Probiotic Effects against Virus Infections: New Weapons for an Old War

foods Review Probiotic Effects against Virus Infections: New Weapons for an Old War Aroa Lopez-Santamarina 1, Alexandre Lamas 1, Alicia del Carmen Mondragón1, Alejandra Cardelle-Cobas 1, Patricia Regal 1, JoséAntonio Rodriguez-Avila 2, JoséManuel Miranda 1,* , Carlos Manuel Franco 1 and Alberto Cepeda 1   Citation: Lopez-Santamarina, A.; Lamas, A.; del Carmen Mondragón, A.; Cardelle-Cobas, A.; Regal, P.; Rodriguez-Avila, J.A.; Miranda, J.M.; Franco, C.M.; Cepeda, A. Probiotic Effects against Virus Infections: New Weapons for an Old War. Foods 2021, 10, 130. https://doi.org/10.3390/ foods10010130 Received: 17 December 2020 Accepted: 7 January 2021 Published: 9 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Laboratorio de Higiene Inspección y Control de Alimentos, Departamento de Química Analítica, Nutrición y Bromatología, Universidad de Santiago de Compostela, 27002 Lugo, Spain; [email protected] (A.L.-S.); alexandr[email protected] (A.L.); [email protected] (A.d.C.M.); [email protected] (A.C.-C.); patricia.r[email protected] (P.R.); [email protected] (C.M.F.); [email protected] (A.C) 2 Área Académica de Química, Instituto de Ciencias Básicas e Ingeniería, Universidad Autónoma del Estado de Hidalgo, Carretera Pachuca-Tulancingo Km. 4.5, Pachuca 42076, Hidalgo, Mexico; [email protected] *Correspondence: [email protected] Abstract: This review aimed to gather the available literature investigating the effects of probiotics against the most common viral infections using in vitro trials in cell lines and in vivo clinical trials in both experimental animals and humans. Probiotics were employed to prevent and reduce symptoms of infections caused by common viruses, especially respiratory tract viruses, but also for viral digestive infections (such as rotavirus, coronavirus, or norovirus) and other viral infections (such as viruses that cause hepatitis, human papillomavirus, human immunodeficiency virus, and herpes simplex virus). Different probiotics have been studied to see their possible effect against the abovementioned viruses, among which different Lactobacillus species, Bifidobacterium,Clostridium, Enterococcus, and Streptococcus can be highlighted. In many cases, mixtures of various probiotic strains were used. Although the results obtained did not show similar results, in most cases, probiotic supplementation improved both barrier and biochemical immune responses, decreased susceptibility to viral infections, and enhanced the effects of concomitant vaccines. Works collected in this review show a beneficial effect of probiotics in the prevention and treatment of different viral infections. We found interesting results related to the prevention of viral infections, reduction of the duration of diseases, and decrease of symptoms. Keywords: probiotic; gut microbiota; viral infection; viruses; influenza 1. Introduction The mammalian intestine is a complex ecosystem, as it is a point of symbiosis between the host and approximately 10 14 types of resident microorganisms, which have been acquired even before birth and continue to exist throughout life [ 1 ]. This community of microorganisms is often called gut microbiota (GM) [ 2 , 3 ]. The microbiome includes the microorganisms and their genetic material, which importantly contributes to host physiology by providing genetic elements that are not already present in the host genome [ 4 ]. Among GM microbes, some species can confer beneficial effects to the physiology and metabolism of the host. Among them, the Food and Agriculture Organization of the United Nations [ 5 ] defined the term probiotic as “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host.” Probiotics are live bacteria that can be given as a supplement or in a food product that, if ingested in an adequate amount, can provide benefits to the host. Probiotics are composed mainly of lactic acid bacteria (LAB) and complex carbohydrate fermenters, which are part of the normal GM of humans and animals. Supplementation with probiotics can provide benefits to the host directly Foods 2021,10, 130. https://doi.org/10.3390/foods10010130 https://www.mdpi.com/journal/foods Foods 2021,10, 130 2 of 20 by preventing infection, or indirectly by enhancing the immune response of the host. There is scientific evidence that consumption of probiotics can play a role in increasing defense against external pathogens, thus maintaining the balance of the intestinal immune system [6,7]. Viral infectious diseases nowadays have a great impact on humankind. Viral infections produce variable morbidity and mortality, negatively affecting community health and causing wide economic losses [ 8 ]. The best example of this global threat may be the infectious disease caused by the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which during the 2019–2020 pandemic has infected millions of people worldwide [ 8 ]. Consequently, it is important to find alternative and safe ways to prevent viral infections and reduce the morbidity and mortality of viral infections. Even partially effective therapies for the treatment and prevention of viral infections can reduce the mortality, morbidity, and economic losses caused by these infections [9]. A large number of antiviral drugs that may be effective in certain infections are now available; however, the appearance of new viral strains through mutations is a major threat. Although combination therapies of drugs are effective against several viral diseases, it is always desirable to have additional approaches that may be used as preventives or supplemental therapies [ 10 ]. Among different strategies to prevent and reduce viral infections, adequate nutrition, including nutrients or food ingredients that enhance and potentiate immune response, are useful alternatives to reduce the number of infections and their severity. One nutritional strategy used in recent years to improve human immunity and reduce the ability to be infected is the intake of probiotics [11]. The main objective of this work was to provide a literature review of the effects of probiotic agents in the prevention and reduction of the severity of symptoms in viral infections, with special emphasis on the most recently published works. 2. Probiotics and the Immune System According to the FAO consensus [ 5 ], criteria for probiotic bacteria include that the bacterial strain: (1) Must be able to survive in the gastrointestinal tract and proliferate in the intestine; (2) must benefit the host through growth or activity in the human body; (3) must be non-toxic and non-pathogenic; (4) must provide protection against pathogenic microorganisms that employ multiple mechanisms; and (5) must lack transferable antibiotic resistance. Bacterial strains of the same genus and species can have completely different effects on the host. Given this, the search for probiotic agents has evolved, and now it is even feasible to modify probiotics with increasingly complex functionalities by transferring mobile genetic elements [ 12 ]. Because probiotics can possess antiviral activity, they can be chosen as alternatives to or complementary antiviral therapies [ 13 ]. Although nowadays there is a significant demand for bioactive components such as probiotics in Western countries, consumers are reluctant to change their dietary habits [ 14 ]. Although in some cases probiotic products were developed by pharmaceutical industry, they have become increasingly popular among the public due to their inclusion in functional foods, generating wider acceptance among consumers [ 15 ]. This suggests that there is great potential for foods that are consumed regularly when they are converted to functional foods [ 14 ], that show better consumer acceptance than pharmacological presentations. The most common genus of microbes used as probiotics are LAB, such as Lactobacillus [ 1 ], and primary oligosaccharide fermenters such as Bifidobacterium [ 16 ], although other genera, and even yeast, such as Saccharomyces, were proposed and used as probiotic agents [ 1 ]. One mechanism that probiotic strains, known as immunobiotics, can provide to human or animal health is modulating the mucosal and systemic immune systems [ 17 , 18 ], thus protecting against infectious diseases, including viral infections [13,19]. The consumption of probiotics has different beneficial effects on human health such as the production of antimicrobial and anti-adhesion substances against pathogens, thus facilitating the modulation of the immune system [ 20 ]. Probiotic bacteria can also inhibit the adhesion of the invading virus to the host-cell receptor by binding to it [ 13 ]. Moreover, Foods 2021,10, 130 3 of 20 probiotics can exert antiviral activity by direct probiotic-virus interaction, production of metabolites with antiviral inhibitory activity, or by stimulating the immune system of the host [ 13 ]. Probiotics may indirectly interfere with the virus by altering the state of cells, stimulating innate and adaptive immunity, or enhancing or suppressing associated molecular signaling pathways [ 21 ]. Probiotic bacteria can also have a protective effect against virus particles competing for adhesion to the cell surface. This has been tested in vitro and reported as a useful mechanism for cell protection in case of mucosal virus infections [ 22 ]. Another way of actuation of probiotics is the regulation of innate immunity using toll receptors and different signaling pathways, thus reducing inflammatory processes [ 23 ]. This regulation in innate immune system of the host can be kept increasing phagocytic activity, the activity of leukocytes (polymorphonuclears and monocytes), the expression of some receptors that are associated with phagocytosis, and the microbicidal function of neutrophils [ 13 ]. Different scientific studies showed that viruses, when they enter the body, activate an innate immune response where the inflammasomes are responsible for destroying the pathogens. The immune system detects pathogens in multiple ways, and there are two first-line of defense systems against viruses: The production of Type I interferons and interleukins (IL) IL-1 β and IL-18 by inflammasomes. On the one hand, type I interferons promote an antiviral state in the infected host, and on the other hand, cytokines, including IL, induce inflammatory processes and modulate immune responses, producing antiviral effects [ 24 ]. For this reason, probiotic bacteria can regulate the activation of the inflammasome in organisms that have previously suffered inflammation due to viral infections. [24]. Another beneficial effect of probiotics is their capacity to help mature and activate the mucosal immune system by secreting metabolites such as organic acid, short chain fatty acids (SCFA), hydrogen peroxide, coagulation molecules, and bacteriocins, which are antimicrobial compounds [ 25 , 26 ]. These metabolites, particularly SCFAs, influence the gut epithelial and immune cells directly, enhancing the immune response. It was demonstrated that SCFAs reduced pattern recognition receptor (PRR) stimulation through activation of activated B-cell nuclear factor kappa-light-chain-enhancer and tumor necrosis factoralpha (TNF α ) [ 27 ]. In in vitro alveolar macrophages, it has been seen that the induction of low-level synthesis of nitric oxide can also influence the protective action of probiotic bacteria against viruses in respiratory cells [ 28 ]. Many studies have demonstrated that probiotics can increase the CD4+ lymphocytes count and regulate TNFα , IL-6, IL-8, IL-10, and IL-12 [26]. 3. Major Viruses Involved in Human Diseases Nowadays, there are up to 200 species of viruses that can infect humans, and their number is increasing at a rate of 3–4 per year [ 29 ]. Consequently, most new human pathogens are viruses, and it is common for the virus to be of animal origin. A substantial proportion of mammalian viruses may cross the species barrier reaching humans. However, only a small number of these have human-to-human transmission and are therefore capable of causing human outbreaks. It will be practically inevitable that new human viruses will continue to emerge, and thus, an effective global surveillance system for new viruses is needed [29]. Although viruses can cause a wide variety of infections in different organs and systems of the human body, viruses were split, for this literature review, into three groups: Respiratory viruses, digestive viruses, and other viruses. Acute viral respiratory infections are among the leading causes of death worldwide, accounting for more than 4 million deaths per year [ 11 ]. In addition, these viruses are a leading cause of pediatric morbidity and mortality worldwide because of the immature immune system of the babies. On the other hand, the elderly are more susceptible to serious complications due to their weakened immune system [11]. These viruses spread easily between humans due to airborne transmission through aerosols, causing outbreaks that are very difficult to control [ 30 ]. Viral respiratory pathogens Foods 2021,10, 130 4 of 20 belong to various virus families, so RNA-containing viruses are more significant: Picornaviridae,Orthomyxoviridae,Paramyxoviridae,Reoviridae,Coronaviridae, and DNA-containing viruses, such as Adenoviridae and Parvoviridae [ 11 , 31 ]. Individuals can also be infected simultaneously with multiple viruses, and in some cases, multiple viruses have synergistic effects against host health [11,27]. Regarding viral gastrointestinal infections, different viruses, such as rotavirus (RV), norovirus (NV), or calicivirus (CV; including the agent Norwalk and astrovirus), can infect the human gastrointestinal tract and are responsible for many illnesses related to childhood diarrhea and gastroenteritis outbreaks worldwide [ 20 ]. These viruses have uncoated RNA, which makes them highly infectious and are transmitted in a fecal-oral manner. These infections are usually mild to moderate in severity and short in duration [ 32 ]. Rotavirus was traditionally the most common cause of severe dehydrating diarrhea in children, estimated to cause approximately 200,000 deaths in children under five years of age each year [ 19 ]. After the large-scale implementation of RV vaccines, NV is now the leading cause of severe diarrhea in children in developed countries and is also considered the most common cause of foodborne illness, nowadays associated with approximately 18% of gastroenteritis cases worldwide [ 32 ]. Astroviruses account for 2–9% of pediatric gastroenteritis cases worldwide [ 32 ]. There are enteric viruses that replicate in the gastrointestinal tract but are asymptomatic, such as reovirus or poliovirus, that can cause severe disease after spreading to peripheral tissues [32]. Another important group of viral infections affecting humans worldwide are liver infections. Among them, enterically-transmitted Hepatitis A (HAV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Hepatitis E (HEV) viruses are causes of acute viral hepatitis in humans [ 33 , 34 ]. These viruses are transmitted through various routes, such as blood transfusions, sexual contact, and consumption of water or food contaminated by feces. HAV use the latter route for transmission; therefore, their outbreaks are more common in underdeveloped countries [35]. Skin viral infections include a large variety of viral agents, among which herpes zoster, which is caused by the reactivation in adults of the varicella-zoster virus, stands out. Herpes viruses can cause a primary infection, establish a latent infection in a specific set of cells in their host, and then reactivate when immunity weakens [ 36 ]. One of the most common members of the herpes virus family is cytomegalovirus (CMV), and more than 80% of primary infections occur in transplants. Herpes simplex virus (HSV) mainly affects the genital and perioral regions [ 36 ]. Another virus that causes human skin infections is the human papillomavirus (HPV), which presents several different types of warts, depending on the infected surface and its relative humidity, and pressure patterns [ 37 ]. Human papillomavirus represents a diverse group of viruses that primarily infect epithelial and mucosal tissues [ 38 ]. Polyomaviruses have been suspected as potential etiological agents in human skin cancer. These viruses infect epithelial tissues throughout the body, producing benign and malignant lesions, including common and genital warts [39]. Concerning viruses that can cause neurological infections, rabies virus (RABV) is one of the diseases that has been known since the beginning of civilization and has caused much fear. According to the World Health Organization [ 40 ], more than 59,000 and 21,476 deaths have been recorded worldwide and in Africa, respectively, due to this virus. Rabies is a disease of zoonotic origin caused by neurotropic viruses and is mostly spread by rabid animals, belongs to the genus lyssavirus, family Rhabdoviridae [ 41 ]. Other viral neurological infections are caused by arboviruses, which include several families of viruses that are transmitted by arthropod vectors. The arbovirus group includes Flaviviridae,Togaviridae, Bunyaviridae, and Reoviridae families that possess a high capacity to adapt rapidly to changing environmental and host conditions [ 42 ]. On the other hand, the most common cause of epidemic viral encephalitis in the United States today is West Nile virus infection. The incidence of this virus has increased significantly since 2008, especially in southern Europe. This and other mosquito-borne flaviviruses are considered endemic in Europe, such as Usutu virus [43]. Foods 2021,10, 130 5 of 20 There are also a large variety of hematological viruses, which cause infections with hemorrhagic fevers, that are RNA viruses encased in a lipid bilayer derived from the host 0 s cell membrane [ 44 ]. Viral hemorrhagic fevers are typically endemic in some regions, can cause large outbreaks, and have high mortality rates. They are characterized by an acute febrile syndrome with hemorrhages and affect both humans and animals [44,45]. 4. Probiotic Usage against Respiratory Viruses It has been demonstrated that the intestinal microbiota affects the health of the lungs due to the direct relationship between the microbiota and the lungs, known as the “gut-lung axis”. This axis is bidirectional, so endotoxins and microbial metabolites can affect the lung through the blood, and on the other hand, when inflammation takes place in the lung it can affect the intestinal bacteria [ 23 ]. Previous studies have found respiratory infections that are related with a change in the composition of the GM [ 23 ]. For example, mice with influenza viral infections in their respiratory tract have increased Enterobacteriaceae and reduced Lactobacillus and Lactococcus in their GM [ 46 ]. Secreted metabolites and immunomodulatory signals, such as secondary bile acids, secreted by commensal bacteria bind to their receptors in innate cells, such as macrophages, stimulating their metabolism and functions [ 23 ]. Additionally, it was demonstrated in murine models that removing some bacterial species from the GM by antibiotic treatments leads to an increased risk of influenza virus [46]. Disrupting the adhesion of the virus to mucosal cells could be beneficial to the host. Probiotic bacteria could bind directly to the virus, producing this disruption [ 25 ]. However, despite the abovementioned results about probiotic bacteria in the prevention and treatment of respiratory viral infections, nowadays there is no clear consensus about this matter, because on the one hand there are clinical trials that demonstrate the benefit of the use of probiotics in respiratory infections, but other clinical trials did not obtain any advantage after probiotic bacteria usage. An important meta-analysis, with more than 8000 preterm infants included in several clinical trials, demonstrated that patients receiving enteral supplementation with probiotics showed a reduction in mortality caused by respiratory infections [ 47 ]. Viruses are especially important in respiratory tract infections because they cause more than 90% of upper respiratory tract infections [ 48 ]. The previous works regarding the effect of probiotic supplementation on viral respiratory infections is shown in Table 1. In most cases, the trials investigating this relationship were performed in mouse models [ 49 – 63 ], but some were also in clinical trials with children [ 64 – 68 ], adults volunteers [ 9 , 69 – 77 ], and the elderly [ 78 , 79 ]. The probiotic bacteria employed to prevent respiratory viral infections, in most cases, were Lactobacillus strains. However, other bacterial genera were also employed, such as Clostridium [ 69 ], Bacillus [ 69 ], Enterococcus [ 69 ], Bifidobacterium [ 25 , 65 , 67 , 68 , 77 , 80 ], Streptococcus [81], and Propionibacterium [67]. The lack of consensus on probiotic strains/gender may be due to differences in studies conducted and outcomes reported measures, the length of intervention, study populations used (children vs. adults), bacterial dose (10 6 –10 10 CFU/day), or different matrices (milk, yogurt, capsules) used. Additionally, decreased immunity due to aging may partly explain the conflicting results in the elderly [ 9 ]. For instance, it was demonstrated that specific strains of lactobacilli could bind and inactivate flu-like respiratory virus in vitro [ 9 ]. Probiotic lactobacilli were reported to protect against respiratory tract infections by modifying innate and acquired host immune responses [ 50 ]. Additionally, a concrete lactobacilli strain (L. plantarum DK119) can prevent influenza A H1N1 and H3N2 infections and mortality in a mouse model, promoting innate host immunity to influenza infection by modulating alveolar macrophages and dendritic cells [51]. Foods 2021,10, 130 6 of 20 Table 1. Effects of probiotics against respiratory viruses. Type of Study Probiotics Dosage and Time of Exposure Viruses Main Findings Reference In vivo using female BALB/c mice 140 different strains of lactic acid bacteria (LAB) 120 mg LAB/day for 28 days Influenza A/X/31 (H3N2) virus Lactobacillus plantarum AYA protects against respiratory influenza virus infection and decreased influenza lethality in mice [49] In vivo using 13 female BALB/c mice Lyophilized Lactobacillus rhamnosus GG (LGG) and Lactobacillus gasseri TMC0356 10 mg of lyophilized LGG and L. gasseri for 19 days Influenza virus A/PR/8/34 (H1N1) The clinical symptom scores and pulmonary virus titers of mice administered oral LGG and L. gasseri were significantly ameliorated [50] In vivo using 96 elderly volunteers Yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (1073R-1-yogurt) 100g of 1073R-1-yogurt for 12 weeks Influenza A virus subtype H3N2-bound Consumption of fermented yogurt affected influenza A virus subtype H3N2-bound Immunoglobulin A (IgA) levels in saliva. [78] In vivo trial using female BALB/c mice L. plantarum DK 119 Intragastric administration (200 µL of 10 8 –10 9 colony count units (CFU) daily for 10 days) or intranasal (107–109CFU/mouse) H1N1 and H3N2 influenza viruses L. plantarum protects against infection with H1N1 and H3N2 influenza viruses by enhancing the innate immunity of CD11c+ dendritic and macrophage cells and antiviral cytokines [51] In vivo using female BALB/c mice L. plantarum 06CC2 20 mg/mouse, twice daily for 10 days Influenza A/PR/8/34 (H1N1) virus L. plantarum relieved influenza symptoms in mice in correlation with increased NK cell activity associated with increased production of interferon-αand Th1 cytokines through gut immunity and reduction of TNF-αin the early stage of infection [52] In vivo using 15 patients Clostridium butyricum CBM588, Bacillus subtilis (unspecified strain), and Enterococcus faecium (unspecified strain) Two tablets of probiotic compound were administered three times per day (~107CFU/tablet for CBM588 and 108CFU for B. subtilis and E. faecium enteric-coated capsules Influenza virus H7N9 No beneficial effects have been seen in the administration of C. butyricum against H7N9 infection. Administration of B. subtilis and E. faecium improved the secondary infection. [69] In vivo using specific pathogen-free female BALB/c mice L. rhamnosus M21 (KCTC 10965BP) Oral administration of 0.3 mL of 1×109CFU/mL of L. rhamnosus Influenza virus A/NWS/3 3 (H1N1) L. rhamnosus increases the production of IgA and decreases the recruitment of inflammatory cells in the lungs, thus exhibiting anti-influenza activity by changing the host response to Th1 [53] Clinical trial in in 272 subjects L. plantarum HEAL 9 (DSM 15312) and Lactobacillus paracasei 8700:2 (DSM 13434) Subjects were supplemented daily with either 109CFU of probiotics for 12 weeks Common cold viruses Oral intake of the strains L. plantarum and L. paracasei decreases the total symptom score and especially the pharyngeal symptoms of common cold infections [70] Foods 2021,10, 130 7 of 20 Table 1. Cont. Type of Study Probiotics Dosage and Time of Exposure Viruses Main Findings Reference Clinical trial in 233 volunteers L. paracasei N1115 Volunteers were given 100-mL bottles of yogurt, which contained living L. paracasei 3.6 x 109 CFU, three bottles per day for 12 weeks Viruses causing upper respiratory tract infections The intake of yogurt containing L. paracasei could protect against the risk of acute upper respiratory tract infection in the mid-aged and elderly, might be that L. paracasei stimulated T-cell immunity [71] Clinical trial in 136 subjects L. paracasei, Lactobacillus casei 431, and Lactobacillus fermentum PCC All subjects received once-daily doses of probiotic drink (150 mL) that contained L. paracasei at 3×107CFU/mL, L. casei at 3×107CFU/mL, and L. fermentum at 3×106CFU/mL or placebo drink for 12 weeks Viruses causing upper respiratory tract infections and influenza virus Administration of these probiotics increased the levels of serum INF-g and IgA in the intestine. Reduced flu-like symptoms and the incidence of respiratory tract infection [72] In vivo using female BALB/c mice L. paracasei CNCM I-1518 Mice were orally gavaged (200 µL) with L. paracasei (2 ×108 CFU) daily for 7 days before infection Influenza A/Scotland/20/74 (H3N2) virus L. paracasei consumption seems to allow an early activation of proinflammatory cytokines (IL1α, IL-1β) and a massive recruitment of immune cells in the lungs after L. paracasei gavage and before influenza infection [54] Clinical trial in 69 children Lactobacillus acidophilus CUL21 (NCIMB 30156), L. acidophilus CUL60 (NCIMB 30157), Bifidobacterium bifidum CUL20 (NCIMB 30153), and Bifidobacterium animalis subsp. lactis CUL34 (NCIMB 30172) 1.25 ×1010 CFU of probiotics plus 50 mg vitamin C or a placebo daily for 6 months Viruses causing upper respiratory tract infections Reduced incidence rate of respiratory tract infection symptoms in the probiotic group. [65] Clinical trial in 1000 volunteers Lactobacillus casei DN-114 001 200 g/day for 3 months Respiratory common infectious diseases Reduced the risk of common infections in stressed individuals such as shift workers [81] Clinical trial in 94 preterm infants L. rhamnosus GG ATCC 53103 1×109CFU/day for 1 to 30 days and 2 × 10 9 CFU/day for 31 to 60 days Adenovirus, coronavirus (229E/NL63 and OC43/HKU1), influenza A and B, Human metapneumovirus, parainfluenza 1, 2, and 3, RSV A and B, rhinovirus, Human enterovirus and bocavirus The incidence of respiratory tract infections was lower in the probiotic group. The incidence of rhinovirus was significantly lower in the probiotic group. Incidence of rhinovirus-induced episodes tended to be lower in the prebiotic but not in the probiotic group [66] Foods 2021,10, 130 8 of 20 Table 1. Cont. Type of Study Probiotics Dosage and Time of Exposure Viruses Main Findings Reference Clinical trial in 629 otitis-prone children L. rhamnosus GG, L. rhamnosus Lc705, Bifidobacterium breve 99,and Propionibacterium freudenreichii JS 8-9 ×109CFU/day for 6 months Human bocavirus 1-4 and rhinovirus/enterovirus Lower number of human bocavirus 1 positive sample during the study, but no effect on rhinovirus/enterovirus occurrence [67] Clinical trial in 210 children B. animalis subsp. lactis (BB-12) 109CFU/day for 3 months Respiratory common infectious diseases This study shows that B. animalis subsp. lactis has no effect on the prevention of respiratory tract infection in children. There was no significant difference in the number of people infected or in the duration of infection in the intervention group and the placebo group [68] Clinical trial in 97 daycare children L. rhamnosus GG 108CFU/day for 28 weeks Human bocavirus 1-4, rhinovirus/enterovirus, RSV, adenovirus, influenza A, and PIV 1-2 Respiratory symptoms decreased in children per month, but there was no effect on the occurrence of respiratory viruses [82] Clinical trial in 192 adults L. rhamnosus GG + B. lactis BB-12 5×109CFU of GG and 2×109of BB-12 CFU/day for 3 to 6 months Human bocavirus, rhinovirus/enterovirus, RSV A and B, adenovirus, coronavirus (229E/NL63 and OC43/HKU1), influenza A and B virus, human metapneumovirus, and PIV 1-4. Lower occurrence of rhinovirus/enterovirus after 3 months, but no significant effect on the occurrence of common respiratory viruses [25] Clinical trial in 209 adults L. plantarum DR7 9 log CFU/day for 12 weeks Viruses causing upper respiratory tract infections Reducing plasma peroxidation and oxidative stress levels [74] Two clinical trials in 86 and 222 elderly volunteers L. casei DN 114 001 Dairy drink (Actimel®) for 7 and 13 weeks Influenza A (H1N1 and H3N2) and B Daily consumption of this product resulted in increased specific antibody responses to influenza virus vaccination in persons over 70 years of age [79] In vivo using BALB/c mice (number not specified) L. rhamnosus (unespecified strain) Sublingually administered at 108, 107, and 10 6 CFU/mouse for 3, 6, 10, 13, and 16 days Influenza A/NWS/33 (H1N1) Sublingual administration of L. rhamnosus increases the production of IgA in the secretion of the mucosa and the activity of T cells and natural killer cells, providing protection against flu virus [55] Clinical trial in 42 healthy adults L. rhamnosus GG Capsules containing 1×1010 CFU twice daily for 28 days Influenza A (H1N1 and H3N2) and B On day 28, a significant increase in seroprotection in the LGG group for the H3N2 vaccine strain was found [75] Foods 2021,10, 130 9 of 20 Table 1. Cont. Type of Study Probiotics Dosage and Time of Exposure Viruses Main Findings Reference In vivo using BALB/c mice (number not specified) L. rhamnosus GG (ATCC 53103) Intranasally administered at 20 µL of LGG solution/day for three days Influenza A/PR/8/34 (PR8, H1N1) Intranasal administration of LGG enhances respiratory cell-mediated immune responses by following the activation of natural killer cells in the lungs, thus protecting the host from IFV infection [56] In vivo using 40 BALB/c mice Lactobacillus pentosus strain b240 Oral administration of non-viable heat-killed b40 diluted at doses of 0.4, 2, or 10 mg/mouse/day for 22 days. Influenza A/PR8/34 (H1N1) Orally administered L. pentosus reduces influenza virus infectious titers in the lungs of influenza virus-infected mice [57] In vivo using BALB/c mice (5–6 per group) L. rhamnosus CRL1505 Two consecutive days of 10 8 CFU/mouse/day inoculated via nostrils using live and heat-killed L. rhamnsosus Influenza A/PR/8/34 (H1N1) Both viable and non-viable L. rhamnsosus reduced lung injury and viral load, protecting infected mice [58] In vivo using BALB/c mice (number not specified) L. pentosus S-PT84 Intranasal administration of 20 µL of L. pentosus at a concentration of 0, 1, or 10 mg/mL once daily for 3 consecutive days Influenza A/PR/8/34 (PR8, H1N1) Intranasal administration of L. pentosus protected against flu virus infection by enhancing Th immunity, induction of INF-αand natural killer activity [59] In vivo using BALB/c mice (number not specified) Bifidobacterium longum MM-2 Orally administered of 2 × 10 9 CFU/day for 17 days from 14 days before 2 days after IFV infection Influenza A/PR/8/1934 (PR8, H1N1) Oral administration of B. longum stimulates immunity by increasing the activity of natural killer cells in the lungs and spleen, resulting in muffled viral proliferation. This probiotic suppresses inflammation in the lower respiratory tract, reduces symptoms, and improves the survival rate of IFV-infected mice [60] In vivo using 60 BALB/c mice Lactobacillus brevis JCM 17312 1 × 10 9 CFU/day for 14 days Influenza A/PR/8/34 (H1N1) L. brevis increases the production capacity of INFα and the increase of the production of specific IgA of the human immunodeficiency virus, which can improve the symptomatology of this infection [61] Clinical trial in 50 volunteers L. fermentun CECT5716 Oral daily dose of 1×1010 CFU 2 weeks before vaccination and 2 weeks after vaccination Influenza A (H1N1 and H3N2) In the probiotic group there was an increase in the production of natural killer cells, two weeks after vaccination. In addition, the antigen-specific IgA was also increased. The incidence of influenza-like illness was lower in this group 5 months after vaccination [76] Foods 2021,10, 130 16 of 20 References 1. 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