrogen peroxide (H 2 O 2 , a secondary type of ROS), by superoxide dismutases (SOD1/2). This weak two-electron oxidant H 2 O 2 is then reduced further by catalase and other professional peroxidase enzymes to eliminate the oxidant. Indeed, polyphenol-rich dried apple peel powder showed lower levels of H 2 O 2 coupled with decreased SOD2 Table 1. Continued. Ref. Method Participants Intervention Mode of action [123] Preclinical in vivo animal experiment n= 32 female C57BL/6J mice; 8/group DSS-induced colitis Lactobacillus acidophilus KBL402 and KBL409 probiotics (1 × 10 9 CFU), supplemented for 8 days Anti-inflammation, restoration of gut microbiota, antioxidation [139] Preclinical in vivo animal experiment n= 20 male C57BL/6 mice; 3–7/group DSS-induced colitis Lactobacillus johnsonii probiotic (1 × 10 9 CFU/day), supplemented for 14 days Anti-inflammation, restoration of gut microbiota [140] Preclinical in vivo animal experiment n= 60 male BALB/C mice; 12/group DSS-induced colitis NKU556-Fe (0.2 mg mL –1 Fe 2+ ), supplemented for 6 days Anti-inflammation, antioxidation [141] Preclinical in vivo animal experiment n= 70 male Sprague Dawley rats; 10/ group DSS-induced colitis Lactobacillus acidophilus (1 × 10 8 CFU) supplemented for 7 days Anti-inflammation, restoration of gut microbiota, antioxidation [142] Preclinical in vivo animal experiment n= 18 male C57BL/6 mice; 6/group DSS-induced colitis Lactobacillus plantarum CBT LP3 probiotic (1 × 10 8 CFU/day), supplemented for 7 days Anti-inflammation, antioxidation [143] Preclinical in vivo animal experiment n= 16 C57BL/6JOlaHsd mice; 4/group DSS-induced colitis Lactobacillus salivarius probiotic (1 × 10 9 CFU/day), supplemented for 7 days Anti-inflammation, restoration of gut microbiota, antioxidation [144] Preclinical in -vivo animal experiment n= 20 female C57BL/6 mice; 5/group DSS-induced colitis ‘Lac@HDP’ probiotic (1 × 10 9 CFU), supplemented 1 d Anti-inflammation, restoration of gut microbiota [146] Preclinical in vivo animal experiment n= 25 female C57BL/6 mice; 5/group DSS-induced colitis Porphyromonas gingivalis and Lactobacillus rhamnosus GG probiotics (50 μg mL −1 ), supplemented for 8 days Anti-inflammation [148] Preclinical in vivo animal experiment n= 60 BALB/c mice; Sex n/i; 12/group DSS-induced colitis Lactobacillus plantarum strains (1 × 10 9 or 1 × 10 10 CFU/mL/day), supplemented for 28 days Anti-inflammation, restoration of gut microbiota, antioxidation [149] Preclinical in vivo animal experiment n= 32 female C57BL/6J mice; 8/group DSS-induced colitis Lactobacillus casei LH23 probiotic (1 × 10 8 CFU/day), supplemented for 7 days Anti-inflammation, antioxidation [150] Preclinical in vivo animal experiment n= 16 BALB/c Wistar Rattus; 8/group DSS-induced colitis Lactobacillus brevis-derived poly Pprobiotic (5 μg/ mice/day), supplemented for 7 days Anti-inflammation [151] Preclinical in vivo animal experiment n= 90 male C57BL/6N mice; 10/group DSS-induced colitis Bifidobacterium bifidum (FL-276.1, FL-228.1) Enterococcus faecalis (ML329, FN249), Lactobacillus rhamnosus (FN518), Lactobacillus fermentum (CECT5716) (1 × 10 9 CFU) probiotics, supplemented for 22 days Anti-inflammation [152] Preclinical in vivo animal experiment n= 48 female C57BL/6 mice; 8/group DSS-induced colitis Bifidobacterium bifidum BGN4-SK probiotic (1 × 10 10 CFU/day), supplemented for 8 days Anti-inflammation, antioxidation [153] Preclinical in vivo animal experiment n= 40 female C57BL/6J and BALB/c ByJ mice; 5–10/group TNBS-induced colitis Bifdobacterium animalis spp. lactis (Bl 5764) and Lactobacillus reuteri (Lr 5454) probiotics (1 × 10 8 CFU/day), supplemented for 5 days Anti-inflammation [155] Preclinical in vivo animal experiment n= 12 male C57BL/6 mice; 6/group DSS-induced colitis Pediococcus pentosaceus probiotic (1 × 10 9 CFU /day), supplemented for 2 weeks Anti-inflammation, restoration of gut microbiota, antioxidation [156] Human observational study; In vivo animal experiment n= 12 UC patients; n= 10 male C57BL/6 mice; n= 3–6/group DSS-induced colitis Akkermansia muciniphila (1 x 10 9 CFU/day), supplemented for 7 days Anti-inflammation [157] Preclinical In vivo animal experiment n= 40 male C57/BL6 mice; 10/group Akkermansia muciniphila 139 and ATCC (2 × 10 8 CFU/ ml/day), supplemented for 56 days Anti-inflammation, antioxidation [158] Preclinical in vivo animal experiment n= 26 male C57BL/6 mice; 6/group DSS-induced colitis Lactic acid (0.25 mM) and Saccharomyces cerevisiae 39# probiotic (1 × 10 9 CFU/ml), for 7 days Anti-inflammation, restoration of gut microbiota, antioxidation ATB, antibiotic properties; APS3a, non-honey-processed Astragalus polysaccharides; AMP,Atractylodes macrocephala Koidz polysaccharide; AOM, azoxymethane; AOS, alginate oligosaccharides; BHB, ketone body B-hydroxybutyrate; BI, Bilobalide; CD, Crohn’s disease; CACC, colitis-associated colorectal cancer; CC, colorectal cancer; Cy, cyclophosphamide; CLP, cecal ligation puncture; CFU, colony-forming units; DSS, dextran sulfate sodium; DAPP, dried apple peel powder; DO, Dendrobium officinaleon; DNBS, dinitrobenzene sulfonic acid; DCA, dichloroacetate; EGCG, epigallocatechin-3-gallate; EC,Eucheuma cottonii;EPS1-1,Rhizopus nigricans extracellular polysaccharide; SFE,Sophora flavescens extract; FMT, fecal microbiota transplantation; F12, probiotic microparticles; GSP, grape seed proanthocyanidin; HAPS3a, honey-processed Astragalus polysaccharides; HAW1,Crataegis pinnatifida (Hawthorn); ‘HE’,Hericium erinaceus;INCLD, International Cohort on Lifestyle Determinants of Health; LPF, live P. freudenreichii KCTC 1063; Lac@HDP,Lactobacillus acdiphilus@Hyaluronic acid grafted with dopaine protected by phenylboric acid; Noni-PLS, isolated polysaccharide from Morinda citrifolia Linn; NPs, nanoparticles; NaB, sodium butyrate; NKU556-Fe,Lactobacillus alimentarius NKU556 iron-enriching from Chinese fermented food; n/i, no-information provided; PPM, parts per million; PSM, poly (DL-lactide-co-glycolide)/ Eudragit Ⓡ S100/montmorillonite; Pt-Lipid@EcN, liposome-coated Escherichia coli Nissle (EcN) 1917; Poly P, long-chain polyphosphate; RGal, Rhamnogalacturonan; SPFC, supernatant of the P. freudenreichii culture; SDEA,Selaginella doederleinii Heiron etyl acetate; TNBS, 2,4,6-Trinitrobenzene sulfonic acid; TFPS, Camellia sinensis L pectic heteropolysaccharides; UC,Ulcerative colitis;ZAVE, Zhenjiang aromatic vinegar extract. 8 S. SHIN ET AL. are warranted before emodin can be considered a useful adjunctive therapy for IBD patients. Emodin as an anti-inflammatory agent In vivo studies using animal models showed significant attenuation of pathological score defined by intestinal necrosis or hemorrhage histopathological in interventions with emodin despite the ongoing presence of significant inflammation, alluding to emodin’s protective mechanism against intestinal damage [80]. In an E. coli O 1 -induced diarrhea experimental model, mice treated with emodin for 7 days showed ameliorated colon shortening, reduced colon atrophy, increased mucosal goblet cell density, and improvement of tight junction barrier compared to the insult group in the absence of intervention. Additionally, emodin was shown to elicite significantly higher MUC-2 fluorescence intensity, indicating goblet cell preservation yielded continued mucin production, along with a reduced levels of IL-1β, IL-6, and TNF-α [80]. Another study reported that emodin prevented intestinal permeability by increasing zonula occludens-1 (ZO-1) and occluding expression – but not as effective as claudin-1 – in the intestine of septic mice [81]. Emodin (EMO)-loaded Poly (DL-lactide-co-glycolide)/Eudragit S100/ montmorillonite nanoparticles (EMO/PSM NPs) showed comparable anti-inflammatory effect to 5-ASA, alluding its therapeutic potential [82]. Once again, further study is necessary to determine efficacy, toxicity, and side effects of nanoparticle delivery of emodin in human subjects. Emodin as scavengers of reactive oxygen species (antioxidant capacity) Emodin shows antioxidant activity as evidenced by significant reduction of MDA levels combined with enhancement of both low- (GSH) and high-molecular weight (SOD) antioxidants, signifying emodin’s potential to protect against oxidative stress through targeting different pathways linked to tissue redox modulation [83]. When delivered via nanovehicle, emodin also showed enhanced biological activities as judged by significant decreases in colonic MPO and nitric oxide (NO) [82]. This activity is likely explained by the chemical reduction of the quinone to a corresponding phenol by biological reductants. For example, o-quinones, a primary product, can be reduced by biological reductants to yield phenols and o-diphenols and then oxidized back to the corresponding o-quinones by tyrosinase [84]. Interestingly, the available evidence indicates that the o-diphenolic structure in the chemically reduced hydroxyanthraquinone molecules could markedly enhance the radical scavenging property of this natural product [85] with potentially the redox recycling of the active scavenger adding to the scavenger efficacy. Emodin as modulators of the gut microbiota Recently, emodin has been also documented to improve richness and diversity microbiota, significantly improvement richness and composition of Bacteroidetes,Firmicutes, Verrucomicrobia, and reduction of Proteobacteria in intestinal disorders [80]. Gao et al. [80] reported that emodin reestablished microbial content in the colon after being disrupted by pathogenic enterotoxigenic Escherichia coli, implying the capacity of emodin to suppress pathogenic microbiota and enhance growth of healthy composition and abundance. Beneficial effects of emodin on oxidative stress, inflammation and gut microbiota are summarized below (Table 4) and demonstrate that the bioactivity for this natural product involves the modulation of many disparate pathways. Short-chain fatty acids (SCFA) Short-chain fatty acids (SCFA) are byproducts produced by gut microbiota commonly categorized by valerate (number of carbons 5; C5) and the most abundant organic substrates: Butyrate (C4), Propionate (C3), and Acetate (C2) [33]. These SCFA are biologically active and have been widely recognized for their beneficial effects and their important role in gut health [8]. Dietary fiber supplements are often incorporated to increase SCFA production, but different fiber and intervention may lead to different effects on the microbial composition, diversity, and the corresponding individual immune response [34]. Interestingly, fiber supplementation with inulin (fructo-oligosaccharide) showed significant elevation of Actinobacteria abundance and suppression of Bacteroidetes, while supplementing isomalto-oligosaccharide fiber significantly increased Bacteroidetes and decreased Firmicutes in the microbiota population, without significant changes on total SCFA levels [34]. On the another hand, dietary choices play a critical role in modulating intestinal SCFA. Diets lacking in fiber exacerbate diseases in experimental models of intestinal injury and colorectal cancer [86]. Conversely, diets high in fiber are documented to protect against inflammatory diseases. For example, data produced by Laurence et al. underpin the protective effects of rich-fiber diet. Specifically, their study documented that fiber-derivated SCFA binds to GPR43 on colonic epithelial cells leading to the stimulation of a K( + )-ion efflux and cellular hyperpolarization, which promotes the activation of the NLRP3 inflammasome pathway, crucial for gut homeostasis [87]. Also, it has been reported that antenatal supplementation with a high-fiber diet leads to a reduction in intestinal inflammation amongst the corresponding adult offspring that are subsequently challenged in an experimental model of colitis [88]. Available evidence has shown that different SCFAs may exhibit varying biological effects depending on the specific change in level of the metabolite under different pathophysiological conditions. For instance, supplementing butyrate and propionate led to diminished proliferation and altered CD4 + and CD8 + T-cell populations; however, only butyrate reduced CD25 + T-cell expression in a dose-dependent manner. Under the same conditions, acetate showed no significant effect [89]. However, Vieira et al. [90] showed that acetate significantly suppressed inflammation by inhibiting pro-inflammatory pathways linked to the transcriptional activation of NF-κB and more broadly the degree of neutrophil activity, and instead promoted the production of anti-inflammatory TGF-β, annexin A1, and IL-10, thereby eliciting an anti-inflammatory activity. Furthermore, foodderived oryzanol (ORY) treatment, which was significantly linked to elevated fecal SCFA contents lowered Firmicutes abundance while improving Bacteroidetes abundance while not markedly altering butyric acid level [91]. Other authors have shown that butyrate synthesis and the bacteria responsible for producing this SCFA have been found to exert the highest anti-inflammatory effect on the gastrointestinal tract and most significant regulation of the immune response through inhibition of proinflammatory cytokines and promotion of anti-inflammatory REDOX REPORT 15 cytokines such as IL-10 [92]. Thus metabolic synthesis of specific SCFA may need to be studied separately to accurately identify an individual biological effect. Notably, SCFA have been shown to provide beneficial effects on gastrointestinal disorders through interaction with immune and epithelial cells in the colon tissue. G protein-coupled receptors (GPCRs) are not only highly expressed on enterocytes and enteroendocrine cells in the gastrointestinal tract but also in the macrophages, dendritic cells, lymphocytes, and neutrophils [93]. SCFAs bind to GPR41 and GPR43 (also known as free fatty acid receptors FFAR3 and FFAR2, respectively), triggering the differentiation and maturation of immune cells and thereby, acting as important mediators of the mature immune state. Both GPR41 and GPR43 receptors activation leads to the inhibition of adenylyl cyclase and, subsequently, decreases the levels of cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK), and impacts transcriptional activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) cascade, which then collectively manifests as a decrease in colon inflammation [94]. Another possible mechanism by which SCFA could enhance intestinal barrier function and reduce inflammation is through histone deacetylase (HDAC) inhibition. Butyrate [86] and Clostridium butyricum-derived butyrate induce an increase of IL-10 expression and upregulate regulatory B cells via inhibiting HDAC1 activation. In addition, SCFA also impact macrophage polarization (that is the ratio M1 to M2 phenotype) through GPR43 activation, HDAC inhibition [95] and/or JAK/STAT3/forkhead box O3 (FOXO3) axis inactivation [96]. Specifically, butyrate induces the expression of synaptopodin, an actin-binding protein that enhances intestinal barrier function, via HDAC inhibition [97] and also to suppress the production of neutrophil-derived MPO and proinflammatory mediator production, perhaps through its HDAC inhibitory function [98]. Furthermore, butyrate may inhibit neutrophil migration and the consequent realizing of NETs in cells from CD and UC patients [98]. Thus this complicate of data reinforces the suppressive effect of SCFA on intestinal inflammation and oxidative stress leading to improved epithelial barrier function. Numerous studies have shown that the pathogenesis of IBD and clinical evolution may be modulated by SCFA; however, the exact mechanism of action and linkage of all SCFA in IBD is still unclear [99]. For instance, the combination of Veillonella ratti (V.ratti) and Lactobacillus acidophilus (LA) leads to significantly elevated total SCFA levels and suppressed lactate, along with significantly ameliorated clinical and histological symptoms in experimental UC [100]. Overall, these outcomes imply a connection between high SCFA, microbiota, and IBD in humans. A link between polysaccharides and SCFA production in the gut has also been proposed. For example, α-galacto-polysaccharide derived from Lupinus albus is also a known prebiotic leading to increased SCFA through gut microbiota abundance [101]. Indeed, its treatment also significantly reduced DAI, improvement intestinal permeability, and goblet cell count but mild inflammation and mucosal damage were still seen [90]. In addition, Lactobacillus plantarum ZJ316 therapy, which showed significantly higher level of SCFA compared to mesalazine, both treatments successfully restored colon weight, clinical markers and IL-1β, IL-8, and TNF-α inflammatory cytokines compared to the DSS (insult) group, however, ZJ316 therapy was more effectively in suppressing IL-6 expression in rodents [102]. Along with butyrate, both propionate and acetate are SCFA metabolites derived from gut microbiota. Butyrate, as shown in the section above, is a more well-known SCFA and has shown evidence as a therapeutic agent for IBD. However, studies have also alluded to possible therapeutic effects of other SCFAs including the protective action of propionate and acetate on colon pathophysiology. After all, SCFAs seem to be tightly related to the colon, as seen in the distribution of olfactory receptor 78 (Olfr78), an SCFA receptor expressed by the enteroendocrine cell, commonly expressed in cecum, distal large intestine, and rectum [103]. The specific affinity of both propionate and acetate to Olfr78 receptor may promote the secretion of the anorexigenic gut peptide YY (PYY) [104], a hormone involved in the maintenance of gastrointestinal function. Indeed, PYY has been shown to be significantly lowered in the colon of patients with inflammatory bowel syndrome, implying its contribution to clinical symptoms [105]. Thus propionate and acetate may have a major role in inhibiting inflammation and oxidative stress as well. Furthermore, Moringa oleifera leaves which resulted in elevated acetic, propionic, and Table 4. Mechanism of actions of emodins in alleviating IBD with reference sources cited in the far-left column. Ref. Active ingredient (where identified) and dose Chemical stimulus Animal Bioactivity summary Change in gut microbiota Proposed antioxidant mechanism [80] Emodin; 8.75, 17.5 or 35 mg/kg E. coli (2.5 × 10 11 CFU/mL) Male & Female Kunming mice; n = 80; 10/groups ↓Pathological score ↓IL-1β, IL-6, TNF-α and COX2 ↑sIgA and MUC-2 ↑Richness and diversity ↑Bacteroidetes, ↑Firmicutes and Verrucomicrobia ↓MPO [81] Emodin; 10, 20 or 40 mg/kg CLP Male BALB/c Mice, n = 150; 30/groups ↓Intestinal injury score ↓IL-1β, IL-4, IL-17, IL-2, IL-3, IL-10, TNF-α, IFN-γ, GM-CSF ↑ZO-1 and occludin ↓Caspase-3 and SIRT1 ↓Proteobacteria and E.coli, ↑Firmicutes and Bacteroidetes - [82] Roots and rhizomes of R. hotaoense – EMO/PSM NPs; 5 or 20 mg/kg DSS (6 g/kg/d) Male BALB/c mice, n = 49; 8/groups ↓Clinical score ↓Colon shortening and morphological damage ↑GSH ↓MPO [83] Emodin; 20, 40 or 80 mg/kg CLP Male BALB/c mice, n = 48; 8/group ↓Sepsis score ↓IL-6 and TNF-α ↑GSH ↑SOD ↓MDA CLP, cecal ligation and puncture; COX-2, cyclooxygenase-2; DSS, dextran sodium sulfate; E. coli,Escherichia coli; EMO/PSM NPs, emodin-loaded poly (DL-lactideco-glycolide)/Eudragit Ⓡ S100/montmorillonite nanoparticles; GM-CSF, granulocyte macrophage colony-stimulating factor; GSH, glutathione; IFN-γ, interferon gamma; MPO, myeloperoxidase; sIgA, secretory immunoglobulin A; SIRT1, Sirtuin 1; TNF-α, tumor necrosis factor-alpha; ZO-1, zonula occludens 1. 16 S. SHIN ET AL. butyric acid, in descending order, led to significantly decreased total polyp burden and reduced proinflammatory chemockine monocyte chemoattractant protein 1 (MCP-1), while increased more than two times IL-10 [106]. However, further identification of SCFA and their corresponding bioactivity is necessary, before concluding that widespread SCFA supplementation is suitable as a therapy for the maintenance of remission in patients diagnosed with IBD. Given the proximity of the gut epithelium to the gut microbiota, multiple pathways downstream of SCFA sensing have evolved to promote gut barrier function; these multiple activities are shown in Figure 2. SCFA – butyrate (C4) Butyrate as anti-inflammatory agents In mice, butyrate oral administration led to significant reduction in disease severity and histopathological signs in IBD such as immune cell infiltration in colon, and promoted autophagy [12,98,107,108]. Moreover, other studies have documented that butyrate partially reduced inflammation in mice through significant inhibition of CitH3 and thus, potentially acting via the inhibition of NET formation [98]. On the other hand, it has been observed that butyrate reversed the depletion of F4/80+ macrophages induced by clodronate liposomes – a common inducer of macrophage apoptosis – in mice insulted with DSS, leading to a significant improvements in goblet cell viability and mucus secretion from the colon mucosa [12]. Furthermore M2 (resolving) macrophage-associated genes and levels of p-STAT6 phosphorylation in F4/80+ macrophages were significantly promoted after supplementing Bhydroxybutyrate (BHB) and this activity was markedly suppressed by the pharmacological agent AS1517499, which inhibits STAT6 phosphorylation [12,108], implicating the STAT6 pathway in the biological action of butyrate. In summary, mice studies showed significant effect of butyrate in lowering DAI and histopathological markers of colon damage with significant promotion of the macrophage M2 phenotype that drives repair and resolution of the inflamed colon. Butyrate administration in human studies showed significant reduction in release of neutrophil-mediated proinflammatory cytokines and suppression of IBD biomarkers such as calprotectin (CP) and LCN2 (lipocalin 2) [98]. Supplemented patients identified with a remissive UC condition also had significantly lower macrophage number than active UC patients, along with a markedly M2-like immunophenotype within the colon lamina propria [12]. The improvement of butyrate’s treatment in mucus barrier damage was also noted due to the increasing expression of MUC2 and SPDEF (SAM pointed domain containing ETS transcription factor) [12], which are linked to improved mucosal function. Overall, butyrate therapy leads to significantly lower disease severity and inflammatory cytokine level with macrophages having a role in its mechanism of action in studies using animal models and in human trials. Following BHB therapy, both humans and mice, displayed significant reduction in colonic tissue protein expression of ACAT1, HMGCS2,BDH1 which are genes commonly expressed in active IBD [109]. However, there was no significant difference in alleviating intestinal permeability (ZO-1, occluding) for BHB treated group compared to control group irrespective of whether studies were conducted with humans or a using mouse model. Interestingly, BHB significantly alleviated DSS-induced inflammatory signs but had no effect without DSS induction, implying its therapeutic effect on only the injured tissues [109]. This conclusion may lead to the deduction that butyrate therapy is only effective in damaged tissues. However, another study showed that butyric acid only showed significant elevation in a healthy group, while significant enhancement of the butyryl-CoA:acetate CoAtransferase pathway, which modulates endogenous butyrate-production in the colon, was noted in this experimental disease model group [101]. This leads to the question of whether modulation of the butyryl-CoA:acetate CoA-transferase pathway and utilization of increased butyric acid depend on inflammatory process and mucosal damage to drive the enhanced production of this SCFA. However, in direct contrast with this notion, supplementing with sodium butyrate showed no significant difference in disease-induced weight loss in a mouse model of IBD [107]. Overall, a pure anti-inflammatory role for butyrate may not be the sole mechanism of action, but rather the extent of bioactivity may show some dependence on healthy or disease state and whether interaction with colonic macrophages occurs at a suitable timeframe during the pathogenesis of the disease stage. Butyrate as scavengers of reactive oxygen species (antioxidant capacity) Several studies have identified that butyrate also displays antioxidant activity. For example, butyrate administration led to decreased ROS production, accumulated lipid oxidation (MDA), and neutrophil-MPO levels while increasing tissue SOD and GSH levels in mice [98]. An increase of L012 intensity, a luminol-based chemiluminescent probe used to detect ROS and reactive nitrogen species (RNS), was also observed in an experimental model, while a less intense abdominal signal observed in mice treated with sodium butyrate which was consistent with decreased amounts of MPO, an enzyme which produces ROS [107]. In addition, sodium butyrate along with 5-ASA treatment significantly reduced lipid peroxidation and restored GSH, and induced Nrf-2 activation leading to enhanced HO-1 expression [107]. In conclusion, butyrate plays a significant role in attenuating oxidative stress in IBD. Butyrate as modulators of the gut microbiota As have been mentioned, SCFA are metabolites derived from microbiota and can alter microbial composition [110]. Most importantly, a human study showed that IBD in remission displayed a significant increase in fecal butyrate and microbiome known to produce butyrate, showing positive association between the alleviation of IBD and butyrate production [12]. In mouse models of IBD, treatment with butyrate showed no significant effect in altering microbial α-diversity. However, supplemented butyrate led to increased abundance in strains such as Firmicutes and Lachnospiraceae and changes in their relative composition [102,109]. Indeed, butyrate-producing bacteria successfully elevated Dact3 expression, which interacts with c-Jun N-terminal kinase (JNK) pathway and was associated with the alleviation of disease severity inflammatory biomarkers, result that nonbutyrate producing microbiota was unable to replicate [108]. Taken together these data show that endogenous REDOX REPORT 17 butyrate levels strongly depend on the microbiome phenotype and its capacity to sustain butyrate production. Another study discussing the mixture between V. ratti and L. acidophilus showed that this dietary mixture significantly elevated SCFA levels and lowered the Firmicutes/Bacteroidetes ratio [100]. Treatment with a mixture of Lupinus albus αgalacto-oligosaccharides (LA-GOS) also elevated Bacteroidetes and Firmicutes abundance and suppressed the relative proportion of Proteobacteria abundance [101]. In the DSS colitis model, intervention with Lactobacillus plantarum ZJ316, which utilizes butyric acid, showed a direct relationship with Faecalibacterium,Agathobacter, and Firmicutes and negative association with Bacteroidetes and Actinobacteria [102]. Interestingly, Faecalibacterium,Agathobacter, unidentified_Lachnospiraceae, and Firmicutes which were associated with butyric acid, showed inverse relationships with inflammatory cytokines, further reinforcing butyric acid’s capacity to alleviate inflammation [102]. Under the same experimental conditions, Bacteroidetes showed a negative association with butyric acid, and was linked to increased levels of inflammatory cytokines [102], suggesting that the relationship between butyrate and microbiota, is critical to ameliorating inflammatory process in the gut. However, a different study showed that butyrate therapy post antibiotic treatment alleviated disease severity, implying butyrate’s independent effect from gut microbiota while butyrate’s dependence on macrophages was also evident [109]. Thus there seem to be conflicting results in the relationship between butyrate and gut microbiota while more consistent evidence exists for butyrate bioactivity in promoting phenotypic change in colonic macrophages. Overall, the role of SCFA butyrate in promoting intestinal epithelial barrier function and regulating the host mucosal immune system in intestinal injury through the regulation of oxidant and inflammatory pathway and microbiota modulation are outlined in Table 5. SCFA – propionate (C3) Propionate as anti-inflammatory agents Anti-inflammatory effect of propionate has been documented in studies focused on different types of gut microbiota, diet, and in direct supplementation of isolated cells. Propionate may be indicative of inflammation, or propionate-producing bacterium are strongly linked with the elevation of colon inflammation and intestinal damage [111]. For example, P. freudenreichii, which has been shown to enhance the production of mucin, is known to produce propionate as its most prominent metabolite. The administration of both live and supernatant derived from cultured P. freudenreichii displays a similar capacity to stabilize goblet cells exposed to inflammatory challenge, indicative of the anti-inflammatory effect of propionate [111]. Consistent with this result mentioned above, MUC2 protein secretion, which is a major component of intestinal mucin, was significantly elevated by both supernatant and live P. freudenreichii in DSS-treated mice compared to DSS-insult alone. This mucin phenotype was linked with decreasing levels of TNF-α, IL-6, IL-1β, and tendency of increase IL-10 production [111]. Moreover, natural compounds have shown a significant increase of butyrate and propionate levels in cecal and fecal content from mice insult with DSS, which are correlated with ameliorate colon inflammation [106]. However, not all available data is supportive for a colon protective role for propionate. Thus propionate’s biological effect may be questioned when delivered by supplementing in the diet. For instance, rats fed on cured meat, which had 18% higher proportion of propionate than comparable Figure 2. Summary SCFA bioactivity on various intestinal and immune cell types. Dietary fiber is fermented by gut microbiota, leading to the production of SCFAs. SCFA are ligands for receptors on colon epithelial cells of the colonic mucosa and immune cells such as macrophages, lymphocytes, and neutrophils. Specifically, butyrate interacts with intestinal synaptopodin, to aid wound healing and intestinal permeability through the suppression of histone deacetylase (HDAC) and NFkB. SCFAs are also associated with macrophage polarization towards anti-inflammatory M2 macrophages, which increases the secretion of anti-inflammatory IL-10 cytokine. SCFA interacts with T-cell proliferation and activation, enhancing T regulatory cells and suppressing pro-inflammatory T cells, along with modulate inflammasome. 18 S. SHIN ET AL. amounts of fresh meat, did not lead to a significant difference in CRP levels, inflammatory cytokines such as IL-6 and proinflammatory TNF-α, which did not increase above the limit of detection in the absence or presence of propionate [112]. A simple explanation for this lack of bioactivity may be that an 18% higher load of dietary propionate was not sufficient to yield a biological difference, albeit that normal dietary propionate intake in humans is commonly less than the level tested in this study [112]. Propionate as scavengers of reactive oxygen species (antioxidant capacity) In colon treated with Moringa oleifera which showed a significant increase in both acetic and propionic acids, a parallel and significant increase in NADH-quinone reductase (NQO1) activity (2.5-fold) and glutathione-S-transferase (GST) (1.5fold) activity was determined in the colon. Parallel decrease of colonic neutrophil recruitment by 2.5-fold was also detected, with a concomitant 20% decrease in MPO concentration leading to 2.3-fold lower detection of the lipid oxidation biomarker MDA in colon tissues, which is consistent with a decrease in oxidative damage in these tissues. These results may suggest a close relation between propionic acid production and alleviate of oxidative stress [106]. Propionate as modulators of the gut microbiota Although reduction in inflammation was observed, propionic acid may encourage pathogenic microbiota growth. For Table 5. Mechanism of actions of butyrate in alleviating IBD with reference sources cited in the far-left column (to be continued) Ref. Active Ingredient (where identified) and dose Chemical stimulus Animal Bioactivity Summary Change in gut microbiota Proposed antioxidant mechanism [89] Butyrate; 0–1.6 mM -UC patients n = 28 T cell treated with Butyrate: ↓CD4+, CD8+ T cell proliferation ↓T cell activation, ↓CD25+ cells ↓HDAC I/II - - [98] Butyrate; 200 mM DSS (2.0%) mice only IBD patients n = 187; n = 112 active CD, n = 43 active UC, n = 32 HC Male C57BL/6 mice, n = 48; 12/group CD and UC patients: ↓IL-6, IFN-γ, TNF-α, IL-17A, IL22, IL-8, S100A8/9 and LCN2 ↓Neutrophil migration Mice: ↓Body weight loss, ↓Colon shortening, ↓Pathological disease score, ↓IL-6, TNF-α, INF-γ, CXCL1, S100A8/9, LCN2 and CitH3. -CD and UC patients: ↓MPO Mice: ↓ROS [12] Butyrate; 20 mg/kg DSS (3.0%) mice only UC patients n = 28; active and inactive UC Male BALB/c mice, n = 24; 6/group Inactive UC patients: ↑Butyrate level ↓Macrophage expression ↑Arg1+ (M2-like immunophenotype) Mice: ↓Body weight loss ↓DAI ↓Epithelial damage ↓Goblet cell loss ↓Leukocyte infiltration and F4/ 80+ macrophages. ↑MUC2 and SPDEF expression. Inactive UC patients: ↑Lachnospirceae ↑Ruminococcaceae Inactive UC patients: ↓iNOS ↑CD206/iNOS [109] BHB ketone; 15 mg/ 25 g DSS (2.5%) mice only IBD patients (active and remission CD and UC);n = 112 Male C57BL/6J mice, n = 20–40; 7–10/ group Active IBD patients: ↓ACAT1, HMGCS2, BDH1. Mice: ↓Body weight loss ↓DAI and colon shortening ↓Histology score ↑IL-4Ra, IL-10, Arg-1, Chil3 ↑F4/80+CD206+ M2 macrophages mRNA expression ↑p-STAT6 in F4/80+ macrophages. Mice: ↑Firmicutes ↑Lachnospiraceae ↓Lactobcillaceae - [107] Sodium butyrate (NaB); 0.1 M or 500 g/kg/day DSS (2.5%) Male C57BL/6 mice, n = 44; 8-12/group ↓Mortality rate ↓DAI\ and colon shortening ↓Histopathology score ↓Inflammatory cell infiltration ↓Tissue damage, ↓NFκB/NLRP3 ↑Pink1/ Parkin axis ↑LC3 II ↓p62*, ↑COX-2 -↓L-012 luminescence intensity ↓Lipid peroxidation products ↑GSH level ↑Nrf-2/ HO-1 ACAT1, acetyl-CoA acetyltransferase 1; Arg-1, arginase 1; BHB, ketone body B-hydroxybutyrate; BDH1, 3-hydroxybutyrate dehydrogenase I; Chil3, chiinase-like protein; CD: Crohn’s disease; CXCL-1, Chemokine ligand 1; CitH3, Citrullinated H3; COX-2, Cyclooxygenase-2; DSS, Dextran sodium sulfate; DAI, Disease Activity Index; HC, healthy volunteers; HDAC, histone deacetylases; HMGCS2, 3-hydroxymethylglutaryl-CoA synthase 2; IFN-γ, Interferon gamma; MPO, Myeloperoxidase; NF-κB, Nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; LCN2, lipocalin-2; LC3, Microtubule-associated protein 1A/1B-light chain 3; TNFα, Tumor Necrosis Factor-alpha; UC, Ulcerative colitis. REDOX REPORT 19 instance, Ormsby et al. [113] have showed that propionic acid encouraged anaerobic biofilm formation, which are considered pathological in the sense that these structures are highly resistant to therapies to modulate bacterial growth and can lead to skewing microbiota populations [114]. Interestingly, it was seen that propionic acid was unable to alter LF82 (a strain of adherent-invasive E. coli (AIEC) infection) in ileum and large colon, however, pre-exposure of AIEC to propionic acid combined with exogenous propionic acid supplementation promoted colonization and long-term persistence [113]. This calls into question whether propionic acid therapy will contribute to aiding survival of pathogenic microbiota due to a nutritional effect, which may lead to an exacerbation of colon inflammation. In fact, LF82 which infected PA-fed mice was significantly more competitive compared to water-fed mice [113]. Although propionic acid may have antimicrobial properties, adaptability of microbial strains should be considered. As has been mentioned previously, cured beef compared to fresh beef displayed 18% higher propionate level and 25% lower butyrate level. Rats treated with cured beef exhibited significantly higher operational taxonomic unit richness and significant difference in microbial composition compared to rats fed on fresh beef. Additionally, rats fed beef had significantly higher cecal levels of valerate (+10.3%), total branched chain fatty acids (BCFA, +16.3%), iso-butyrate (+14.8%) and trend of higher iso-valerate levels (+17.8%) compared to rats on the chicken diets [112]. However, total SCFA (including acetate) did not show a significant difference based on the group comparisons, which may imply propionate as the prominent bioactive metabolite that is involved in colon protective actions [112]. Interestingly, even though the alteration of propionate level was observed, there was no significant change in abundance for Lactobacillus [112], strains that have shown to significantly produce SCFA [115]. Other nutritional factors have to be investigated to detect microbiota alteration. For example, in this study the salt content in the cured meat may explain why Lactobacillus was not significantly affected. Most relevant changes of propionate and its impact on intestinal inflammation are shown in Table 6. SCFA – acetate (C2) Acetate as an anti-inflammatory agent Supplementing acetate or acetate-producing microbiota is documented to ameliorate inflammatory response, leading to preserved body weight, lower mortality, lower disease severity, less shortening of colon, amelioration of intestinal permeability or barrier, lower histopathological score, lowered inflammatory cell infiltration, anticancer activity, and inhibited cell damage and death in experimental animal models [116–119]. Furthermore, IL-1β, IL-13, and TNF-α were also significantly inhibited by added acetate [116]. The increase of acetate production and its potential beneficial effect on inflammation can be mediated by fiber intake. For instance, when acetate was administrated in mice with a deficiency fiber diet, the suppression of disease severity, neutrophil level, and body weight loss but not colon shortening was observed [120]. Significant suppression of IL-1β release was also observed in mice that received oral Christensenella minuta DSM 22607, which produce 5:1 ratio of acetate and butyrate, but no significant effect on weight gain [121]. There may be factors influencing these results. For instance, alginate oligosaccharide administration – a source of dietary fiber – led to significantly increased weight in male rats compared to female rats, which may allude to sex difference in AOS effectiveness [122]. An elevated total SCFA content and an increased microbiome abundance/ diversity in the presence of butyrate and acetate, but not propionate, were seen in males compared to females [122]. Preexisting colonic damage may be a significant factor as well, as dichloroacetate showed no significant changes in healthy colon, indicating its therapeutic action may be contained only to damaged colon [116]. Besides, dichloroacetate did not lead to attenuation of nuclear factor of activated T cells 1 (NFATC1), NLRP3 inflammasome, NF-κB nuclear fraction, cleaved caspase-1 expression in normal healthy mice. However, in experimental colitis in mice significant attenuation of proteins mentioned above was seen [116]. Furthermore, more researchers have mentioned different treatments such as Zearalenone – an estrogenic mycotoxin – has a significant impact in increasing the abundance of SCFAs producing bacteria as well as the fecal acetate content, along with suppressing Ras/Raf/ERK/cyclin D1 pathway [118]. Acetate as scavengers of reactive oxygen species (antioxidant capacity) As acetate displays anti-inflammatory action, anti-ROS action was expected as well. Indeed, biomarkers of inflammation and oxidative stress were significantly attenuated by dichloroacetate, including NO and MPO [116]. MPO was also significantly lowered in mice treated with L. acidophilus and C. minuta, likely due to suppression of LCN-2 and cytokines such as IL-1β in the colon [121,123]. There are limited data to demonstrate antioxidant effect of acetate; however, it is possible to suspect that the reduction in inflammatory cytokines level may also contribute to reducing oxidative stress in the same local tissue environment. Acetate as modulators of the gut microbiota Besides alteration on inflammatory pathways and oxidative stress, significant changes to gut microbial composition were seen in therapies that significantly affect acetate levels, which can be found in Table 7. Amino acids such as tryptophan and phenylalanine showed association with gut microbiota, which call into question whether the effects are due to acetate itself or an accumulation of multiple factors [124]. In support of this point, L. bacillus shows direct relationships with the elevation of endogenous acetate, glycine, and aspartic acid, and Prevotella is linked with the elevation glycine and aspartic acid [123], hence any biological action cannot be ascribed to acetate alone. Zearalenone, which showed a significant anti-inflammatory response, also led to a significant increase in unidentified Ruminococcaceae,Parabacteroides,Blaustia, which are known as SCFA producing bacteria. Consequently, significantly elevated fecal acetate was detected, and fecal acetate showed inverse relationship with smaller tumors (<2 mm), implying anticancer quality of acetate [118]. However, the therapeutic response may be associated with the capacity to respond to altered gut microbiota or endogenous SCFA production. In support of this idea, an increase of goblet mucus-secreting cells occurs in parallel 20 S. SHIN ET AL. with increased abundance of Verrucomicrobiota,Bifidobacterium,Anaerostipes,Anaeroplasma,Blautia, and Akkermania in male rats compared to female rats after alginate oligosaccharide therapy, along with a significant parallel increase in acetate and butyrate compared to female rats [122]. This may imply that the extent of therapeutic response may depend on an individual’s respond to SCFA producing therapy, as male rats showed significantly enhanced therapeutic response when acetate and butyrate production increased in parallel. Probiotics Probiotics may be an essential therapeutic agent that can modulate the host–microbe interaction leading to potentially beneficial outcomes for IBD patients, which can be used both as a single agent and an adjunctive supplement conventional therapeutics [125]. Probiotics, along with prebiotics and symbiotic, are dietary supplements which can produce a synergistic effect when taken together. Prebiotics, which usually consists of non-digestible fiber, is a nutritional source for probiotics through active fermentation in the GI tract that yields several benefits for the host including promotion of selective bacterial growth, which may confer a health benefit [126]. Flavonoids and fiber can be considered prebiotics, as described above. At the same time, synbiotics are a combination of probiotics and prebiotics. The notion to induce synergistic effects by combining pro and prebiotics is commonly formulated with a combination of lactobacillus GG or Bifidobacteria, and inulin or oligosaccharides in a range of proportions and these formulations in IBD [127]. A meta-analysis of randomized controlled trials revealed both fecal microbiota transplant (FMT) and VSL#3 (a mixture of probiotics, including strains of lactobacilli,bifidobacteria, AND Streptococcus salivarius) showed beneficial therapeutic response in UC with significantly more patients achieving clinical remission compared to placebo controls. Outcomes from this review also highlighted fewer serious side effects from VSL#3′s compared to FMT treatment [128]. In terms of mechanism of action, the available data shows significant reduction of TNF-α, IL-1β, IFN-γ, and significant elevation of IL-10 in pouchitis of the ileal reservoir after VSL#3 therapy implying a specific probiotic effect in the ileal pouch [129]. Similarly, VSL#3 showed marked efficacy for post ileo-anal pouch surgery or antibiotic-induced remission of pouchitis [130]. Indeed, when VSL#3 adjuvant therapy was added to balsalazide (as a conventional anti-inflammatory IBD drug), significantly more patients (p< 0.02) were able to achieve remission and improve their endoscopic, clinical, and histology scores compared to treatment with balsalazide alone, including attaining remission significantly faster compared to the conventional treatment [131]. More recent evidence has shown the clinical benefit of combining VSL#3 (prescribed a dose of 3.6 × 10 12 CFU [132,133]) with primary yields improved rates of remission and clinical score (UC Disease Activity Index; UCDAI) for UC patients compared to conventional therapy alone. However, despite these documented positive outcomes, the effectiveness of probiotics as a potential treatment for UC remains uncertain. For instance, another review of randomized controlled trials showed a very low certainty that probiotics administered either alone or combined with 5-ASA, help to prevent clinical relapse and maintenance of remission [134]. Similarly, the current guidelines for IBD management in children do not recommend probiotic adjuvant therapy for CD and furthermore, is unclear on whether VSL#3 or E. coli Nissle 1917 is beneficial for the treatment in children with UC [135]. Alternatively, VSL#3 together with antibiotic therapy has shown therapeutic benefits in the prevention of post-operative recurrence of CD [136]. On balance it is reasonable to conclude that the current body of available evidence is conflicting and does not provide a clear pathway to develop guidelines on the use of probiotic therapy for IBD. Contemporary approaches that may improve the use of probiotics for clinical application include probiotic delivery with nanoenzyme coating therapy. Testing of this novel probiotic form led to significant improvement in weight loss, epithelial cell apoptosis, which subsequently enhanced MUC2 expression levels, tight junction protein interactions, and decreased DAI in an animal model of IBD [35]. In addition, in vivo studies using mesalamine loaded with probiotics showed significant restoration of body weight, fecal consistency, and decreased fecal bleeding [36]. Below, we briefly discuss the anti-inflammatory, gut microbiota restorative, and anti-oxidative effects of probiotics; more details are shown in Table 8. Probiotics as an anti-inflammatory adjuvant therapy Microbiota have been considered a key factor in the development of IBD, which can be modified by diet and/or supplements using beneficial bacteria or beneficial compound Table 6. Mechanism of actions of propionate in alleviating IBD with reference sources cited in the far-left column (To be continued). Ref. Active Ingredient (where identified) and dose Chemical stimulus Animal Bioactivity Summary Change in gut microbiota Proposed antioxidant mechanism [113] Butyrate; 200 mM E. coli strains (1 × 10 9 CFU) Male C57BL/6 mice, n = 24; 4/ group –↑Adhesion and invasion, ↑Biofilm, ↑Acid tolerance, ↑Persistence in ileum and colon – [112] Cured chicken or beef; containing 20 g/ kg nitrite salt and 0.5 g/kg sodium ascorbate. – Male SpragueDawley rats, n = 40; 8/ group Cured meat: ↑Urine production, ↓Mesenteric fat, ↓Retroperitoneal fat, ↑PCC in rats. Cured meat (mainly Beef): ↑BCFA, ↑Valerate, total iso-butyrate, carbon disulfide, indole and cresol ↑OTU, ↑18% propionate, ↓25% butyrate. Cured meat (mainly Beef): ↓Oxidative stress ↑stomach 4-HNE ↑GSH-Px. BCFA, branched-chain fatty acids; CFU, Colony-forming unit; GSH-Px, Glutathione peroxidase; 4HNE, 4-hydroxynonenal; OTUs, Operational taxonomic units; PCC, Protein carbonyl compounds. REDOX REPORT 21 derivates from bacteria (post-biotic) [137,138]. Of note, Lactobacillus and Bifidobacterium strains are more likely to be studied in the management of IBD. For instance, Lactobacillus administration led to significant amelioration of disease severity including reducing goblet cell and colonic crypt damage, improvement in DAI, colon shortening, inflammatory cell infiltration, epithelial damage, inflammatory factor expression, and migration of CD206 + macrophages into the colon tissue [139–143]. Furthermore, the expression of proteins such as occludin, claudin-1, and ZO-1 was significantly elevated with Lactobacillus supplementation [140,144], leading to enhanced intestinal permeability and barrier function [145]. Significantly lowered Th17 cell level and elevated Treg cells were also observed in parallel, implying probiotics’ ability to regulate T cells [146]. The evidence for specific bacterial strain and their impact on IBD is listed below: -Lactobacillus rhamnosus strain GG has not shown robust evidence to induce or maintain remission in CD after 6 months [147]. Such difference in the therapeutic effect of Lactobacillus may be dependent on the presence of ongoing insult or damage. Lactobacillus rhamnosus GG showed greater anti-apoptotic effect when combined with a pathogen bacteria [146], implying probiotics’ effect may depend on threat or damage. - Live Lactobacillus acidophilus significantly inhibited IL-18, IL1β, NLRP3 activation, enhancing autophagy. However, no reduction of these inflammatory markers was observed when L. acidophilus was provided in nonviable bacterial or supernatant (containing secreted compound) forms [141]. -Lactobacillus salivarius UCC118 improved IL-10 level including M2 macrophages but showed no significant difference in terms of colon shortening, and intestinal permeability shown by tight junction protein expression [143]. -Lactobacillus plantarum strains showed efficacious effects on body weight, colon length, and anti-inflammatory cytokine production. In addition, high dose of L. plantarum L1 markedly diminished DAI score and simultaneously reduced pro-inflammatory cytokine production, by downregulating the expression of TLR4, MyD88, and NF-κB [148]. -Lactobacillus casei strains LH23, LH1129, and LH1134 showed significantly elevated capacity to adhere to mucosal cells in in vitro studies, indicating its potential to be more effective compared to other strains with lower adhesive qualities. Improved SCFA level and promotion of Treg differentiation lead to diminished immune responses [149]. -Lactobacillus brevis-derived long-chain polyphosphate significantly increased platelet accumulation and aggregation and in vitro, leading to enhanced healing of the colonic mucosa. Interestingly, it did not significantly elevate other known factors contributing to mucosal healing such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factorβ (TGF-β) [150], suggesting its mechanism of action remains to be identified. On the other hand, the most frequently investigated probiotic as an alternative treatment for IBD is Bifidobacterium. Notably: -Bifidobacterium bifidum strains (FL-276.1 and FL-228.1) are generally considered to offer the best beneficial impact on IBD when compared with other strains or the antiinflammatory agent 5-ASA. For example, the administration of FL276.1 and FL228.1 ameliorates the decline in DAI and body weight while also inhibiting colon shortening. Additionally, mice treated with these two strains showed an up-regulation of the ZO-1, claudin-4, occludin, and Muc2 genes in colon tissue, while TNF-α, IL-1β, and IL-6 were downregulated [151]. -Bifidobacterium bifidum BGN4 significantly ameliorated the symptoms of DSS-induced colitis, increasing the expression of tight junction genes and decreasing proinflammatory cytokines such as IL-6, IL-1β, and TNF-α [152]. -Bifdobacterium animalis spp. Lactis (BI 5764) strain showed antimicrobial effect against C. rodentium infection, Table 7. Mechanism of actions of acetate in alleviating IBD with reference sources cited in the far-left column (To be continued). Ref. Active ingredient (where identified) and dose Chemical stimulus Animal Bioactivity summary Change in gut microbiota Proposed antioxidant mechanism [116] Dichloroacetate; 100 mg/kg Topical Oxazolone (3%) → Enema oxazolone (1%) Male BALB/c mice; n = 20; 35/group ↓Histopathological score and disease activity index ↑Colon length ↓NLRP3, NFATC, NF-κB and caspase-1 ↓IL-1β and IL-13 -↓MPO ↓NO [117] Acetate enema; 10 mM DSS (2.5%) Male C57BL/ 6 mice; n = 10; 5/ group ↓DAI ↓Mucosal break ratio - - [120] Sodium acetate; 200 mM DSS (0.5–2.5%) No Fiber Male C57BL/ 6J mice; n = 20; 5/ group ↓DAI ↑Body weight ↓Colon length ↓Blood neutrophils ↓CXCR2 - - CXCR2, Interleukin 8 receptor; DSS, Dextran sodium sulfate; DAI, Disease Activity Index; MPO, Myeloperoxidase; NFATC, Nuclear factor of activated T cells; NF-κB, Nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; NO, Nitric oxidase; NLRP3, NOD-like receptor protein 3. 22 S. SHIN ET AL. Table 8. Mechanism of actions of probiotics in alleviating IBD with reference sources cited in the far-left column (to be continued) Ref. Active ingredient (where identified) and dose Chemical stimulus Animal Bioactivity Summary Change in gut microbiota Proposed antioxidant mechanism [35] Pt-Lipid@EcN; dose n/i DSS (3%) Sex unspecified, C57BL/6 Mice; n = 15; 4 group ↑Body weight ↓DAI ↑Colon length ↓Histopathology score ↓IL-6, TNF-α and IL-1β ↑Occludin-1 and ZO-1 -↓MPO activity [36] Mesalamine and Lactobacillus acidophilus microparticles (F12);23 mg/kg/day DNBS (15 mg/kg) Female and Male Wistar rats: n = 30; 6/ group ↓Body weight loss, ↑Stool consistency, ↓Lesion score ↓Macroscopy score -↑GSH ↓MPO ↓LPO [96] 7-mix strains (E. hirae, L. casei, S. salivarius, F. prausnitzii, A. muciniphila, C. butyricum, L. salivarius), mix-sup or hu-FMT; 1×10 8 CFU per strain and 0.1 mL/10 g of body weight for hu-FMT. DSS (3%) Male BALB/c Mice; n=30; 6/group ↑Body weight ↓Colon shortening ↓Histology score ↑Occludin, ZO-1 and Muc2 ↓IL-6, IL-1β, IL-12 and TNF-α ↑IL-5 ↓M1 (CD86+) for mixsup only ↑M2(CD206+) macrophages for mixsup and 7 mix only. ↓JAK/STAT3/FOXO3 for mix-sup and 7 mix only. Mix-sup and 7-mix: ↑α-diversity ↑A. muciniphila ↑L. salivarius ↑F. prausnitzii ↑Acetic acid ↑Propionic acid ↑Butyric acid ↑Valeric acid ↑Lactobacillaceae, Lactobacillus, Lachnospiraceae, Lactobacillus murinus in mixsup ↑Bacteroidales in the 7-mix group ↓MPO ↓iNOS for 7mix and mixsup only. [100] Butyrate-producing Veillonella and lactobacillus; 1 × 10 9 CFU mL −1 DSS (2.5%) Male C57BL/6 mice; n = 60; 12/ group ↓Body weight loss ↓DAI score ↓Fecal occult blood ↓Colon shortening ↓Histological scores ↑Occludin ↑Acetic acid ↑Isobutyric, ↑Total SCFA ↓Lactate ↑Ligilactobacillus ↑total Lactic acid bacteria ↑Verrucomicrobiota ↑Akkermansia ↑bacteroides ↑SOD ↑GSH ↓MDA ↓MPO [102]Lactobacillus plantarum ZJ31; 2.5 × 10 9 CFU mL −1 DSS (2.5%) Male BALB/c mice; n = 25; 5/ group ↑Colon weight ↑Colon length ↓Histological score ↓IL-6, IL-8, IL-1β and TNF-α ↑Faecalibacterium ↑Agathobacter, ↑Roseburia. ↑Firmicutes ↓Bacteroidetes ↓Actinobacteria ↑Intestinimonas ↑Butyricoccus ↓Paracoccus ↓Erysipelatoclostridium ↓Acinetobacter ↓Luteimonas ↑Acetic acid ↑Propionic acid ↑Isobutyric and Butyric acid ↑Valeric acid - [108] Butyrate-producing Faecalibacterium prausnitzii A2–165; 1 × 10 9 CFU DNBS (200 mg/kg) Male C57BL/6 mice; n = 24; 8/ group ↑Dact3 ↓Body weight loss ↓IFN-γ, IL-6, IL-17A, MCP-1 -↓MPO activity [111]Propionibacterium freudenreichii; ‘LPF’; 1 × 10 8 CFU and ‘SPFC’; 1 mL DSS (5%) Male SpragueDawley rats; n = 30; 6/ group SPFC: ↓Histopathology score ↑Goblet cell and Mucin LPF: ↑Body weight change ↓ DAI ↓Histopathology score ↑Goblet cells and MUC2 level ↓TNF-α, IL-6, IL-1β SPFC: ↑Acetate ↑Propionate ↑Butyrate LPF: ↑Acetate ↑Propionate ↑Butyrate - [121] Acetate-producing bacteria Christensenella minuta; 1 × 10 9 CFU/ mL DNBS (175 mg/kg) Male C57BL/6J mice; n = 40; 10/ group ↓Macroscopic and microscopic score ↓ Colon weight ↓IL-1β -↓MPO [123]Lactobacillus acidophilus KBL402 and KBL409; 1 × 10 9 CFU DSS (2%) Female C57BL/ 6J mice; n = 32; 8/ group ↑Body weight change % ↓DAI ↑Colon length ↓Histological score ↓FN-γ, IL-1β, IL-4, IL-6, IL-17A, TNF-α ↑Akkermansia ↓Bacteroidetes ↓Mucispirillum ↑Prevotella ↓CCL2 ↓CXCL-1 ↓MPO (Continued) REDOX REPORT 23 Table 8. Continued. Ref. Active ingredient (where identified) and dose Chemical stimulus Animal Bioactivity Summary Change in gut microbiota Proposed antioxidant mechanism [139]Lactobacillus johnsonii; 1 × 10 9 CFU/day DSS (2%) Male C57BL/6 mice; n = 10; 5/ group ↑Colon length ↓Histology score ↑Muc2 and ZO-1+ ↓Macrophages infiltration ↑F4/80+CD11b+Ly-6G ↑IL-10 in ↑C206+ from BMDMs ↑Prevotellaceae, ↑Clostridia, ↑Bacteroidota, ↓Actinobactriota, ↓Lachnospiraceae, ↓Erysipelotrichaceae, ↓Oscillospiraceae ↓Fermicuts - [140] Chinese fermented foods Lactobacillus alimentarius NKU556; 0.2 mg mL –1 Fe 2+ DSS (4%) Male BALB/C mice, n = 60; 12/ group ↓Colon shortening ↓Histological score ↓DAI ↓Body weight loss ↓TNF-α, IL-17, IL-1β, ↓LCN2 ↑Claudin-1, occluding and ZO-1 ↑Hepcidin -↓MDA ↑SOD ↑GSH-PX [141]Lactobacillus acidophilus; 1×10 8 CFU DSS (5%) Male Sprague Dawley rats; n = 70; 10/ group Live L. acidophilus: ↑Body weight ↓DAI ↑Colon length ↓Histologic score ↑Occludin, Claudin, ZO1 and TFF-3 ↓TNF-α, IL-6 and MCP-1 ↑IL-10 ↓NLRP3, Caspase 1 and ASC ↓IL-1β and IL-18 ↑LC3II/I and ↓P62 ↑Fecal acetic acid ↑Propionic acid ↑Butyric acid ↑Caproic acid ↑Blautia fae ↑Faecalibacteria prausnitzii ↑Rumicococcus torques ↑GSH-PX ↓MDA ↑CAT [142]Lactobacillus plantarum CBT LP3; 1 × 10 8 CFU/day DSS (2.5%) Female C57BL/6 mice; n = 25; 5/ group ↓Body weight loss ↓DAI ↓Histomorphological score ↑Colon length ↑Goblet cell count ↓TNF-α, IL-1β and IL-17 -↓iNOS [143]Lactobacillus salivarius; 1 × 10 9 CFU/day DSS (2.5%) C57BL/6JOlaHsd mice; n = 16; 4/ group ↑Blood score ↓Stool score ↓DAI ↑Colon length ↑Transepithelial resistance ↑IL-10 ↑Verrucomicrobia ↑Lactobacillus ↑Clostridia XIVa ↑Akkermansia ↓Prevotella ↓Alloprevotella, ↓Bacteroides ↓Porphyromonadaceae ↓Alistipes ↓MPO activity [144]Lactobacillus acidophilus@hyaluronic acid grafted with phenylboric acid (Lac@HDP); 1 × 10 9 CFU DSS (3%) Female C57BL/6 mice: n = 20; 5/ group ↑Colon length ↓IL-6, IL-1β, TGF-β ↑IL-10 ↑ZO-1 and occludin-1 ↑Bacterial counts ↑Adhesion ability Lac@HDP ↑Bacterial abundance ↓Desulfovibrionaceae ↑Lactobacillus ↑Akkermansia - [146]Porphyromonas gingivalis and Lactobacillus rhamnosus GG probiotics; 50 μg mL −1 DSS (3%) Female C57BL/6 mice; n = 25; 5/ group ↑Colon length ↓DAI ↓Histological activity index ↓IL-17/ Foxp3+ cell ratio ↓Th17/ Treg ratio ↓IL-17A, IL-17F and IL-6 - - [148]Lactobacillus plantarum strains; 1 × 10 9 (Low dose) or 1 × 10 10 (High Dose) CFU/mL/day DSS (3.5%) BALB/c mice Sex n/i; n = 60;12/ group Low Dose: ↑Body weight change% ↓DAI ↑Colon length ↑IL-10 ↓TNF-α, IL-1β and IL-12 High Dose: Same results as the ‘low dose’ PLUS ↓Histological score ↓TLR-4 ↓MyD88, p-p65 and pIkB High Dose: ↑Butyricoccus ↑Bacteroides ↑Lachnospiraceae_NK4A136 ↑Lactobacillus ↑Bifidobacterium ↑Turicibacter ↑Faecalibacterium ↓Campylobacter ↓Aliestipes ↓Parabacteroides ↓Alloprevotella ↓Helicobacter ↓Desulfovibrio ↓Odoribacter ↓Blautia ↓Escherichia-Shigella Low and High Dose: ↓MPO activity (Continued) 24 S. SHIN ET AL. experimental colitis. Phytomedicine. 2020;78:153293. doi:10.1016/ j.phymed.2020.153293 [83] Shang L, Liu Y, Li J, et al. Emodin protects sepsis associated damage to the intestinal mucosal barrier through the VDR/ Nrf2 /HO-1 pathway. Front Pharmacol. 2021;12:724511. doi:10.3389/ fphar.2021.724511 [84] Ito S, Sugumaran M, Wakamatsu K. Chemical reactivities of orthoquinones produced in living organisms: fate of quinonoid products formed by tyrosinase and phenoloxidase action on phenols and catechols. Int J Mol Sci. 2020;21(17):6080. doi:10. 3390/ijms21176080 [85] Cai, Sun M, Xing J, et al. Antioxidant phenolic constituents in roots of Rheum officinale and Rubia cordifolia: structure−radical scavenging activity relationships. J Agric Food Chem. 2004;52(26):7884– 7890. doi:10.1021/jf0489116 [86] Zou F, Qiu Y, Huang Y, et al. Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function. Cell Death Dis. 2021;12(6):582. doi:10.1038/s41419-021-03880-9 [87] Macia L, Tan J, Vieira AT, et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun. 2015;6(1):6734. doi:10.1038/ncomms7734 [88] Barbian ME, Owens JA, Naudin CR, et al. A high fiber diet or supplementation with Lactococcus lactis subspecies cremoris to pregnant mice confers protection against intestinal injury in adult offspring. Gut Microbes. 2024;16(1). doi:10.1080/19490976.2024. 2337317 [89] Magnusson MK, Vidal A, Maasfeh L, et al. Impaired butyrate induced regulation of T cell surface expression of CTLA-4 in patients with ulcerative colitis. Int J Mol Sci. 2021;22(6):3084. doi:10.3390/ijms22063084 [90] Vieira AT, Galvão I, Macia LM, et al. Dietary fiber and the shortchain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice. J Leukoc Biol. 2017;101(1):275– 284. doi:10.1189/jlb.3A1015-453RRR [91] Xia X, Lin H, Luo F, et al. Oryzanol ameliorates DSS-stimulated gut barrier damage via targeting the gut microbiota accompanied by the TLR4/NF-κB/NLRP3 cascade response in vivo. J Agric Food Chem. 2022;70(50):15747–15762. doi:10.1021/acs.jafc.2c04354 [92] Liu H, Wang J, He T, et al. Butyrate: a double-edged sword for health? Adv Nutr. 2018;9(1):21–29. doi:10.1093/advances/nmx009 [93] Tan JK, Macia L, Mackay CR. Dietary fiber and SCFAs in the regulation of mucosal immunity. J Allergy Clin Immunol. 2023;151(2):361–370. doi:10.1016/j.jaci.2022.11.007 [94] Carretta MD, Quiroga J, López R, et al. Participation of short-chain fatty acids and their receptors in gut inflammation and colon cancer. Front Physiol. 2021;12:662739. doi:10.3389/fphys.2021. 662739 [95] Huang C, Du W, Ni Y, et al. The effect of short-chain fatty acids on M2 macrophages polarization in vitro and in vivo. Clin Exp Immunol. 2022;207(1):53–64. doi:10.1093/cei/uxab028 [96] Zhao H, Zhou Y, Xu J, et al. Short-chain fatty acid-producing bacterial strains attenuate experimental ulcerative colitis by promoting M2 macrophage polarization via JAK/STAT3/FOXO3 axis inactivation. J Transl Med. 2024;22(1):369. doi:10.1186/s12967024-05122-w [97] Wang RX, Lee JS, Campbell EL, et al. Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin. Proc Natl Acad Sci USA. 2020;117(21):11648–11657. doi:10.1073/pnas.1917597117 [98] Li G, Lin J, Zhang C, et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut Microbes. 2021;13(1):1968257. doi:10.1080/19490976.2021.1968257 [99] Akhtar M, Chen Y, Ma Z, et al. Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation. Anim Nutr. Mar. 2022;8:350–360. doi:10.1016/j.aninu.2021.11.005 [100] Li N, Wang H, Zhao H, et al. Cooperative interactions between Veillonella ratti and Lactobacillus acidophilus ameliorate DSSinduced ulcerative colitis in mice. Food Funct. 2023;14(23):10475–10492. doi:10.1039/D3FO03898J [101] Godínez-Méndez LA, Gurrola-Díaz CM, Zepeda-Nuño JS, et al. In vivo healthy benefits of galacto-oligosaccharides from Lupinus albus (LA-GOS) in butyrate production through intestinal microbiota. Biomolecules. 2021;11(11):1658. doi:10.3390/biom11111658 [102] Gu Q, Xia C, Liu N, et al. Lactobacillus plantarum ZJ316 alleviates ulcerative colitis by inhibiting inflammation and regulating short-chain fatty acid levels and the gut microbiota in a mouse model. Food Funct. 2023;14(9):3982–3993. doi:10.1039/ D2FO02567A [103] Nishida A, Miyamoto J, Shimizu H, et al. Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice. Biochem Biophys Res Commun. 2021;557:48–54. doi:10.1016/j. bbrc.2021.03.167 [104] Nishida A, Miyamoto J, Shimizu H, et al. Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice. Biochem Biophys Res Commun. 2021;557:48–54. doi:10.1016/j. bbrc.2021.03.167 [105] El-Salhy M, Hatlebakk JG, Hausken T. Possible role of peptide YY (PYY) in the pathophysiology of irritable bowel syndrome (IBS). Neuropeptides. 2020;79:101973. doi:10.1016/j.npep.2019.101973 [106] Cuellar-Núñez ML, Gonzalez de Mejia E, Loarca-Piña G. Moringa oleifera leaves alleviated inflammation through downregulation of IL-2, IL-6, and TNF-α in a colitis-associated colorectal cancer model. Food Res Int. 2021;144:110318. doi:10.1016/j.foodres.2021.110318 [107] Bian Z, Zhang Q, Qin Y, et al. Sodium butyrate inhibits oxidative stress and NF-κB/NLRP3 activation in dextran sulfate sodium salt-induced colitis in mice with involvement of the Nrf2 signaling pathway and mitophagy. Dig Dis Sci. 2023;68(7):2981–2996. doi:10.1007/s10620-023-07845-0 [108] Lenoir M, Martín R, Torres-Maravilla E, et al. Butyrate mediates antiinflammatory effects of Faecalibacterium prausnitzii in intestinal epithelial cells through Dact3. Gut Microbes. 2020;12(1):1826748. doi:10.1080/19490976.2020.1826748 [109] Huang C, Wang J, Liu H, et al. Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway. BMC Med. 2022;20(1):148. doi:10.1186/s12916-022-02352-x [110] Peterson CT, Perez Santiago J, Iablokov SN, et al. Short-chain fatty acids modulate healthy gut microbiota composition and functional potential. Curr Microbiol. 2022;79(5):128. doi:10.1007/ s00284-022-02825-5 [111] Ma S, Yeom J, Lim Y-H. Dairy Propionibacterium freudenreichii ameliorates acute colitis by stimulating MUC2 expression in intestinal goblet cell in a DSS-induced colitis rat model. Sci Rep. 2020;10(1):5523. doi:10.1038/s41598-020-62497-8 [112] Van Hecke T, Vossen E, Goethals S, et al. In vitro and in vivo digestion of red cured cooked meat: oxidation, intestinal microbiota and fecal metabolites. Food Res Int. 2021;142:110203. doi:10. 1016/j.foodres.2021.110203 [113] Ormsby MJ, Johnson SA, Carpena N, et al. Propionic acid promotes the virulent phenotype of Crohn’s disease-associated adherentinvasive Escherichia coli. Cell Rep. 2020;30(7):2297–2305.e5. doi:10.1016/j.celrep.2020.01.078 [114] Motta J-P, Wallace JL, Buret AG, et al. Gastrointestinal biofilms in health and disease. Nat Rev Gastroenterol Hepatol. 2021;18(5):314–334. doi:10.1038/s41575-020-00397-y [115] Xie Z, Li M, Qian M, et al. Co-cultures of Lactobacillus acidophilus and Bacillus subtilis enhance mucosal barrier by modulating gut microbiota-derived short-chain fatty acids. Nutrients. 2022;14(21):4475. doi:10.3390/nu14214475 [116] Abdel-Razek EA-N, Mahmoud HM, Azouz AA. Management of ulcerative colitis by dichloroacetate: impact on NFATC1/NLRP3/ IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification. Inflammopharmacology. 2024;32(1):667–682. doi:10.1007/s10787-023-01362-2 [117] Nakano T, Uchiyama K, Ushiroda C, et al. Promotion of wound healing by acetate in murine colonic epithelial cell via c-Jun Nterminal kinase activation. J Gastroenterol Hepatol. 2020;35(7):1171–1179. doi:10.1111/jgh.14987 [118] Leung HKM, Lo EKK, Chen C, et al. Zearalenone attenuates colitis associated colorectal tumorigenesis through Ras/Raf/ERK pathway suppression and SCFA-producing bacteria promotion. Biomed Pharmacother. 2023;164:114973. doi:10.1016/j.biopha. 2023.114973 REDOX REPORT 31 [119] Li S, Wang X, Wang G, et al. Ethyl acetate extract of Selaginella doederleinii Hieron induces cell autophagic death and apoptosis in colorectal cancer via PI3K-Akt-mTOR and AMPKα-signaling pathways. Front Pharmacol. 2020;11:565090. doi:10.3389/fphar. 2020.565090 [120] Shen S, Prame Kumar K, Wen SW, et al. Deficiency of dietary fiber modulates gut microbiota composition, neutrophil recruitment and worsens experimental colitis. Front Immunol. 2021;12:619366. doi:10.3389/fimmu.2021.619366 [121] Kropp C, Le Corf K, Relizani K, et al. The keystone commensal bacterium Christensenella minuta DSM 22607 displays anti-inflammatory properties both in vitro and in vivo. Sci Rep. 2021;11(1):11494. doi:10.1038/s41598-021-90885-1 [122] Wei X, Yu L, Ye Z, et al. Responses of the colonic microbiota and metabolites during fermentation of alginate oligosaccharides in normal individuals: an in vitro and in vivo study. Food Biosci. 2023;52:102413. doi:10.1016/j.fbio.2023.102413 [123] Kim W-K, Han DH, Jang YJ, et al. Alleviation of DSS-induced colitis via Lactobacillus acidophilus treatment in mice. Food Funct. 2021;12(1):340–350. doi:10.1039/D0FO01724H [124] Dodd D, Spitzer MH, Van Treuren W, et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017;551(7682):648–652. doi:10.1038/nature24661 [125] Tarasiuk A, Eibl G. Nutritional support and probiotics as a potential treatment of IBD. Curr Drug Targets. 2020;21(14):1417–1427. doi:10.2174/1389450121666200504075519 [126] Yadav MK, Kumari I, Singh B, et al. Probiotics, prebiotics and synbiotics: safe options for next-generation therapeutics. Appl Microbiol Biotechnol. 2022;106(2):505–521. doi:10.1007/s00253021-11646-8 [127] Martyniak A, Medyńska-Przęczek A, Wędrychowicz A, et al. Prebiotics, probiotics, synbiotics, paraprobiotics and postbiotic compounds in IBD. Biomolecules. 2021;11(12):1903. doi:10.3390/ biom11121903 [128] Dang X, Xu M, Liu D, et al. Assessing the efficacy and safety of fecal microbiota transplantation and probiotic VSL#3 for active ulcerative colitis: A systematic review and meta-analysis. PLoS One. 2020;15(3):e0228846. doi:10.1371/journal.pone.0228846 [129] Ulisse S, Gionchetti P, D’Alo S, et al. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J Gastroenterol. 2001;96(9):2691–2699. doi:10.1111/j.1572-0241.2001.04139.x [130] Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119(2):305–309. doi:10.1053/gast.2000.9370 [131] Tursi A, Brandimarte G, Giorgetti GM, et al. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute mildto-moderate ulcerative colitis. Med Sci Monit. 2004;10(11):PI126– PI131. [132] Mardini HE, Grigorian AY. Probiotic Mix VSL#3 Is effective adjunctive therapy for mild to moderately active ulcerative colitis. Inflamm Bowel Dis. 2014;20(9):1562–1567. doi:10.1097/MIB. 0000000000000084 [133] Sood A, Midha V, Makharia GK, et al. The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7(11):1202–1209.e1. doi:10.1016/j.cgh.2009.07.016 [134] Iheozor-Ejiofor Z, Kaur L, Gordon M, et al. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2020;3(3):CD007443. doi:10.1002/14651858.CD007443.pub3 [135] Cheng H, Ma Z, Yu B, et al. Quality assessment of clinical guidelines on probiotics therapy in children with IBD using the AGREE II instrument. J Clin Pharm Ther. 2021;46(4):1155–1165. doi:10. 1111/jcpt.13422 [136] Campieri M, Rizzello F, Venturi A, et al. Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of post-operative recurrence of Crohn’s disease: a randomized controlled study VS mesalamine. Gastroenterology. 2000;118(4):A781. doi:10.1016/ S0016-5085(00)85267-1 [137] Bourebaba Y, Marycz K, Mularczyk M, et al. Postbiotics as potential new therapeutic agents for metabolic disorders management. Biomed Pharmacother. 2022;153:113138. doi:10.1016/j.biopha. 2022.113138 [138] Shamoon M, Martin NM, O’Brien CL. Recent advances in gut microbiota mediated therapeutic targets in inflammatory bowel diseases: emerging modalities for future pharmacological implications. Pharmacol Res. 2019;148:104344. doi:10.1016/j.phrs. 2019.104344 [139] Jia D-J-C, Wang Q-W, Hu Y-Y, et al. Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206 + macrophages IL-10 activation. Gut Microbes. 2022;14(1):2145843. doi:10.1080/ 19490976.2022.2145843 [140] Zhao N, Liu J-M, Yang F-E, et al. A novel mediation strategy of DSSinduced colitis in mice based on an iron-enriched probiotic and in vivo bioluminescence tracing. J Agric Food Chem. 2020;68(43):12028–12038. doi:10.1021/acs.jafc.0c05260 [141] Li P, Chen G, Zhang J, et al. Live Lactobacillus acidophilus alleviates ulcerative colitis via the SCFAs/mitophagy/NLRP3 inflammasome axis. Food Funct. 2022;13(5):2985–2997. doi:10.1039/D1FO03360C [142] Kim DH, Kim S, Ahn JB, et al. Lactobacillus plantarum CBT LP3 ameliorates colitis via modulating T cells in mice. Int J Med Microbiol. 2020;310(2):151391. doi:10.1016/j.ijmm.2020.151391 [143] Iyer N, Williams MA, O’Callaghan AA, et al. Lactobacillus salivarius UCC118TM dampens inflammation and promotes microbiota recovery to provide therapeutic benefit in a DSS-induced colitis model. Microorganisms. 2022;10(7):1383. doi:10.3390/ microorganisms10071383 [144] Huang Q-X, Liang J-L, Yang C-H, et al. Stimulation-responsive mucoadhesive probiotics for inflammatory bowel disease treatment by scavenging reactive oxygen species and regulating gut microbiota. Biomaterials. 2023;301:122274. doi:10.1016/j. biomaterials.2023.122274 [145] Chaiyasut C, Sivamaruthi BS, Lailerd N, et al. Probiotics supplementation improves intestinal permeability, obesity index and metabolic biomarkers in elderly Thai subjects: a randomized controlled trial. Foods. 2022;11(3):268. doi:10.3390/foods11030268 [146] Jia L, Wu R, Han N, et al. Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2. Clin Transl Immunology. 2020;9(11):e1213. doi:10. 1002/cti2.1213 [147] Schultz M, Timmer A, Herfarth HH, et al. Lactobacillus GG in inducing and maintaining remission of Crohn’s disease. BMC Gastroenterol. 2004;4:5. doi:10.1186/1471-230X-4-5. [148] Yu P, Ke C, Guo J, et al. Lactobacillus plantarum L15 alleviates colitis by inhibiting LPS-mediated NF-κB activation and ameliorates DSSinduced gut microbiota dysbiosis. Front Immunol. 2020;11:575173. doi:10.3389/fimmu.2020.575173 [149] Liu M, Ding J, Zhang H, et al. Lactobacillus casei LH23 modulates the immune response and ameliorates DSS-induced colitis via suppressing JNK/p-38 signal pathways and enhancing histone H3K9 acetylation. Food Funct. 2020;11(6):5473–5485. doi:10.1039/ D0FO00546K [150] Isozaki S, Konishi H, Fujiya M, et al. Probiotic-derived polyphosphate accelerates intestinal epithelia wound healing through inducing platelet-derived mediators. Mediators Inflamm. 2021;2021:1–14. doi:10.1155/2021/5582943 [151] Cui Q, Tian X-Y, Liang X, et al. Bifidobacterium bifidum relieved DSSinduced colitis in mice potentially by activating the aryl hydrocarbon receptor. Food Funct. 2022;13(9):5115–5123. doi:10.1039/ D1FO04219J [152] Kang S, Lin Z, Xu Y, et al. A recombinant Bifidobacterium bifidum BGN4 strain expressing the streptococcal superoxide dismutase gene ameliorates inflammatory bowel disease. Microb Cell Fact. 2022;21(1):113. doi:10.1186/s12934-022-01840-2 [153] Hrdý J, Alard J, Couturier-Maillard A, et al. Lactobacillus reuteri 5454 and Bifidobacterium animalis ssp. lactis 5764 improve colitis while differentially impacting dendritic cells maturation and antimicrobial responses. Sci Rep. 2020;10(1):5345. doi:10.1038/s41598-02062161-1 [154] Ma L, Lyu W, Song Y, et al. Anti-inflammatory effect of Clostridium butyricum-derived extracellular vesicles in ulcerative colitis: impact on host microRNAs expressions and gut microbiome profiles. Mol Nutr Food Res. 2023;67(13):e2200884. doi:10.1002/mnfr. 202200884 [155] Hua H, Pan C, Chen X, et al. Probiotic lactic acid bacteria alleviate pediatric IBD and remodel gut microbiota by modulating macrophage polarization and suppressing epithelial apoptosis. Front Microbiol. 2023;14:1168924. doi:10.3389/fmicb.2023.1168924 32 S. SHIN ET AL. [156] Qu S, Fan L, Qi Y, et al. Akkermansia muciniphila alleviates dextran sulfate sodium (DSS)-induced acute colitis by NLRP3 activation. Microbiol Spectr. 2021;9(2):e0073021. doi:10.1128/Spectrum. 00730-21 [157] Zhai R, Xue X, Zhang L, et al. Strain-specific anti-inflammatory properties of two Akkermansia muciniphila strains on chronic colitis in mice. Front Cell Infect Microbiol. 2019;9:239. doi:10. 3389/fcimb.2019.00239 [158] Sun S, Xu X, Liang L, et al. Lactic acid-producing probiotic Saccharomyces cerevisiae attenuates ulcerative colitis via suppressing macrophage pyroptosis and modulating gut microbiota. Front Immunol. 2021;12:777665. doi:10.3389/fimmu.2021.777665 [159] Santana PT, Rosas SLB, Ribeiro BE, et al. Dysbiosis in inflammatory bowel disease: pathogenic role and potential therapeutic targets. Int J Mol Sci. 2022;23(7):3464. doi:10.3390/ijms23073464 [160] Singh SB, Coffman CN, Varga MG, et al. Intestinal alkaline phosphatase prevents sulfate reducing bacteria-induced increased tight junction permeability by inhibiting snail pathway. Front Cell Infect Microbiol. 2022;12:882498. doi:10.3389/fcimb.2022.882498 [161] Na YR, Stakenborg M, Seok SH, et al. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol. 2019;16(9):531–543. doi:10. 1038/s41575-019-0172-4 [162] Fusco W, Lorenzo MB, Cintoni M, et al. Short-Chain fatty-acid-producing bacteria: key components of the human Gut microbiota. Nutrients. 2023;15(9):2211. doi:10.3390/nu15092211 [163] Chen L, Shao J, Luo Y, et al. An integrated metabolism in vivo analysis and network pharmacology in UC rats reveal anti-ulcerative colitis effects from Sophora flavescens EtOAc extract. J Pharm Biomed Anal. 2020;186:113306. doi:10.1016/j.jpba.2020.113306 [164] Long-Smith C, O’Riordan KJ, Clarke G, et al. Microbiota–gut–brain axis: new therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2020;60(1):477–502. doi:10.1146/annurev-pharmtox-010919-023628 [165] Li Y, Zhang S-X, Yin X-F, et al. The gut microbiota and its relevance to peripheral lymphocyte subpopulations and cytokines in patients with rheumatoid arthritis. J Immunol Res. 2021;2021:1– 9. doi:10.1155/2021/6665563 [166] Wilchowski SM. The role of the gut microbiome in psoriasis: from pathogens to pathology. J Clin Aesthet Dermatol. 2022;15(3 Suppl 1):S25–S28. [Online]. http://www.ncbi.nlm.nih.gov/pubmed/ 35382440. [167] Federici S, Kredo-Russo S, Valdés-Mas R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell. 2022;185(16):2879–2898.e24. doi:10.1016/j.cell.2022.07.003 [168] Vich Vila A, Collij V, Sanna S, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun. 2020;11(1):362. doi:10.1038/s41467019-14177-z [169] Wastyk HC, Fragiadakis GK, Perelman D, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137–4153.e14. doi:10.1016/j.cell.2021.06.019 [170] Wang Y, Qi W, Song G, et al. High-fructose diet increases inflammatory cytokines and alters gut microbiota composition in rats. Mediators Inflamm. 2020;2020:1–10. doi:10.1155/2020/6672636 [171] Zhang M, Mo R, Wang H, et al. Grape seed proanthocyanidin improves intestinal inflammation in canine through regulating gut microbiota and bile acid compositions. FASEB J. 2023;37(12): e23285. doi:10.1096/fj.202300819RR [172] Zhang H, Wang Y, Su Y, et al. The alleviating effect and mechanism of Bilobalide on ulcerative colitis. Food Funct. 2021;12(14):6226– 6239. doi:10.1039/D1FO01266E [173] Li G, Lin J, Zhang C, et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut Microbes. 2021;13(1):1968257. doi:10.1080/19490976.2021.1968257 REDOX REPORT 33