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Cited by 177Gut microbiota and healthProbiotics and Fermented FoodsBacteriophages and microbial interactions

Viral Infections, the Microbiome, and Probiotics

Open access
Harper, Ashton, Vijayakumar, Vineetha, Ouwehand, Arthur C., ter Haar, Jessica, Obis, David, Espadaler, Jordi, Binda, Sylvie, Desiraju, Shrilakshmi +1 more·2021·Frontiers in Cellular and Infection Microbiology
DOI 10.3389/fcimb.2020.596166PMC PMC7907522
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Abstract

Viral infections continue to cause considerable morbidity and mortality around the world. Recent rises in these infections are likely due to complex and multifactorial external drivers, including climate change, the increased mobility of people and goods and rapid demographic change to name but a few. In parallel with these external factors, we are gaining a better understanding of the internal factors associated with viral immunity. Increasingly the gastrointestinal (GI) microbiome has been shown to be a significant player in the host immune system, acting as a key regulator of immunity and host defense mechanisms. An increasing body of evidence indicates that disruption of the homeostasis between the GI microbiome and the host immune system can adversely impact viral immunity. This review aims to shed light on our understanding of how host-microbiota interactions shape the immune system, including early life factors, antibiotic exposure, immunosenescence, diet and inflammatory diseases. We also discuss the evidence base for how host commensal organisms and microbiome therapeutics can impact the prevention and/or treatment of viral infections, such as viral gastroenteritis, viral hepatitis, human immunodeficiency virus (HIV), human papilloma virus (HPV), viral upper respiratory tract infections (URTI), influenza and SARS CoV-2. The interplay between the gastrointestinal microbiome, invasive viruses and host physiology is complex and yet to be fully characterized, but increasingly the evidence shows that the microbiome can have an impact on viral disease outcomes. While the current evidence base is informative, further well designed human clinical trials will be needed to fully understand the array of immunological mechanisms underlying this intricate relationship.

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Written from the paper’s full text.

TL;DR

This narrative review synthesizes evidence that the gastrointestinal, vaginal, and respiratory microbiomes influence antiviral immunity and that probiotics may help prevent or ameliorate some viral infections. It concludes that the evidence is promising for viral gastroenteritis and upper respiratory tract infections, but causal relationships and optimal clinical use remain incompletely established.

Key findings

  • A 2010 Cochrane meta-analysis of 63 RCTs and 8,014 participants found probiotics reduced mean duration of diarrheal symptoms by 24.76 h (95% CI 15.9–33.6 h) versus placebo.
  • A 2015 Cochrane review of 12 probiotic RCTs and 3,720 participants found probiotics reduced acute URTI episodes (OR 0.53; 95% CI 0.37–0.76, P<0.001), mean episode duration (MD −1.89 days; 95% CI −2.03 to −1.75, P<0.001), antibiotic prescriptions (OR 0.65; 95% CI 0.45–0.94), and cold-related school absence (OR 0.10; 95% CI 0.02–0.47).
  • A meta-analysis of probiotics as influenza vaccine adjuvants found significantly higher hemagglutination inhibition titers for A/H1N1, A/H3N2, and B, with increases of 20%, 19.5%, and 13.6%, respectively.
  • In an HPV study of 54 women, daily probiotic drink was associated with twice the chance of clearance of cytological abnormalities versus control (60 vs. 31%, P=0.05); HPV clearance was 29% vs. 19% (P=0.41). In HIV prevention, tenofovir gel reduced HIV incidence by 61% in Lactobacillus-dominant women but only 18% in CST-IV women.

Methods

  • Narrative review covering three areas: microbiome–host immunity–viral pathogen interactions; dysbiosis from early life, antibiotics, aging, diet, and inflammatory disease; and probiotic evidence for viral gastroenteritis, hepatitis, HIV, HPV, URTI, influenza, SARS-CoV-2, and critical care.
  • Evidence base includes preclinical studies, human observational studies, randomized controlled trials, systematic reviews, and meta-analyses; no systematic search strategy or formal risk-of-bias assessment is described.
  • Main analysis is qualitative synthesis of cited literature, with selected quantitative results reported from prior meta-analyses and trials.

Limitations

  • The paper states that further well-designed human clinical trials are needed to understand the immunological mechanisms and that causal relationships largely remain to be proven in humans.
  • The paper notes limitations of meta-analyses, including heterogeneous probiotic formulations, variable pathogens, and small participant numbers in some analyses; it also states that no probiotic strain had completed a randomized, placebo-controlled trial in COVID-19 patients at the time of writing.
  • Evident from the text: this is a narrative review without a described systematic search or bias assessment, and several authors report employment or prior employment with probiotic, nutrition, or pharmaceutical companies, with submission funding from the International Probiotics Association.

Model-written summary. Check it against the paper before relying on it.

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Crossref · 10.3389/fcimb.2020.596166

Cites

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Claims the paper makes

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  • Premisecitation

    Regulation of tight junctional proteins by the gastrointestinal microbiota is a well-documented mechanism.

    “Regulation of tight junctional proteins, which are multiprotein complexes controlling paracellular transport between epithelial cells, by the GI microbiota is a well-documented mechanism in this instance (Al-Asmakh and Hedin, 2015).”
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    A variety of studies suggest that probiotics are able to improve mucosal barrier function.

    “a variety of studies do suggest that probiotics are able to improve mucosal barrier function (Bron et al., 2017).”
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    Lacticaseibacillus casei and Bifidobacterium adolescentis indirectly maintain barrier permeability by producing metabolites associated with reduced expression of the rotavirus toxin NSP4.

    “some species, including Lacticaseibacillus casei and Bifidobacterium adolescentis, have been found to indirectly maintain barrier permeability by producing metabolites associated with reduced expression of the rotavirus toxin NSP4, which acts to disrupt the structure and function of tight junctions during infection (Gonzalez-Ochoa et al., 2017).”
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    Duramycin, a class-1 bacteriocin produced by Streptomycetes, prevents Zika virus entry by blocking its co-receptor TIM1.

    “duramycin, a class-1 bacteriocin produced by Streptomycetes, has been found to prevent Zika virus entry by blocking its co-receptor TIM1 (Tabata et al., 2016).”
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    In the gastrointestinal tract, the microbiota induces expression of the genes encoding mucin 2, the main constituent of the glycoprotein network of gastrointestinal mucus.

    “In the GI tract, for instance, the microbiota induces expression of the genes encoding mucin 2; the main constituent of the glycoprotein network of GI mucus (Schroeder, 2019).”
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    A Lactobacillus crispatus-dominant vaginal microbiota impedes diffusion of HIV-1 virions, whereas a Lactobacillus iners-dominant microbiota or significant Gardnerella vaginalis permits rapid diffusion.

    “A Lactobacillus crispatus-dominant microbiota has been shown to impede the diffusion of HIV-1 virions, in contrast to the rapid diffusion observed with a Lactobacillus iners-dominant microbiota, or when Gardnerella vaginalis is present in significant amounts (Nunn et al., 2015).”
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    Various commensal and probiotic bacteria influence the mucus layer, innate immune defenses, and adaptive immune defenses, with relevance to a range of viral infections.

    “Evidence suggests that various commensal and probiotic bacteria influence each of these lines of defense with important relevance to a range of viral infections.”
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    A 5kDa bacteriocin of Lactobacillus delbrueckii has no effect on early steps of influenza virus infection but reduces production of viral proteins in infected cells.

    “a 5kDa bacteriocin of Lactobacillus delbrueckii has no effect on early steps of influenza virus infection, but reduces production of viral proteins in infected cells (Serkedjieva et al., 2000).”
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    The gastrointestinal microbiome is an important variable in human health, contributing to digestion, vitamin synthesis, and development and maintenance of the immune system.

    “this has been repeatedly shown to be an important variable in human health, given its contribution to multiple aspects of human physiology including digestion, vitamin synthesis, and development and maintenance of the immune system (Olszak et al., 2012; Yatsunenko et al., 2012).”
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    Enterocin CRL35 from Enterococcus faecium lowers glycoprotein gD synthesis, disrupting a slightly earlier step in the HSV infectious cycle compared to subtilosin.

    “enterocin CRL35 from Enterococcus faecium was found to lower glycoprotein gD synthesis, (Wachsman et al., 2003) thus seemingly disrupting a slightly earlier step in the infectious cycle of HSV compared to subtilosin.”
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    Probiotic strains including LGG increase IgA in animal models and virus-neutralizing serum immunoglobulins in humans when administered as adjuncts to some viral vaccines.

    “probiotic strains, including LGG, have been shown to increase IgA in animal models (Wang Y. et al., 2017), and virus neutralizing serum immunoglobulins in humans when administered as adjuncts to some viral vaccines (De Vrese et al., 2005).”
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    These metabolites create an acidic pH that is known to inactivate some common enteric viruses while the infant immune system matures.

    “These metabolites create an acidic pH which is known to inactivate some common enteric viruses (Al Kassaa et al., 2014), while the infant immune system matures.”
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    Breast-fed infants have consistently greater levels of bifidobacteria and an overall lower diversity compared to formula-fed infants.

    “breast-fed infants have consistently greater levels of bifidobacteria and an overall lower diversity compared to formula-fed infants (Milani et al., 2017).”
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    Breast milk contains more than 200 structurally different human milk oligosaccharides that cannot be digested by the infant but promote the growth of selected genera such as Bifidobacteria and Bacteroides.

    “Breast milk also contains >200 structurally different human milk oligosaccharides (HMOs) (Jost et al., 2015), which cannot be digested by the infant, but rather promote the growth of selected genera, such as Bifidobacteria and Bacteroides (Marcobal et al., 2010), thought to promote the healthy development of the GI tract and immune system.”
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    Some bacterial species found in human breast milk, such as Lactobacillus spp. and Bifidobacterium spp., may transfer from the maternal gut via an entero-mammary pathway and are thought to protect against many respiratory and gastrointestinal infections.

    “Some of the bacterial species found in human breast milk, such as Lactobacillus spp. (sensu lato) and Bifidobacterium spp., may transfer from the maternal gut via an entero-mammary pathway, a recently discovered form of mother-neonate communication, and are thought to protect against many respiratory and GI infections (Le Doare et al., 2018).”
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    Early life treatment with probiotics reduces the incidence of some atopic diseases such as atopic dermatitis, but results in asthma have been less impressive.

    “Although early life treatment with probiotics have demonstrated a benefit in reducing the incidence of some atopic diseases, such as atopic dermatitis (Li L. et al., 2019), the results in asthma, to date, have been less impressive (Wei et al., 2020).”
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    Diversity of the Bacteroidetes phylum and overall microbiota diversity is lower in cesarean-delivered infants during the first 2 years of life.

    “the diversity of the Bacteroidetes phylum, and microbiota diversity overall, is lower in CS delivered infants during the first 2 years of life (Jakobsson et al., 2014).”
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    Epidemiological studies show an association between cesarean section delivery and chronic immune disorders such as asthma, which are associated with an increased risk of viral infections.

    “Epidemiological studies have shown an association between CS delivery and chronic immune disorders, such as asthma (Sevelsted et al., 2015), which are associated with an increased risk of viral infections (Juhn, 2014).”
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    • Rests on an assumption: Bacterial colonization is necessary for the development and regulation of the immune system.

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    Oral antibiotic treatment impairs this antiviral mechanism in rodents and thus increases susceptibility to viral infections, and this impairment is reversed with fecal transplantation from control mice.

    “Oral antibiotic treatment in this study was shown to impair this antiviral mechanism in rodents and thus increase susceptibility to viral infections. Intriguingly, this antibiotic induced impairment was shown to be reversed with fecal transplantation from control mice (Bradley et al., 2019).”
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    Breastfeeding reduces the odds of childhood obesity, which is known to increase the risk of adulthood obesity, itself a risk factor for some viral infections.

    “Evidence also suggests that breastfeeding reduces the odds of childhood obesity (Weng et al., 2012), which is known to increase the risk of adulthood obesity; itself a risk factor for some viral infections (Milner and Beck, 2012).”
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    Early life antibiotic exposure in humans appears to impair antiviral immunity, but this relationship may not be causal and may be explained by genetic variants impacting antiviral immunity.

    “Early life antibiotic exposure in humans also appears to impair antiviral immunity, however this relationship may not be causal but rather explained by genetic variants impacting antiviral immunity (Semic-Jusufagic et al., 2014).”
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    Human infants receiving greater amounts of arachidonic acid were at lower risk of contracting HIV from their HIV-positive mothers, and enhanced TH17 populations have been associated with reduced viral loads in simian immunodeficiency virus infection.

    “human infants receiving greater amounts of arachidonic acid were at lower risk of contracting HIV from their HIV+ mothers, and enhanced TH17 populations have been associated with reduced viral loads associated with infection from simian immunodeficiency virus (Ardeshir et al., 2014).”
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    In gnotobiotic or antibiotic-treated mice, manipulation of commensal bacteria causes impaired lymphoid tissue development, dysregulated immune cell homeostasis, and altered susceptibility to infectious and inflammatory diseases in the gastrointestinal tract.

    “Studies using gnotobiotic (germ-free), antibiotic-treated, mice have demonstrated that manipulation of commensal bacteria causes impaired lymphoid tissue development, dysregulated immune cell homeostasis, and altered susceptibility to infectious and inflammatory diseases in the GI tract (Abt et al., 2012).”
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    In a rodent model, antibiotic administration to mothers during pregnancy and lactation caused substantial alterations to their and their offspring's gastrointestinal microbiota, and infant mice experienced increased and accelerated mortality following viral infection.

    “In a rodent model antibiotic administration to mothers during pregnancy and lactation caused substantial alterations to theirs and their offspring’s GI microbiota (Gonzalez-Perez et al., 2016). The infant mice in this study experienced increased and accelerated mortality following viral infection.”
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    Premisecitation

    Depletion of commensal bacteria is associated with secretion of IL-33 from the vaginal epithelium, which suppresses local antiviral immunity by blocking migration of effector T cells to the vaginal tissue, thereby inhibiting IFN-γ production.

    “depletion of commensal bacteria was associated with secretion of IL-33 from the vaginal epithelium, which suppressed local antiviral immunity by blocking the migration of effector T cells to the vaginal tissue, thereby inhibiting the production of IFN-γ.”
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    Premisecitation

    Responses to Rotarix correlated with an increased abundance of Streptococcus bovis, and lack of response correlated with high abundance of Bacteroidetes, especially Bacteroides and Prevotella.

    “Responses to Rotarix® correlated with an increased abundance of Streptococcus bovis and the lack of response is correlated with the high abundance of Bacteroidetes phylum, especially several bacteria related to species from the Bacteroides and Prevotella genera.”
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    In infant rhesus macaques, breast-fed compared to formula-fed animals had greater microbiota community richness, evenness, and diversity, features positively correlated with TH1, cytotoxic T, and TH17 cells.

    “Community richness, evenness and diversity was greater in the microbiota of breast-fed compared to formula-fed animals, features that were positively correlated with TH1, cytotoxic T, and TH17 cells.”
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    In 78 Ghanaian infants, overall microbiome composition was significantly different between responders and non-responders to Rotarix vaccination, with Ghanaian responders being more similar to healthy Dutch infants than non-responders.

    “The overall microbiome composition was significantly different between responders and non-responders to vaccination, with the Ghanaian responders being more similar to healthy Dutch infants than non-responders.”
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    Interpretationcitation

    Probiotics are able to support the intestinal barrier, which may dampen the increased inflammatory tone seen in aging and enhance the immune response to viral infections and vaccinations.

    “There is compelling evidence that probiotics are able to support the intestinal barrier (Bron et al., 2017), which may act to dampen the increased inflammatory tone seen in aging and enhance the immune response to viral infections and vaccinations.”
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    Western diets high in processed foods and animal fats and low in plant-derived elements alter the microbiome, promote inflammation, and deleteriously affect immunity.

    “Western diets, high in processed foods and animal fats, and low in plant-derived elements, have been shown to alter the microbiome, promote inflammation and deleteriously affect immunity with important implications to health (Tilg and Moschen, 2015).”
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    Interpretationcitation

    Chronic low-level inflammation exacerbates or maintains hyperpermeability of the intestinal barrier, which combined with increased production of reactive oxygen species contributes to diminished T-cell function and thus possible impairment in viral clearance during infection.

    “This chronic low level inflammation exacerbates, or maintains, the hyperpermeability of the intestinal barrier, which combined with increased production of reactive oxygen species (ROS), contributes to diminished T-cell function (Pinti et al., 2016) and thus possible impairment in viral clearance during infection.”
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    An early dietary shift away from plant-based foods toward animal tissues likely initiated bacterial depauperation, which has been dramatically accelerated in the last approximately 200 years with the widespread introduction of refined flour and sugar into diets.

    “Early dietary shift away from plant-based foods toward animal tissues likely initiated this bacterial depauperation, however this has been dramatically accelerated in the last ~200 years (i.e., since the Industrial Revolution) with the widespread introduction of refined flour and sugar into our diets (Adler et al., 2013).”
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    In a rodent model, depriving animals of enteral nutrition significantly alters intestinal bacterial colonization and causes defects in specific mucosal immunity.

    “in a rodent model, depriving animals of enteral nutrition (e.g., parenteral nutrition – intravenous nourishment) significantly alters intestinal bacterial colonization (e.g., increases levels of Proteobacteria (Demehri et al., 2015)) and causes defects in specific mucosal immunity (e.g., lowered secretory IgA levels).”
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    Reduced immunogenicity of HBV and influenza vaccines in IBD patients is thought to be influenced by this immunological impairment, but underlying pathomechanism remains to be elucidated.

    “This is thought to influence the reduced immunogenicity of HBV and influenza vaccines in IBD patients, for which the underlying pathomechanism remains to be elucidated (Marín et al., 2015).”
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    Antibiotic-induced gut dysbiosis impaired response to H1N1 vaccination with enhanced inflammation.

    “For Influenza, antibiotic-induced gut dysbiosis impaired response to H1N1 vaccination (Hagan et al., 2019) with enhanced inflammation.”
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    IBD patients, either UC or CD, are at higher risk of viral infections and require specific antiviral care including sero-surveillance, vaccination and anti-infective therapies.

    “IBD patients, either ulcerative colitis (UC) or Crohn’s disease (CD), are at higher risk of viral infections and therefore require specific antiviral care including sero-surveillance, vaccination and anti-infective therapies.”
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    Obesity is linked with longer influenza A virus shedding and more severe forms of COVID-19 infections.

    “Obesity has also been linked with longer influenza A virus shedding (Maier et al., 2018) and more severe forms of COVID-19 infections (Stefan et al., 2020).”
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    Premisecitation

    Variations in TLR5 genes are associated with a number of inflammatory diseases.

    “Interestingly, variations in TLR5 genes are associated with a number of inflammatory diseases (Leifer et al., 2014).”
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    GI metagenomes of IBD patients are markedly different from non-IBD controls, showing increased tolerance for oxidative stress and correlation with inflammatory markers.

    “The GI metagenomes of IBD patients are also markedly different from non-IBD controls, showing an increased tolerance for oxidative stress and a correlation with inflammatory markers (Franzosa et al., 2019).”
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    Interpretationreasoning

    Alterations in dietary fiber and resultant short-chain fatty acid profiles, as well as the route of energy provision, impact the microbiome and may potentially influence viral immunity.

    “Thus alterations in dietary fiber, and resultant SCFA profiles, as well as the route of energy provision impacts on the microbiome and may potentially influence viral immunity.”
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    Premisecitation

    These changes are associated with increased intestinal bacterial translocation and the loss of respiratory antiviral defenses in mice.

    “These changes are associated with increased intestinal bacterial translocation and the loss of respiratory antiviral defenses in mice (Renegar et al., 2001).”
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    Interpretationcitation

    Probiotics may provide an option to mitigate some microbiome-related effects in IBD and help restore normal immune function by acting on intestinal gut barrier integrity.

    “Probiotics may provide an option to mitigate some microbiome-related effects in IBD and to help restore a normal immune function by acting on the intestinal gut barrier integrity for example (Sartor and Wu, 2017).”
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    Premisecitation

    Current clinical research findings suggest a role for probiotics in pouchitis and mild/moderate UC but not in CD.

    “Current clinical research findings suggest a role for probiotics in pouchitis and mild/moderate UC but not in CD (Abraham and Quigley, 2017).”
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    Premisecitation

    Dysbiosis seen in obesity is associated with low grade systemic inflammation, which may be responsible for impaired viral immunity.

    “A wealth of research has identified that the dysbiosis seen in obesity is associated with a low grade systemic inflammation (Hartstra et al., 2015), which may be responsible for impaired viral immunity.”
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    Interpretationreasoning

    Interventions aimed at maintaining or recovering both gut and lung microbiomes, in an inflammatory context (e.g., probiotics, prebiotics and synbiotics) are rational and may indirectly help to enhance the immune response to both acute and future viral infections.

    “Nevertheless, interventions aimed at maintaining or recovering both gut and lung microbiomes, in an inflammatory context (e.g., such as probiotics, prebiotics and synbiotics) are rational and may indirectly help to enhance the immune response to both acute and future viral infections.”
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    Premisecitation

    Asthma features deficient antiviral immunity and exacerbations are elicited by respiratory viruses.

    “Asthma features deficient antiviral immunity and exacerbations are elicited by respiratory viruses (Altman et al., 2020).”
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    Metagenomic sequencing of oral and fecal microbiomes of RA patients identified enrichment in gram positive bacteria and depletion in gram negative bacteria compared to healthy controls, but overall richness and diversity were comparable.

    “Metagenomic shotgun sequencing and metagenome-wide association analysis of the oral and fecal microbiomes of RA patients have identified enrichment in gram positive bacteria and depletion in gram negative bacteria compared to healthy controls, however, the overall richness and diversity were comparable between groups (Zhang et al., 2015).”
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    Premisecitation

    Other metabolites and bacterial cell fragments may interfere with virus binding, and Levilactobacillus brevis cell wall fragments have been reported to inhibit herpes simplex replication.

    “Also other metabolites and bacterial cell fragments may interfere with virus binding (Martín et al., 2010) and Levilactobacillus brevis cell wall fragments have been reported to inhibit herpes simplex replication (Mastromarino et al., 2011).”
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    Premisecitation

    Direct virucidal effects have been observed for selected probiotic lactobacilli, with primary metabolites such as hydrogen peroxide or lowering pH by organic acids having such effects.

    “Direct virucidal effects have been observed for selected probiotic lactobacilli, primary metabolites such as hydrogen peroxide or lowering the pH by organic acids have such effects (Zabihollahi et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zabihollahi et al., 2012 source

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    Premisecitation

    A recent meta-analysis of four probiotic trials in RA identified some improvement, but due to scarcity in data, further definitive research is needed.

    “A recent meta-analysis of four probiotic trials in RA identified some improvement, however, due to a scarcity in data, further definitive research is needed (Aqaeinezhad Rudbane et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aqaeinezhad Rudbane et al., 2018 source

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  • May combine two claims.

    Premisecitation

    Available evidence from human intervention studies is limited to early childhood, where synbiotics have shown positive effects in asthma associated with an increase in bifidobacteria.

    “The available evidence from human intervention studies is limited to early childhood, where, for example, synbiotics have shown positive effects in asthma associated with an increase in bifidobacteria (Wopereis et al., 2014; Zhao et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wopereis et al., 2014 source

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    • cites Zhao et al., 2019 source

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    Interpretationreasoning

    Patterns of dysbiosis vary between different inflammatory diseases and the mechanisms linking these microbiome features to viral infection susceptibility are currently unknown.

    “Patterns of dysbiosis also vary between different inflammatory diseases and the mechanisms linking these microbiome features to viral infection susceptibility are currently unknown.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Probiotics may improve mucosal barrier function, limiting viral particles crossing and maintaining barrier during viral disease.

    “Similar as the endogenous microbiota, probiotics may improve mucosal barrier function, limiting the ability of viral particles to cross this physical barrier and maintain this barrier during viral disease (Bron et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bron et al., 2017 source

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    Interpretationcitation

    It is currently unclear if asthma is indeed a risk factor for COVID-19 complications, and studies so far have not conclusively observed the expected increase in incidence.

    “However, it is currently unclear if asthma is indeed a risk factor for COVID-19 complications (Hosoki et al., 2020), and studies so far have not conclusively observed the expected increase in incidence.”
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    • cites Hosoki et al., 2020 source

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  • May combine two claims.

    Interpretationreasoning

    Overall, while there is an increased risk of viral infection in certain chronic inflammatory disorders, this association is not systematic and varies with disease and viral pathogen.

    “Overall, while there is an increased risk of viral infection in certain chronic inflammatory disorders, this association is not systematic and varies with disease and viral pathogen.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Antiviral cytokine responses such as IFN-γ, IL-2, IL-12, and IL-18 as well as improved antibody responses have been reported for probiotics.

    “Also antiviral cytokine responses such as IFN-γ, IL-2, IL-12, and IL-18 as well improved antibody responses have been reported (Lehtoranta et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lehtoranta et al., 2020 source

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    Premisecitation

    Protective mechanisms offered by bifidobacteria include reduction in endotoxin levels, compositional modulation of gut microbiota, antimicrobial production, enhanced GI barrier function and modulation of local and systemic immunity.

    “The protective mechanisms offered by bifidobacteria include reduction in endotoxin levels (GI and plasma), compositional modulation of gut microbiota, antimicrobial production, enhanced GI barrier function and modulation of local and systemic immunity (Zeng et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zeng et al., 2020 source

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    Premisecitation

    Dysbiosis associated with HepB infection involves a gain in potentially pathogenic bacteria (e.g., some Enterobacteriaceae) and a loss in potentially beneficial bacteria, namely Bifidobacterium species.

    “The dysbiosis associated with HepB infection appears to involve a gain in potentially pathogenic bacteria (e.g., some Enterobacteriaceae) and a loss in potentially beneficial bacteria; namely Bifidobacterium species (Zeng et al., 2020).”
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    • cites Zeng et al., 2020 source

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  • May combine two claims.

    Premisecitation

    GI bacterial alpha diversity significantly decreases in CHC patients compared with healthy individuals and is associated with severity of clinical stage.

    “GI bacterial alpha diversity significantly decreases in CHC patients compared with healthy individuals and is associated with the severity of the clinical stage (Inoue et al., 2018).”
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    • cites Inoue et al., 2018 source

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    Premisecitation

    NSP4 is a viral toxin that affects intestinal mucosa structure, targeting tight junctional complexes, affecting electrolyte balance, and resulting in secretory diarrhea.

    “NSP4 protein is a viral toxin which affects the structure of the intestinal mucosa (targeting tight junctional complexes) and affecting the relative intra- and extra-cellular electrolytes balance and ultimately result in secretory diarrhea.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gonzalez-Ochoa et al., 2017 source

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    Premisecitation

    NSP1 inhibits INF production, leading to down-regulation of inflammatory cytokines.

    “NSP1 has been shown to inhibit INF production, leading to down-regulation of inflammatory cytokines (Gonzalez-Ochoa et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gonzalez-Ochoa et al., 2017 source

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  • May combine two claims.

    Premisecitation

    In an in vitro cellular model, cell extract of B. adolescentis SPM0212 inhibits HBV, and its antiviral mechanism is associated with the Mx GTPase pathway.

    “In an in vitro cellular model (HepG2.2.15 - contains integrated HBV DNA and secretes HBsAg) cell extract of B. adolescentis SPM0212 inhibits HBV, and its antiviral mechanism is associated with the Mx GTPase pathway; one of the four main effector pathways of the IFN-mediated antiviral response (Lee D. K. et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lee D. K. et al., 2013

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    Premisecitation

    Selected probiotic strains decreased both duration of diarrhea and hospitalization by approximately 24 h.

    “Furthermore, a 2016 review concluded that selected probiotic strains decreased both the duration of diarrhea and hospitalization by approximately 24 h (Vandenplas, 2016).”
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    • cites Vandenplas, 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Canadian Pediatric Society recommends using probiotics to shorten duration of symptoms in cases of viral gastroenteritis.

    “Added to this, the Canadian Pediatric Society recommends using probiotics to shorten the duration of symptoms in cases of viral gastroenteritis (Marchand et al., 2012).”
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    • cites Marchand et al., 2012 source

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    Premisecitation

    American Gastroenterological Association has advised against probiotic use for acute gastroenteritis in infants, arguing most studies documenting effect were done outside North America.

    “In contrast, the American Gastroenterological Association has recently advised against such use, arguing that most of the studies documenting the effect of probiotics on acute gastroenteritis in infants were done outside of North-America (Su G. et al., 2020).”
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    • cites Su G. et al., 2020

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vaginal microbiomes of reproductive-aged women can be broadly categorized into five different community state types (CSTs).

    “Advances in molecular technologies in recent years have revealed that the vaginal microbiomes of reproductive-aged women can be broadly categorized into five different community state types (CSTs) (Smith and Ravel, 2017).”
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    • cites Smith and Ravel, 2017

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    Premisecitation

    A recent systematic review of 34 clinical studies concluded that probiotics hold promise for BV cure and prevention, but high heterogeneity and suboptimal quality of many studies prevented definitive conclusions.

    “A recent systematic review examined the impact of vaginally applied Lactobacillus-based probiotics (sensu lato) on the vaginal microbiome in 34 clinical studies (van de Wijgert and Verwijs, 2020). The authors concluded that probiotics hold promise for BV cure and prevention, however high heterogeneity and suboptimal quality of many studies prevented definitive conclusions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites van de Wijgert and Verwijs, 2020

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    Premisecitation

    Healthy vaginal microbial composition is characterized by low microbial diversity and often dominated by a single Lactobacillus species.

    “The healthy microbial composition of the vagina is characterized, unlike other mucosal niches, by a low microbial diversity and is often dominated by a single Lactobacillus (sensu lato) species.”
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    • cites Smith and Ravel, 2017

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    Premisecitation

    Research has shown a significant increase in Alcaligenaceae, Porphyromonadaceae, Veillonellaceae, Enterococcus, Megasphaera, and Burkholderia in GI microbiomes of cirrhotic patients with HE; this taxonomic shift was associated with hyperammonaemia and systemic inflammation contributing to exacerbation of HE symptoms.

    “Interestingly, research has shown a significant increase in Alcaligenaceae, Porphyromonadaceae, Veillonellaceae, Enterococcus, Megasphaera, and Burkholderia in the GI microbiomes of cirrhotic patients with HE. This taxonomic shift was associated with hyperammonaemia and systemic inflammation contributing to the exacerbation of HE symptoms (Sung et al., 2019).”
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    • cites Sung et al., 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HPV is estimated to infect up to 80% of sexually active women by age 50.

    “Human papillomavirus (HPV), a type of DNA virus, is estimated to infect up to 80% of sexually active women by age 50 (Moscicki, 2005).”
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    • cites Moscicki, 2005 source

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    Premisecitation

    Vaginal Lactobacillus spp. limit colonization of BV-associated microbes and are protective against deleterious viral effects through maintenance of low pH and bacteriocin production.

    “This is significant because it then follows that vaginal Lactobacillus spp. (sensu lato) limit colonization of BV-associated microbes and thus by extension are protective against the aforementioned deleterious viral effects through maintenance of a low pH (Breshears et al., 2015), and bacteriocin production (Stoyancheva et al., 2014).”
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    • cites Breshears et al., 2015 source

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    • cites Stoyancheva et al., 2014 source

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    Premisecitation

    BV is associated with an increased risk of HIV infection in women, possibly by as much as 60%, and increased HIV shedding.

    “BV is associated with an increased risk of HIV infection in women, possibly by as much as 60% (Atashili et al., 2008), and increased HIV shedding (Bolton et al., 2008), therefore BV treatment may help to reduce HIV transmission by various means.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Atashili et al., 2008 source

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    • cites Bolton et al., 2008 source

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    Premisecitation

    Cervicovaginal microbiota plays a substantial role in persistence and regression of HPV and has implications for subsequent disease.

    “Further evidence indicates that the cervicovaginal microbiota plays a substantial role in the persistence and regression of the virus and thus has important implications for subsequent disease (Chang and Parsonnet, 2010; Mitra et al., 2016).”
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    • cites Chang and Parsonnet, 2010

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    • cites Mitra et al., 2016 source

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    Premisecitation

    Tenofovir reduced HIV incidence by 61% in Lactobacillus-dominant women but only 18% in CST-IV women.

    “Interestingly, the researchers identified that tenofovir reduced HIV incidence by 61% (P = 0.013) in Lactobacillus (sensu lato) dominant women but only 18% (P = 0.644) in CST-IV women (Klatt et al., 2017).”
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    • cites Klatt et al., 2017 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CSTs fall into two groups: Lactobacillus dominant (>90%) and non-Lactobacillus dominant (<30% polymicrobial).

    “A key commonality is that CSTs fall into two clear groups: (i) Lactobacillus (sensu lato) dominant, where one or more species of Lactobacillus (sensu lato) make up >90% of the total copy number or sequencing reads (L. crispatus CST-I, L. gasseri CST-II, L. iners CST-III and L. jensenii CST-V), and (ii) non–Lactobacillus (sensu lato) dominant (CST-IV), in which Lactobacillus (sensu lato) makes up <”
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    • cites Smith and Ravel, 2017

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    Premisecitation

    This permits microbially derived compounds to access the liver via portal circulation, stimulating production of pro-inflammatory cytokines that promote liver inflammation, fibrogenesis and ultimately cirrhosis.

    “This situation permits microbially derived compounds (e.g., ethanol, acetaldehyde, lipopolysaccharide) to access the liver via the portal circulation stimulating production of pro-inflammatory cytokines that promote liver inflammation, fibrogenesis and ultimately cirrhosis (Wang et al., 2019).”
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    • cites Wang et al., 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Vaginal dysbiosis consists of prolonged deviation from low-diversity, Lactobacillus-dominated microbiome; bacterial vaginosis (BV) is the most common type.

    “Vaginal dysbiosis consists of a prolonged deviation from a low-diversity, Lactobacillus (sensu lato) dominated microbiome; bacterial vaginosis (BV), an anaerobic polymicrobial disease, associated with subclinical vaginal inflammation, is the most common type (De Seta et al., 2019).”
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    • cites De Seta et al., 2019 source

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    Premisecitation

    Progression of cirrhosis is associated with increased intestinal permeability, small intestinal bacterial overgrowth, and bacterial translocation.

    “The progression of cirrhosis is associated with increased intestinal permeability, small intestinal bacterial overgrowth, and bacterial translocation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al., 2019 source

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    Premisecitation

    Ingestion of probiotic strain L. paracasei CNCM I-1518 reduced susceptibility to influenza infection, reduced inflammatory cell infiltrates in lungs, and enhanced speed of viral clearance in an influenza infection rodent model.

    “However, promising data from an influenza infection rodent model has revealed that the ingestion of probiotic strain L. paracasei CNCM I-1518 reduced susceptibility to influenza infection, reduced inflammatory cell infiltrates in the lungs and enhanced the speed of viral clearance (Belkacem et al., 2017).”
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    • cites Belkacem et al., 2017 source

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    Premisecitation

    Both murine and human studies have revealed that antibiotics decrease pulmonary IgA production and increase risk of pneumonia.

    “Moreover, both murine and human studies have revealed that antibiotics act to decrease pulmonary IgA production and increase the risk of pneumonia (Libertucci and Young, 2019).”
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    • cites Libertucci and Young, 2019

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    Premisecitation

    In Europe only 44% of at-risk individuals receive an annual influenza vaccination, far from the 75% target coverage rate set by the EU Council Recommendation in 2009.

    “In Europe only 44% of at risk individuals actually receive an annual influenza vaccination; far from the 75% target coverage rate set by the EU Council Recommendation in 2009 (Council of the European Union, 2009).”
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    • cites Council of the European Union, 2009

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    Premisecitation

    Vaccine effectiveness in adults aged >65 years was only 37% compared to 51% for working-age adults.

    “Moreover, a recent review identified that vaccine effectiveness in adults aged >65 years was only 37% compared to 51% for working-age adults (Rondy et al., 2017).”
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    • cites Rondy et al., 2017 source

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    Premisecitation

    Predominant determinant of severity of influenza disease is extent to which lower respiratory tract becomes breached by virus; risk factors include extremes of age (<5 and >65), Caucasians, and comorbid chronic cardiorespiratory diagnoses.

    “The predominant determinate of the severity of associated disease is the extent to which the lower respiratory tract becomes breached by the virus, risk factors for which include extremes of age (<5 years and > 65 years), Caucasians and comorbid chronic cardiorespiratory diagnoses (Kalil and Thomas, 2019).”
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    • cites Kalil and Thomas, 2019 source

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    Premisecitation

    Long-term addition of vaginal probiotics has superior ability to reduce cytological anomalies (P=0.041) and enhance HPV clearance (P=0.044) compared to short-term probiotic administration.

    “Interestingly, long-term addition of vaginal probiotics has been demonstrated to have a superior ability to reduce cytological anomalies (P=0.041) and enhance HPV clearance (P=0.044) compared to short-term probiotic administration (Palma et al., 2018).”
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    • cites Palma et al., 2018 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Influenza viruses primarily attach to and replicate within respiratory epithelial cells from upper to lower respiratory tract.

    “These viruses primarily attach to, and replicate within, respiratory epithelial cells running from the upper (nasal cavity, oral cavity, pharynx, larynx) to lower respiratory tract (trachea, bronchi, bronchioles and alveoli) (Kalil and Thomas, 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kalil and Thomas, 2019 source

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    Premisecitation

    3-month application of L. rhamnosus GR-1 and L. reuteri RC-14 in double-blind RCT of 121 women with genital HR-HPV did not influence genital HR-HPV clearance, but decreased rates of mildly abnormal and unsatisfactory cervical smears (P=0.017).

    “The 3-month application of two probiotic strains, Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14, in a double-blind RCT involving 121 women with genital high-risk HPV (HR-HPV) infection did not influence genital HR-HPV clearance, but was able to decrease the rates of mildly abnormal and unsatisfactory cervical smears (P= 0.017) (Ou et al., 2019).”
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    • cites Ou et al., 2019

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    Premisecitation

    Influenza viruses A, B, and C are RNA viruses of the family Orthomyxoviridae.

    “Human influenza viruses A, B, and C are RNA viruses of the family Orthomyxoviridae (Bouvier and Palese, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bouvier and Palese, 2008

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    Interpretationcitation

    Even though trials were heterogeneous, there appears to be a promising therapeutic benefit of taking probiotics for URTI prevention, as confirmed with strain-specific meta-analyses.

    “However, even though the trials included in this analysis utilized heterogeneous interventions (different probiotic strains or combinations of strains), at variable dosages and durations, there at least appears to be a promising therapeutic benefit of taking probiotics for URTI prevention, as confirmed with strain-specific meta-analyses (Poon et al., 2020).”
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    • cites Poon et al., 2020 source

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    • Rests on an assumption: Probiotic effects observed for specific strains can be generalized to probiotics as a class for viral infections.

  • May combine two claims.

    Premisecitation

    L. crispatus-dominated vaginal microbiota produces high concentrations of D-lactate which increases cervicovaginal mucus viscosity and enhances viral particle trapping, and tends to have least likelihood of viral infections of all CSTs.

    “A L. crispatus-dominated vaginal microbiota produces high concentrations of D-lactate which has been recently shown to increase cervicovaginal mucus viscosity and enhance its viral particle trapping potential (Nunn et al., 2015), and tends to have the least likelihood of viral infections of all CSTs (Borgdorff et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Nunn et al., 2015 source

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    • cites Borgdorff et al., 2014 source

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    Premisecitation

    Specific effects of probiotics may include enhancing phagocytic activity of peripheral leucocytes, increasing secretion of immunoglobulins (IgA, IgG, IgM) and increasing production of cytokines.

    “Specific effects may include enhancing phagocytic activity of peripheral leucocytes, increasing secretion of immunoglobulins (IgA, IgG, and IgM) and increasing production of cytokines (e.g., interleukins, TNF-α and interferon-α) (Hao et al., 2015).”
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    • cites Hao et al., 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Viral URTIs are most frequently caused by rhinoviruses, respiratory syncytial virus, adenoviruses, coronaviruses, influenza viruses, para-influenza viruses and human metapneumovirus.

    “Viral URTIs are most frequently caused by rhinoviruses, respiratory syncytial virus, adenoviruses, coronaviruses, influenza viruses, para-influenza viruses and human metapneumovirus (Bosch et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bosch et al., 2013 source

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    Premisecitation

    Economic modeling study applied to US population, utilizing Cochrane data, concluded probiotic use could achieve >54 million fewer days of infection, >2 million averted antibiotic courses, and >4 million avoided missed work days.

    “Additionally, an economic modeling study applied to the US population, utilizing this same Cochrane data, concluded that probiotic use could achieve >54 million fewer days of infection, >2 million averted antibiotic courses, and >4 million avoided missed work days (Lenoir-Wijnkoop et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lenoir-Wijnkoop et al., 2019 source

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    Premisecitation

    Antibiotic eradication of the GI microbiome can impair both innate and adaptive immune responses and lead to impaired CD4+ and CD8+ T cell function in animal studies.

    “Indeed, animal studies have shown that antibiotic-eradication of the GI microbiome can impair both innate and adaptive immune responses and lead to impaired CD4+ and CD8+ T cell function (Chen et al., 2017).”
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    • cites Chen et al., 2017 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Numerous factors influence vaccine efficacy, including nutrition, sex, age, genetics, and health status.

    “It is important to appreciate that numerous factors influence vaccine efficacy including nutrition, sex, age, genetics, and health status (Vlasova et al., 2019).”
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    • cites Vlasova et al., 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Including adjuvants is one approach to improve influenza and other vaccines.

    “One approach to improve influenza vaccines, and other vaccines, is to include adjuvants; substances that boost the immune response (Tregoning et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tregoning et al., 2018 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Diarrhea is the most common GI symptom in children and adults with COVID-19, with a mean duration of 4.1 ± 2.5 days.

    “Diarrhea seems to be the most common GI symptom in children and adults, with a mean duration of 4.1 ± 2.5 days, while vomiting seems to be more prominent in children (Tian et al., 2020).”
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    • cites Tian et al., 2020 source

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    Premisecitation

    Immunosenescence involves a decrease in key immune cell types, including T lymphocytes, natural killer cells, dendritic cells, and loss of B-cell diversity.

    “As detailed earlier, this process involves a decrease in a number of key immune cell types (e.g., T lymphocytes, natural killer cells, dendritic cells numbers, and loss of the diversity of B-cells).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pera et al., 2015 source

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  • May combine two claims.

    Interpretationreasoning

    Probiotics could facilitate correction of the microbiota disturbances observed in some COVID-19 cases by inhibiting growth of specific opportunistic bacteria and/or facilitating recovery of beneficial bacteria.

    “In this regard, probiotics could facilitate a correction of the microbiota disturbances observed in some COVID-19 cases by inhibiting the growth of those specific opportunistic bacteria and/or facilitating the recovery of beneficial bacteria.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Immunosenescence results in a reduced capacity to mediate effective immune responses to vaccination and invading pathogens, increasing susceptibility to infectious diseases.

    “This results in a reduced capacity to mediate effective immune responses to vaccination and invading pathogens, which both increase susceptibility to infectious diseases (Pera et al., 2015).”
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    • cites Pera et al., 2015 source

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    Premisecitation

    In a meta-analysis, HI titers were significantly higher in the probiotic group compared to control for influenza A/H1N1, A/H3N2, and B, with increases of 20%, 19.5%, and 13.6% respectively.

    “In this meta-analysis the authors found significantly higher HI titers in the probiotic group compared to control for both strain A/H1N1, A/H3N2 and strain B, with increases of 20%, 19.5%, and 13.6% respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yeh et al., 2018 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Critically ill patients have a high prevalence of at least one organ failure (51%-72%) at some point during ICU stay, with respiratory failure being the most prevalent (87% of patients with organ failure).

    “Such patients have a high prevalence of at least one organ failure (51%–72%) at some point during their stay in ICU, with respiratory failure being the most prevalent (constituting 87% of patients with organ failure) (Pedersen et al., 2017).”
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    • cites Pedersen et al., 2017 source

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    Premisecitation

    One of the most feared consequences of influenza infection is secondary bacterial infection and resulting ARDS, due to the substantial increase in morbidity and mortality.

    “One of the most feared consequences of influenza infection is secondary bacterial infection (this is bacterial infection that occurs during or after an infection from another pathogen; commonly viruses) (Morris et al., 2017) and resulting ARDS, due to the substantial increase in morbidity and mortality.”
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    • cites Morris et al., 2017 source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    At the time of writing, no probiotic strain has completed a randomized, placebo-controlled trial in COVID-19 patients, and therefore their use remains experimental.

    “However, it must be stressed that, at the time of writing, no probiotic strain has completed a randomized, placebo-controlled trial in COVID-19 patients, and therefore their use remains experimental.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Respiratory failure may be caused by exacerbation of chronic airway diseases, and viruses are unambiguous precipitants.

    “Respiratory failure may also be caused by exacerbation of chronic airway diseases (e.g., asthma, chronic obstructive pulmonary disease, and cystic fibrosis), and whereas bacteria play a controversial role in their pathogenesis, viruses are unambiguous precipitants (Dickson, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dickson, 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pneumonia is the most common cause of sepsis.

    “Pneumonia is the most common cause of sepsis (Dickson, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dickson, 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ARDS was the deadliest complication of the pneumonia caused by severe acute respiratory syndrome (SARS) and H1N1 influenza viral epidemics.

    “ARDS was the deadliest complication of the pneumonia caused by severe acute respiratory syndrome (SARS) and H1N1 influenza viral epidemics (Hendrickson and Matthay, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hendrickson and Matthay, 2013

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A causative role for microbiota disturbances in COVID-19 severity remains to be confirmed.

    “However, a causative role for microbiota disturbances in COVID-19 severity remains to be confirmed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Probiotics could boost immune system activity by direct cross-talk with immune cells and/or reduction of intestinal permeability, a proposed mechanism behind the beneficial effect of probiotics on respiratory tract infections.

    “Moreover, probiotics could boost immune system activity by direct cross-talk with immune cells and/or reduction of intestinal permeability, which has been proposed as one of the mechanisms behind the beneficial effect of probiotics on respiratory tract infections (Baud et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baud et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tryptophan metabolism across the serotonin, kynurenine and indole pathways is under control of the microbiota and has a strong influence on mucosal immunity and numerous systemic effects.

    “Tryptophan metabolism across the serotonin, kynurenine and indole pathways, which are under control of the microbiota (Agus et al., 2018), has a strong influence on mucosal immunity and numerous systemic effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Agus et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 17 studies confirmed that SARS-CoV-2 mRNA is detected in stools of almost half of COVID-19 patients, with detection rate markedly higher in severe cases and in those displaying GI symptoms.

    “and a recent meta-analysis of 17 studies confirmed that SARS-CoV-2 mRNA is detected in stools of almost half of coronavirus disease 2019 (COVID-19) patients; detection rate being markedly higher in severe cases and in those displaying GI symptoms (Gao et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gao et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Among viral indications, probiotics have been most extensively studied in the management of viral diarrhea and upper respiratory tract infections, and generally the evidence supporting their efficacy and safety is positive.

    “Among these indications probiotics have been most extensively studied in the management of viral diarrhea (Szajewska et al., 2020) and URTIs (Hao et al., 2015) and, generally, the evidence supporting their efficacy and safety are positive.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Szajewska et al., 2020 source

      Not checked in the free run.

    • cites Hao et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysbiosis, a well-established result of both infection and antibiotics, may partly explain the association between initial infection and higher severe sepsis readmission.

    “Dysbiosis, a well-established result of both infection and antibiotics, may partly explain this latter association.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Numerous pre-clinical studies have shown that oral probiotics are capable of positively influencing gut barrier function and systemic immunity, and thus in pneumonia may enhance the host's ability to suppress and clear reproducing lung pathogens.

    “Numerous pre-clinical studies have shown that oral probiotics are capable of positively influencing gut barrier function and systemic immunity, and thus, in the case of pneumonia, may enhance the host’s ability to suppress and clear reproducing lung pathogens as they emerge (Bron et al., 2017) (Forsythe, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bron et al., 2017 source

      Not checked in the free run.

    • cites Forsythe, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The vaginal microbiome profile appears to be highly relevant to viral pathogens such as HIV and HPV, and represents a novel target to reduce the burden of these diseases.

    “The vaginal microbiome profile also appears to be highly relevant to viral pathogens, such as HIV and HPV, and thus represents a novel target to reduce the devastating burden of these diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ICU interventions increase intestinal permeability and bacterial translocation.

    “Beyond the impact on the body’s resident microbial populations, ICU interventions also increase intestinal permeability (e.g., non-steroidal anti-inflammatory drugs and parenteral feeding) and bacterial translocation – the movement of bacteria through the gut mucosa to normally sterile tissues (Dickson, 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dickson, 2017 source

      Not checked in the free run.

110 of 110

  • The paper relies on this without support.

    Bacterial colonization is necessary for the development and regulation of the immune system.

    “considering that bacterial colonization is necessary for the development and regulation of the immune system.”

  • The paper relies on this without support.

    Findings from animal models and in vitro studies about microbiome-immune interactions are informative about human viral immunity.

    “Although the translation of in vitro and animal study outcomes to human populations is challenging, a variety of studies do suggest that probiotics are able to improve mucosal barrier function (Bron et al., 2017).”

  • The paper relies on this without support.

    Probiotic effects observed for specific strains can be generalized to probiotics as a class for viral infections.

    “However, even though the trials included in this analysis utilized heterogeneous interventions (different probiotic strains or combinations of strains), at variable dosages and durations, there at least appears to be a promising therapeutic benefit of taking probiotics for URTI prevention, as confirmed with strain-specific meta-analyses (Poon et al., 2020).”

  • The paper relies on this without support.

    Probiotics have an excellent safety record and are cost-effective.

    “Considering the excellent safety record and cost-effective nature of probiotics, the prospect of achieving even minimally clinically significant benefits makes further exploration worthwhile.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Beneficial butyrogenic bacteria Faecalibacterium and Anaerostipes, as well as Bifidobacterium, were inversely correlated with diagnosis and/or severity of COVID-19.

    “and the beneficial butyrogenic bacteria Faecalibacterium and Anaerostipes, as well as Bifidobacterium, were inversely correlated with the diagnosis and/or severity of COVID-19.”

    From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [154]

  • In two studies, opportunistic pathogens Actinomyces, Erysipelaclostridium, Streptococcus, Veillonella, Rothia, and Enterobacter were associated with diagnosis and/or severity of COVID-19.

    “Also, [154] reported that in two studies, the opportunistic pathogens Actinomyces, Erysipelaclostridium, Streptococcus, Veillonella, Rothia, and Enterobacter were associated with the diagnosis and/or severity of COVID-19”

    From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [154]

  • Functional support of probiotics and eventual restoration of the protective vaginal microbiota are critical elements for successfully combating HPV infections regardless of treatment approach or duration.

    “However, it seems that the functional support of probiotics and the eventual restoration of the protective vaginal microbiota are critical elements for successfully combating HPV infections regardless of the treatment approach or duration [154].”

    From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [154]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Human Microbiome Project reference has conflicting years

    Minor

    The text cites the Human Microbiome Project paper as Turnbaugh et al. (2007), but the matching entry in the reference list gives its publication year as 2017.

1 of 1

The citation lists haven’t been fetched yet

References 263 · Cited by 177

Research works printed but not linked: 1

  1. 2009, Council Recommendation of 22 December 2009 on seasonal influenza vaccination, Off. J. Eur. Union, 0071

Authors
Harper, A., Vijayakumar, V., Ouwehand, A. C., ter Haar, J., Obis, D., Espadaler, J., Binda, S., Desiraju, S., & Day, R.
Affiliations
  • DuPont (Finland) (FI)
  • Danone (France) (FR)
  • AB-Biotics (Spain) (ES)
  • Lallemand (Canada) (CA)
Corresponding author
Vijayakumar, Vineetha
ORCID
Venue
Frontiers in Cellular and Infection Microbiology
Publisher
Frontiers Media SA
Published
2021-02-12
Volume
10
Pages
596166-596166
ISSN
2235-2988 (ISSN-L)
DOI
10.3389/fcimb.2020.596166
PMC
PMC7907522
OpenAlex
W3132617495
Semantic Scholar
ca6fb4dc6cf3566f4628e20b9c5edb2552fed6ff
Cited by
177
References
263
Citations by year
2026: 18 · 2025: 31 · 2024: 44 · 2023: 37 · 2022: 33 · 2021: 13 · 2020: 1
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
Keywords
viral infection, gastrointestinal microbiome, probiotics, host-microbiota interactions, antiviral immunity, microbiota-based therapy, viral gastroenteritis, viral hepatitis, HIV, human papillomavirus, upper respiratory tract infection, influenza, SARS-CoV-2, immunosenescence, antibiotic exposure, diet, inflammatory diseases, early life factors, commensal microorganisms
MeSH terms
Gastrointestinal Microbiome, Host Microbial Interactions, COVID-19, SARS-CoV-2, Animals, Humans, Viral Vaccines, Virus Diseases, Probiotics, Microbiota, Dysbiosis

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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