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Cited by 835Gut microbiota and healthGastrointestinal motility and disordersAnimal Nutrition and Physiology

Regulation of Intestinal Barrier Function by Microbial Metabolites

Open access
Ghosh, Sweta, Whitley, Caleb Samuel, Haribabu, Bodduluri, Jala, Venkatakrishna Rao·2021·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2021.02.007PMC PMC8025057
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Abstract

The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how gut microbial metabolites regulate intestinal barrier function through shared pathways and discusses potential therapeutic strategies. It highlights metabolites such as SCFAs, indole derivatives, bile acids, conjugated fatty acids, polyamines, and polyphenolic derivatives, while noting that mechanisms and clinical translation remain early.

Key findings

  • The gut barrier comprises mucus, epithelial, and mucosal immune layers; junctional complexes (tight junctions, adherens junctions, desmosomes, gap junctions) regulate paracellular permeability via the pore pathway (excludes molecules ≤8 Å), the leak pathway (exclusion limit ∼100 Å), and an unrestricted pathway from IEC death.
  • Microbial metabolites influence barrier function: butyrate at 1–10 mM improved epithelial barrier function and increased MUC2 in E12 human colon cells, whereas 50–100 mM showed no beneficial effect; indole levels in fecal samples of germ-free mice were 27-fold lower than conventionally raised mice, and indole supplementation restored junctional protein expression; UroA enhanced TJ proteins via an AhR-Nrf2–dependent pathway and mitigated DSS- or TNBS-induced colitis; DCA increased gut permeability >1.5-fold, while UDCA blocked DCA-induced permeability.
  • Bacterial structural components signal through TLRs and NLRs: TLR2 activation increases TEER and TJ sealing; LPS/TLR4 disrupts junctional complexes and increases permeability; TLR5/flagellin and NOD1/NOD2 also modulate barrier integrity, with Nod1−/− and Nod2−/− mice showing increased paracellular permeability and DSS colitis susceptibility.
  • Treatment strategies include FMT, probiotics, UroA/UAS03, divertin, hormone treatment, and dietary supplements, but the review states that no microbial metabolites or their analogues are in clinical use.

Methods

  • Narrative review; no primary experimental data. It synthesizes recent advances on gut microbial metabolites and intestinal barrier function, with tables of intestinal cell types, junctional components, and microbial metabolites, plus figures of pathways and treatment strategies.
  • Cites preclinical and human studies, including cell lines (Caco-2, T84, E12), mouse models (germ-free, DSS/TNBS colitis, AhR−/−, Nrf2−/−, etc.), piglet models, and human trials/observations.
  • Main analysis is qualitative synthesis of the literature; no systematic search strategy or meta-analysis is described.

Limitations

  • The paper states that mechanisms of action of these metabolites are only beginning to emerge and that detailed mechanisms are yet to be elucidated.
  • The paper states that no microbial metabolites or their analogues are in clinical use, that UroA production and function in vivo have yet to be directly determined using gnotobiotic animals, and that extensive longitudinal studies are needed.
  • Evident from the text: as a narrative review, it does not provide systematic search criteria, risk-of-bias assessment, or quantitative synthesis; conclusions rely on cited studies with varying models, doses, and species.

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

Integrity signals

Registry

Crossref · 10.1016/j.jcmgh.2021.02.007

Cites

211 of 211 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 187 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Intestinal epithelial cells allow selective penetration of nutrients, water, and electrolytes while simultaneously excluding microbial pathogen-associated molecular pattern, toxins, and foreign antigens.

    “Intestinal epithelial cells (IECs) allow for selective penetration of nutrients, water, and electrolytes while simultaneously excluding microbial pathogen-associated molecular pattern, toxins, and foreign antigens.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Kunzelmann, 2002, Electrolyte transport in the mammalian colon: mechanisms and implications for disease, Physiol Rev source

      Not checked in the free run.

  • Premisecitation

    Fecal microbiota transplantation from healthy hosts is positively correlated with disease reversal, especially those stemming from gut barrier dysfunction like IBD, IBS, celiac disease, and Clostridium difficile infections.

    “Studies have revealed that fecal microbiota transplantation (FMT) from healthy hosts are positively correlated with disease reversal, especially those stemming from gut barrier dysfunction like IBD, IBS, celiac disease, and Clostridium difficile infections.19,20”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Moayyedi, 2015, Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial, Gastroenterology source

      Not checked in the free run.

    • cites [20] Kim, 2019, Fecal microbiota transplantation in recurrent Clostridium difficile infection: a retrospective single-center chart review, JGH Open source

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  • Premisecitation

    Gut barrier dysfunction is strongly correlated with autoimmune, inflammatory, and metabolic diseases such as diabetes, obesity, atherosclerosis, heart failure, hypertension, and food allergies, as well as with cancer.

    “Gut barrier dysfunction is also strongly correlated with other autoimmune, inflammatory, and metabolic diseases such as diabetes, obesity, atherosclerosis, heart failure, hypertension, and food allergies, as well as with cancer.10,11”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Gopalakrishnan, 2018, The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy, Cancer Cell source

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    • cites [11] Martini, 2017, Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease, Cell Mol Gastroenterol Hepatol source

      Not checked in the free run.

  • Premisenone given

    Microbiota significantly influence the functions of the intestinal barrier that separates internal organs from harmful entities including microorganisms, luminal antigens, and luminal proinflammatory factors.

    “Microbiota significantly influence the functions of the intestinal barrier that separates internal organs from harmful entities including microorganisms, luminal antigens, and luminal proinflammatory factors.”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    The gut microbiota and their metabolites significantly regulate the pore and leak pathways leading to either enhancement or reduction of gut barrier function.

    “The gut microbiota and their metabolites significantly regulate these pathways leading to either enhancement or reduction of gut barrier function.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 73
  • The quote only partly states this claim. 1

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

    Premisecitation

    Enterocytes connect with each other in a continuous epithelial cell layer via adhesive junctional proteins that make up tight junction proteins, adherens junction proteins, gap junction proteins, and desmosomes.

    “Enterocytes connect with each other in a continuous epithelial cell layer via adhesive junctional proteins that make up tight junction (TJ) proteins, adherens junction (AJ) proteins, gap junction proteins, and desmosomes (Table 2).31,32”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Niessen, 2007, Tight junctions/adherens junctions: basic structure and function, J Invest Dermatol source

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    • cites [32] Groschwitz, 2009, Intestinal barrier function: molecular regulation and disease pathogenesis, J Allergy Clin Immunol source

      Not checked in the free run.

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

    Premisenone given

    Increased gut barrier permeability occurs through dysregulation of epithelial apoptosis/enterocyte death, mucus degradation, and increased paracellular permeability due to disruption of tight junctions.

    “Increased gut barrier permeability occurs through dysregulation of epithelial apoptosis/enterocyte death, mucus degradation, and increased paracellular permeability due to disruption of TJs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TNF-α induced loss of epithelial integrity due to apoptosis accounted for about 56% of the damage, and the rest was by disruption of tight junctions in nonapoptotic areas.

    “TNF-α induced loss of the epithelial integrity due to apoptosis accounted for about 56% of the damage and the rest was by disruption of TJs in nonapoptotic areas.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Gitter, 2000, Leaks in the epithelial barrier caused by spontaneous and TNF-alpha-induced single-cell apoptosis, FASEB J source

      Not checked in the free run.

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

    Premisecitation

    Humans and microbes have coevolved over millions of years, contributing to the interdependency of host and microbiota physiological activities.

    “Humans and microbes have coevolved over millions of years, thereby contributing to the interdependency of host and microbiota physiological activities.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Li, 2008, Symbiotic gut microbes modulate human metabolic phenotypes, Proc Natl Acad Sci U S A source

      Not checked in the free run.

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    Premisecitation

    TNF-α disrupts the gut barrier not only by degradation in tight junctions, but also through the induction of epithelial apoptosis.

    “For example, Gitter et al57 showed that tumor necrosis factor alpha (TNF-α) disrupts the gut barrier not only by degradation in TJs, but also through the induction of epithelial apoptosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Gitter, 2000, Leaks in the epithelial barrier caused by spontaneous and TNF-alpha-induced single-cell apoptosis, FASEB J source

      Not checked in the free run.

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

    Premisecitation

    Tight junction proteins consist of over 50 proteins that are crucial for maintaining cell-to-cell adhesion and gut barrier health.

    “TJ proteins consist of over 50 proteins that are crucial for maintaining cell-to-cell adhesion and gut barrier health.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Chiba, 2008, Transmembrane proteins of tight junctions, Biochim Biophys Acta source

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    Premisecitation

    The leak pathway is believed to be regulated by myosin light-chain kinase, where constitutively active MLCK is sufficient to increase the leak pathway-dependent permeability both in vitro and in vivo.

    “The leak pathway is believed to be regulated by myosin light-chain kinase (MLCK), where constitutively active MLCK is sufficient to increase the leak pathway–dependent permeability both in vitro and in vivo.52,53”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Shen, 2006, Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure, J Cell Sci source

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    • cites [53] Su, 2009, Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis, Gastroenterology source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The gut barrier is composed of 3 main interlinked/interdependent layers that provide a physical barrier against bacterial intrusion from the gut lumen.

    “The gut barrier is composed of 3 main interlinked/interdependent layers that provides a physical barrier against bacterial intrusion from the gut lumen.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Functional or physical disruption of tight junction, adherens junction, and gap junction proteins and desmosomes leads to increased gut permeability causing dysregulated translocation/transportation of inflammatory mediators, which potentially manifests as chronic gut inflammation.

    “The functional or physical disruption of TJ, AJ, and gap junction proteins and desmosomes leads to increased gut permeability causing dysregulated translocation/transportation of inflammatory mediators, which potentially manifests as chronic gut inflammation.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The flux that occurs due to cell death (global barrier loss) is classified as the unrestricted pathway, in which there is no size limit of molecules or antigens that can cross the membrane.

    “The flux that occurs due to cell death (global barrier loss) is classified as “unrestricted pathway,” in which there is no size limit of molecules or antigens that can cross the membrane.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Zuo, 2020, Tight junctions as targets and effectors of mucosal immune homeostasis, Cell Mol Gastroenterol Hepatol source

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    Premisecitation

    Deletion of AhR in intestinal epithelial cells led to a defective barrier and uncontrolled proliferation of intestinal stem cells, leading to increased tumors in an azoxymethane-DSS-induced colon tumorigenesis model.

    “It was demonstrated by the Stockinger group that deletion of AhR in IECs led to a defective barrier and uncontrolled proliferation of intestinal stem cells, leading to increased tumors in an azoxymethane-DSS–induced colon tumorigenesis model.100”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Metidji, 2019, The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity, Immunity source

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    Premisecitation

    Supplementation of dietary AhR ligands (like I3C) guarded the intestinal stem cell niche and maintained intestinal barrier function and decreased tumor burden in the azoxymethane-DSS-induced colon tumorigenesis model.

    “Supplementation of dietary AhR ligands (like I3C) guarded the intestinal stem cell niche and maintained intestinal barrier function and decreased tumor burden in the azoxymethane-DSS–induced colon tumorigenesis model.100”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Metidji, 2019, The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity, Immunity source

      Not checked in the free run.

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    Premisecitation

    Fecal microbiota transplantation has resulted in enhanced metabolic functions of gut microbiota associated with indole alkaloid biosynthesis such as indole-3-acetic acid that in turn enhances gut barrier homeostasis.

    “FMT has resulted in enhanced metabolic functions of gut microbiota associated with indole alkaloid biosynthesis such as indole-3-acetic acid that in turn enhances gut barrier homeostasis.91”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Geng, 2018, Faecal microbiota transplantation reduces susceptibility to epithelial injury and modulates tryptophan metabolism of the microbial community in a piglet model, J Crohns Colitis

      Not checked in the free run.

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    Premisecitation

    Microbial metabolites have been shown to significantly influence the maintenance of gut barrier integrity itself and intestinal homeostasis.

    “Further, they have been shown to significantly influence the maintenance of gut barrier integrity itself and intestinal homeostasis.73,74”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Alam, 2018, Role of gut microbiota in intestinal wound healing and barrier function, Tissue Barriers source

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    • cites [74] Prochazkova, 2019, Microbiota, microbial metabolites, and barrier function in a patient with anorexia nervosa after fecal microbiota transplantation, Microorganisms source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    The host-microbiota relationship has been defined as the synergistic effect of microbial metabolites on host immunity, health and disease, energy metabolism, and cellular communication.

    “The host-microbiota relationship has been defined as the synergistic effect of microbial metabolites on host immunity, health and disease, energy metabolism, and cellular communication.59, 60, 61, 62, 63,64”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [59] Jandhyala, 2015, Role of the normal gut microbiota, World J Gastroenterol source

      Not checked in the free run.

    • cites [60] Thursby, 2017, Introduction to the human gut microbiota, Biochem J source

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    • cites [61] Li, 2018, Effects of metabolites derived from gut microbiota and hosts on pathogens, Front Cell Infect Microbiol source

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    • cites [62] Araki, 1995, Enhancement of resistance to bacterial infection in mice by vitamin B2, J Vet Med Sci source

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    • cites [63] Donia, 2015, Human microbiota. Small molecules from the human microbiota, Science source

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    • cites [64] Artis, 2008, Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut, Nat Rev Immunol source

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  • May combine two claims.

    Premisecitation

    Activation of AhR by tryptophan metabolites promotes immune cell maturation and decreased pathogen colonization.

    “Activation of AhR by tryptophan metabolites promotes immune cell maturation and decreased pathogen colonization.89”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Zelante, 2013, Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22, Immunity source

      Not checked in the free run.

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    Premisecitation

    Levels of tight junction proteins in AhR-/- mice are significantly reduced compared with wild type mice leading to increased gut leakiness.

    “Levels of TJ proteins in AhR–/– mice are also significantly reduced compared with wild type mice leading to increased gut leakiness.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Singh, 2019, Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Butyrate treatment resulted in downregulation of IL-1β levels, suggesting it may be beneficial for protection against inflammation-promoted barrier disruption.

    “Moreover, butyrate treatment resulted in downregulation of IL-1β levels, suggesting it may be beneficial for protection against inflammation-promoted barrier disruption.87”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Diao, 2019, Gastric infusion of short-chain fatty acids can improve intestinal barrier function in weaned piglets, Genes Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Butyrate improved barrier function at lower doses, but reduced barrier function at higher doses in Caco-2 cells.

    “Similarly, butyrate improved barrier function at lower doses, but reduced barrier function at higher doses in Caco-2 cells.80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Peng, 2007, Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier, Pediatr Res source

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    Premisecitation

    At higher concentrations (50-100 mM), sodium butyrate showed no beneficial effects on MUC2 expression patterns, likely due to the induction of apoptosis at higher doses.

    “However, at higher concentrations (50–100 mM), it showed no beneficial effects on MUC2 expression patterns,79 likely due to the induction of apoptosis at higher doses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Nielsen, 2018, Effect of butyrate and fermentation products on epithelial integrity in a mucus-secreting human colon cell line, Journal of Functional Foods source

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    Premisecitation

    Microbial metabolites produced in the gut directly interact with intestinal epithelial cells and immune cells and impact host health.

    “Microbial metabolites produced in the gut directly interact with IECs and immune cells and impact host health.61,62”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Li, 2018, Effects of metabolites derived from gut microbiota and hosts on pathogens, Front Cell Infect Microbiol source

      Not checked in the free run.

    • cites [62] Araki, 1995, Enhancement of resistance to bacterial infection in mice by vitamin B2, J Vet Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AhR activation by FICZ was therapeutic in the dextran sodium sulfate-induced mouse colitis model in which FICZ treatment upregulated tight junction protein expression in inflamed mouse colons.

    “AhR activation by FICZ was therapeutic in the dextran sodium sulfate (DSS)–induced mouse colitis model in which FICZ treatment upregulated TJ protein expression in inflamed mouse colons.92,93”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Yu, 2018, Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity, Int J Biol Sci source

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    • cites [93] Teng, 2018, Plant-derived exosomal MicroRNAs shape the gut microbiota, Cell Host Microbe source

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

    Premisenone given

    It is estimated that approximately 50,000 microbial metabolites are produced by microbes in the human gut.

    “Thus far, it is estimated that ∼50,000 microbial metabolites are produced by microbes in the human gut.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Primary bile acids, cholic acid and chenodeoxycholic acid, are transported into the gut through the enterohepatic circulation system and are further metabolized by gut microbiota by dehydroxylation, dehydrogenation, and epimerization to generate secondary bile acids.

    “These primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), are transported into the gut through the enterohepatic circulation system and are further metabolized by gut microbiota by dehydroxylation, dehydrogenation, and epimerization to generate secondary bile acids reviewed previously.102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Dawson, 2015, Intestinal transport and metabolism of bile acids, J Lipid Res source

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  • May combine two claims.

    Interpretationreasoning

    Bile acids have been shown to be a double-edged sword and an appropriate balance (ratio) of different bile acids is required to mediate gut barrier protective activity.

    “In summary, bile acids have been shown to be a double-edged sword and an appropriate balance (ratio) of different bile acids is required to mediate gut barrier protective activity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Polyamines exhibit numerous beneficial effects including increased longevity, recovery of injured mucosa, and favorable effects on cognitive function.

    “Polyamines exhibit numerous beneficial effects including increased longevity, recovery of injured mucosa, as well as favorable effects on cognitive function.122, 123, 124”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [122] Tofalo, 2019, Polyamines and gut microbiota, Front Nutr source

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    • cites [123] Timmons, 2012, Polyamines and gut mucosal homeostasis, J Gastrointest Dig Syst

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    • cites [124] Matsumoto, 2011, Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production, PLoS One source

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    Premisecitation

    Treatment with the trans-10 CLA isomer caused a redistribution of ZO-1 and OCLN and increased paracellular permeability in Caco-2 colon epithelial cells.

    “Treatment with the trans-10 CLA isomer caused a redistribution of ZO-1 and OCLN and increased paracellular permeability in Caco-2 colon epithelial cells.119”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Roche, 2001, Fatty acids and epithelial permeability: effect of conjugated linoleic acid in Caco-2 cells, Gut source

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    Premisecitation

    CLNA1 and CLNA2 significantly reduced inflammatory mediators TNF-α, IL-1β, and IL-6 while upregulating the expression of colonic anti-inflammatory cytokine IL-10 and nuclear receptor peroxisome-activated receptor-γ.

    “Additionally, treatment with CLNA1 and CLNA2 significantly reduced inflammatory mediators (TNF-α, IL-1β, and IL-6) while upregulating the expression of the colonic anti-inflammatory cytokine IL-10 and nuclear receptor peroxisome-activated receptor-γ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice exposed to broad-spectrum antibiotics such as ampicillin, clindamycin and streptomycin resulted in reduced gut bacterial diversity and richness and impacted gut barrier integrity.

    “It was showed that mice exposed to broad-spectrum antibiotics such as ampicillin, clindamycin and streptomycin resulted in reduced gut bacterial diversity and richness and impacted gut barrier integrity.112”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Liu, 2020, Naturally occurring TPE-CA maintains gut microbiota and bile acids homeostasis via FXR signaling modulation of the liver-gut axis, Front Pharmacol source

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    Premisecitation

    L. plantarum ZS2058 produced isomers of conjugated fatty acids, α-linolenic acid (CLNA1 and CLNA2), that mitigated DSS-induced colitis by enhancing gut barrier function through upregulation of ZO-1, OCLN, CLDN-3, and E-cadherin 1 in colonic tissues.

    “Ren et al reported that the probiotic L. plantarum ZS2058 produced isomers of conjugated fatty acids, α-linolenic acid (conjugated linolenic acid (CLNA) 1 and CLNA2) mitigated DSS-induced colitis by enhancing gut barrier function through upregulation of ZO-1, OCLN, CLDN-3, and E-cadherin 1 in colonic tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TPE-CA treatment induced the expression of tight junction proteins such as ZO-1 and OCLN-associated proteins in these mice and improved the barrier integrity.

    “TPE-CA treatment induced the expression of TJ proteins such as ZO-1 and OCLN-associated proteins in these mice and improved the barrier integrity.112”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Liu, 2020, Naturally occurring TPE-CA maintains gut microbiota and bile acids homeostasis via FXR signaling modulation of the liver-gut axis, Front Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The colons of GP-BAR1-/- mice exhibit altered subcellular distribution of ZO-1, leading to increased gut permeability.

    “The colons of GP-BAR1–/– mice exhibit altered subcellular distribution of ZO-1, leading to increased gut permeability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    UDCA did not alter gut permeability but blocked the DCA-induced permeability in murine jejunal and colonic preparations.

    “In contrast, UDCA did not alter gut permeability but blocked the DCA-induced permeability in murine jejunal and colonic preparations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment with dietary flavanones and their glycosyl derivatives such as total phenolic extracts of Citrus aurantium L (TPE-CA) restored bacterial diversity and improved gut barrier integrity and homeostasis of bile acids.

    “Further, treatment with dietary flavanones and their glycosyl derivatives such as total phenolic extracts of Citrus aurantium L (TPE-CA) restored bacterial diversity and improved gut barrier integrity and homeostasis of bile acids.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Treatment with CDCA decreased the expression of Ocln and TEER values leading to increased permeability as well as an increase in the inflammatory cytokine IL-8.

    “Treatment with CDCA decreased the expression of Ocln and TEER values leading to increased permeability as well as an increase in the inflammatory cytokine IL-8.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The effects of DCA and CDCA were mediated by the Src family kinases and were abolished by EGF treatment.

    “The effects of these bile acids were mediated by the Src family kinases and was abolished by EGF treatment.110”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Raimondi, 2008, Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation, Am J Physiol Gastrointest Liver Physiol source

      Not checked in the free run.

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    Premisecitation

    Using a Caco-2 cell model, DCA and CDCA, but not UDCA, treatment decreased TEER and increased permeability.

    “Using a Caco-2 cell model, Raimondi et al110 showed that DCA and CDCA, but not UDCA, treatment decreased TEER and increased permeability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Raimondi, 2008, Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation, Am J Physiol Gastrointest Liver Physiol source

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    Premisecitation

    Fexaramine, an intestine-restricted FXR agonist, restored intestinal FXR activity and gut barrier integrity in an ALD model.

    “Fexaramine, an intestine-restricted FXR agonist, restored intestinal FXR activity and gut barrier integrity in an ALD model.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    CLNA1 and CLNA2 treatments rebalanced the intestinal microbial composition in the colons of DSS-treated mice, including increasing α-diversity.

    “These treatments also rebalanced the intestinal microbial composition in the colons of DSS-treated mice, including increasing the α-diversity.121”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Ren, 2020, c9, t11, c15-CLNA and t9, t11, c15-CLNA from Lactobacillus plantarum ZS2058 ameliorate dextran sodium sulfate-induced colitis in mice, J Agric Food Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CLA treatment reduced the prevalence of Bacteroides and increased Bifidobacterium and Odoribacter in the DSS-induced colitis mouse model.

    “Importantly, CLA treatment reduced the prevalence of Bacteroides and increased Bifidobacterium and Odoribacter in this model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Chen, 2019, Orally administered CLA ameliorates DSS-induced colitis in mice via intestinal barrier improvement, oxidative stress reduction, and inflammatory cytokine and gut microbiota modulation, J Agric Food Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some bile acid metabolites can both improve as well as exert negative effects on gut barrier tight junction function.

    “Some bile acid metabolites can both improve as well as exert negative effects on gut barrier TJ function.104”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Sarathy, 2017, The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium, Physiol Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    LCA by itself neither altered barrier function nor increased IL-8 production, but LCA attenuated CDCA-induced barrier permeability and IL-8 production.

    “Although LCA by itself neither altered barrier function nor increased IL-8 production, LCA attenuated CDCA-induced barrier permeability and IL-8 production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Among urolithins, urolithin A displays potent anti-inflammatory, antioxidative, and antiaging properties.

    “Among urolithins, urolithin A (UroA) displays potent anti-inflammatory, antioxidative, and antiaging properties.130,133, 134, 135”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [130] Espin, 2013, Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far, Evid Based Complement Alternat Med source

      Not checked in the free run.

    • cites [133] Tomas-Barberan, 2017, Urolithins, the rescue of 'old' metabolites to understand a 'new' concept: metabotypes as a nexus between phenolic metabolism, microbiota dysbiosis and host health status, Mol Nutr Food Res source

      Not checked in the free run.

    • cites [134] Ryu, 2016, Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A human phase I clinical trial showed that a polyphenol-rich diet modulates gut microbiota and reduces intestinal permeability, including decreased transport of pathogenic microbes into the bloodstream.

    “A human phase I clinical trial showed that a polyphenol-rich diet modulates gut microbiota and reduces intestinal permeability, including decreased transport of pathogenic microbes into the bloodstream.150”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Guglielmetti, 2020, Effect of a polyphenol-rich dietary pattern on intestinal permeability and gut and blood microbiomics in older subjects: study protocol of the MaPLE randomised controlled trial, BMC Geriatr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Numerous microbial metabolites exhibit direct impact on gut epithelium and play an important role in regulating gut barrier function thereby mucosal immunity and vice versa.

    “In summary, numerous microbial metabolites discussed previously shown to exhibit direct impact on gut epithelium and play an important role in regulating gut barrier function thereby mucosal immunity and vice versa.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary polyphenols such as isoflavones and lignans and corresponding microbial metabolites protected the gut epithelium by reducing permeability and inhibited LPS-induced inflammation.

    “Johnson et al151 reported that dietary polyphenols such as isoflavones and lignans and corresponding microbial metabolites protected the gut epithelium by reducing permeability and inhibited LPS-induced inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Johnson, 2019, Polyphenol microbial metabolites exhibit gut and blood(-)brain barrier permeability and protect murine microglia against LPS-induced inflammation, Metabolites source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two factors are critical for the generation of UroA in humans: presence of UroA producing bacteria and consumption of EA/ET-containing foods.

    “Two factors are critical for the generation of UroA in humans (1) presence of UroA producing bacteria and (2) consumption of EA/ET-containing foods (eg, pomegranate, berries, walnuts).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Bacterial polyamines include spermidine, homospermidine, norspermidine, putrescine, cadaverine, and 1,3-diaminopropane with putrescine and spermidine.

    “Bacterial polyamines include spermidine, homospermidine, norspermidine, putrescine, cadaverine, and 1,3-diaminopropane with putrescine and spermidine.125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Michael, 2016, Biosynthesis of polyamines and polyamine-containing molecules, Biochem J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of cellular polyamines by α-difluoromethylornithine reduced intracellular free Ca2+ concentrations in normal IECs (IEC-6 cell line), leading to decreased expression of E-cadherin and increased paracellular permeability.

    “It was shown that depletion of cellular polyamines by α-difluoromethylornithine reduced intracellular free Ca2+ concentrations in normal IECs (IEC-6 cell line),127 which leads to decreased expression of E-cadherin and increased paracellular permeability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Guo, 2003, Regulation of adherens junctions and epithelial paracellular permeability: a novel function for polyamines, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous supplementation of spermidine reversed the effects of α-difluoromethylornithine on intracellular Ca2+ and E-cadherin expression and restored paracellular permeability to near normal levels.

    “However, exogenous supplementation of the spermidine reversed the effects of α-difluoromethylornithine on intracellular Ca2+ and E-cadherin expression and restored paracellular permeability to near normal levels.128”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Guo, 2005, Polyamines are necessary for synthesis and stability of occludin protein in intestinal epithelial cells, Am J Physiol Gastrointest Liver Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with UroA mitigated DSS- or TNBS-induced colitis in mice through enhancing gut barrier function and blocking the production of inflammatory cytokines.

    “Importantly, treatment with UroA mitigated DSS- or TNBS-induced colitis in mice through enhancing gut barrier function and blocking the production of inflammatory cytokines.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Singh, 2019, Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOD1 and NOD2 knockout mice exhibit increased paracellular permeability and are more susceptible to DSS colitis mediated intestinal injury.

    “NOD1 and NOD2 knockout mice exhibit increased paracellular permeability and are reported to be more susceptible to DSS colitis mediated intestinal injury.177”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Natividad, 2012, Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1–/–; Nod2–/– mice, Inflamm Bowel Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These receptors play crucial roles in host-microbiota interactions and are expressed at various levels in different cell types such as IECs, innate lymphoid cells, macrophages, T cells, and dendritic cells.

    “These receptors, which play crucial roles in host-microbiota interactions, are expressed at various levels in different cell types such as IECs, innate lymphoid cells, macrophages, T cells, and dendritic cells.184”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Furusawa, 2013, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking TLR4 with antibodies limited acute inflammation in the DSS model but hampered subsequent tissue repair, suggesting an important role for TLR4 in the resolution of inflammation and restoration of tissue integrity.

    “Although blocking TLR4 with antibodies limited acute inflammation in the DSS model, subsequent tissue repair was hampered, suggesting an important role for TLR4 in the resolution of inflammation and restoration of tissue integrity.162”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Ungaro, 2009, A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis, Am J Physiol Gastrointest Liver Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Flagellin exerts activities through TLR5 and plays an essential and nonredundant role in protecting the gut from enteric microbes.

    “Flagellin, a structural component of bacterial flagellum, is exerted activities through TLR5 and has been shown to play an essential and nonredundant role in protecting the gut from enteric microbes.164”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Steiner, 2007, How flagellin and toll-like receptor 5 contribute to enteric infection, Infect Immun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOD2 deficiency leads to microbial dysbiosis leading to increased risk of colitis.

    “Couturier-Millard et al178 reported that NOD2 deficiency leads to microbial dysbiosis leading to increased risk of colitis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Couturier-Maillard, 2013, NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer, J Clin Invest

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR9-/- mice are more susceptible to DSS-induced colitis compared with wild types mice, suggesting that activation of TLR9 is important for protection against intestinal damage through induction of vascular EGF and intestinal progenitor cell differentiation as well as being critical for wound repair mechanisms.

    “TLR9–/– mice are more susceptible to DSS-induced colitis compared with wild types mice, suggesting that activation of TLR9 is important for protection against intestinal damage through induction of vascular EGF and intestinal progenitor cell differentiation as well as being critical for wound repair mechanisms.171”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Rose, 2012, TLR9 is important for protection against intestinal damage and for intestinal repair, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPS disrupts junctional protein complexes and increases inflammatory cytokines leading to increased gut permeability.

    “Numerous studies including ours showed that LPS disrupts junctional protein complexes and increases inflammatory cytokines leading to increased gut permeability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muramyl dipeptide or peptidoglycan mediated activation of NOD2 negatively regulates TLR signaling and provides protection of wildtype mice against colitis.

    “Furthermore, muramyl dipeptide or peptidoglycan mediated activation of NOD2 is reported to negatively regulate TLR signaling and provide protection of wildtype mice against colitis.175,176”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [175] Watanabe, 2008, Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis, J Clin Invest

      Not checked in the free run.

    • cites [176] Macho Fernandez, 2011, Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide, Gut source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IECs express TLR2 that recognizes bacterial lipopeptides, lipoteichoic acid and yeast zymosan, and forms heterodimers with TLR1 or TLR6.

    “IECs express TLR2 that recognizes bacterial lipopeptides, lipoteichoic acid and yeast zymosan, and forms heterodimers with TLR1 or TLR 6.157”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Creagh, 2006, TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity, Trends Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression and activation of TLR5 on IECs regulates the composition and localization of microbiota and prevents disease associated intestinal inflammation.

    “It was demonstrated in numerous reports from Dr Gewirtz’s group that expression and activation of TLR5 on IECs regulates the composition and localization of microbiota and prevents disease associated intestinal inflammation.165, 166, 167, 168”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [165] Chassaing, 2014, Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice, Gastroenterology source

      Not checked in the free run.

    • cites [166] Vijay-Kumar, 2007, Deletion of TLR5 results in spontaneous colitis in mice, J Clin Invest

      Not checked in the free run.

    • cites [167] Leifer, 2014, Linking genetic variation in human Toll-like receptor 5 genes to the gut microbiome's potential to cause inflammation, Immunol Lett source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Functional immune responses often modulate gut barrier integrity; hence, the fine tuning of gut microbiota to evoke necessary immune responses to alter intestinal barrier function is critical.

    “Functional immune responses often modulate gut barrier integrity; hence, the fine tuning of gut microbiota to evoke necessary immune responses to alter intestinal barrier function is critical.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nod1-/- mice have increased levels of intestinal permeability and inflammation in the murine DSS-induced colitis model compared with wild type mice, suggesting an important role in intestinal barrier function.

    “It was reported that Nod1–/– mice have increased levels of intestinal permeability and inflammation in the murine DSS-induced colitis model compared with wild type mice,174 suggesting an important role in intestinal barrier function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Chen, 2008, The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Ligand-induced TLR2 activation leads to the specific activation of PKC-α and PKC-δ and is responsible for increased TEER as well as increased apical tightening and sealing of the TJs.

    “Ligand-induced TLR2 activation leads to the specific activation of protein kinase C α (PKC-α) and PKC-δ and is responsible for increased TEER as well as increased apical tightening and sealing of the TJs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    PKC phosphorylation by TLR2 activation leads to stabilization of ZO-1, which is a target of PKC.

    “PKC phosphorylation by TLR2 activation leads to stabilization of ZO-1, which is a target of PKC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The absence of NOD protein-mediated microbial sensing leads to a loss of gut barrier homeostasis and leads to increased susceptibility to gut inflammatory diseases.

    “The absence of NOD protein–mediated microbial sensing leads to a loss of gut barrier homeostasis and leads to increased susceptibility to gut inflammatory diseases.176”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Macho Fernandez, 2011, Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide, Gut source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRs proteins are responsible for maintaining gut barrier integrity by sensing the presence of commensal microbiota and the regulation of intestinal inflammation.

    “NLRs proteins are also responsible for maintaining gut barrier integrity by sensing the presence of commensal microbiota and the regulation of intestinal inflammation.172,173”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Parlato, 2014, NOD-like receptors in intestinal homeostasis and epithelial tissue repair, Int J Mol Sci source

      Not checked in the free run.

    • cites [173] Yeretssian, 2012, Effector functions of NLRs in the intestine: innate sensing, cell death, and disease, Immunol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of TLR5 by flagellin in ileal tissues of SAMP1/YitFc mice led to decreased epithelial barrier resistance and altered expression of the TJ proteins CLDN-3, OCLN, and ZO-1.

    “Activation of TLR5 by flagellin in ileal tissues of SAMP1/YitFc (SAMP) mice (a spontaneous model of Crohn's disease–like ileitis) led to decreased epithelial barrier resistance and altered expression of the TJ proteins CLDN-3, OCLN, and ZO-1.169”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Lopetuso, 2017, Epithelial-specific Toll-like receptor (TLR)5 activation mediates barrier dysfunction in experimental ileitis, Inflamm Bowel Dis source

      Not checked in the free run.

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

    Premisecitation

    Another therapeutic approach includes blocking Th1 responses or using neutralizing antibodies such as infliximab (anti-TNF) antibody.

    “Another therapeutic approach includes blocking Th1 responses or using neutralizing antibodies such as infliximab (anti-TNF) antibody.189,190”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [189] Powrie, 1994, Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells, Immunity source

      Not checked in the free run.

    • cites [190] Noth, 2012, Anti-TNF-alpha antibodies improve intestinal barrier function in Crohn's disease, J Crohns Colitis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sex hormones such as estrogen and progesterone induced expression of TJ proteins and inhibited gut permeability in inflammatory organoid models from IBD patients and 2D cell line models.

    “For example, sex hormones such as estrogen and progesterone induced expression of TJ proteins and inhibited gut permeability in inflammatory organoid models from IBD patients and 2D cell line models.200”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] van der Giessen, 2019, A direct effect of sex hormones on epithelial barrier function in inflammatory bowel disease models, Cells source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Implantation of 17 pre-selected clostridial bacterial strains capable of enhancing Treg cell abundance and inducing anti-inflammatory mediators IL-10 and inducible T-cell co-stimulator into GF mice attenuated TNBS-induced colitis and enhanced gut barrier function.

    “Implantation of 17 pre-selected clostridial bacterial strains that are capable of enhancing Treg cell abundance and inducing anti-inflammatory mediators, IL-10 and inducible T-cell co-stimulator, into GF mice attenuated TNBS-induced colitis and enhanced gut barrier function.192”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Atarashi, 2013, Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progesterone upregulated OCLN expression in the gut and inhibited NF-κB activation to maintain gut barrier homeostasis.

    “Zhou et al201 reported that progesterone upregulated OCLN expression in the gut and inhibited NF-κB activation to maintain gut barrier homeostasis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Zhou, 2019, Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UroA and UAS03 blocked unwarranted inflammation and mitigated colitis in pre-clinical models.

    “Additionally, UroA and UAS03 also blocked unwarranted inflammation and mitigated colitis in pre-clinical models.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Singh, 2019, Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Dietary habits and a healthy lifestyle are of the foremost importance in maintaining healthy intestinal barrier functions.

    “Last, but definitely not the least, dietary habits and a healthy lifestyle are of the foremost importance in maintaining healthy intestinal barrier functions.207”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Camilleri, 2019, Leaky gut: mechanisms, measurement and clinical implications in humans, Gut source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with divertin corrected increased intestinal permeability in IL-10-/- mice (spontaneous colitis model) without significant systemic, mucosal, or epithelial toxicity.

    “Further, they demonstrated that treatment with divertin corrected increased intestinal permeability in IL-10–/– mice (spontaneous colitis model) without significant systemic, mucosal, or epithelial toxicity.191”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Graham, 2019, Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis, Nat Med source

      Not checked in the free run.

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

    Premisecitation

    Conventional treatment strategies include the use of immunosuppressants such as azathioprine and mesalamine that are used in the clinic to treat ulcerative colitis and Crohn's disease.

    “Conventional treatment strategies include the use of immunosuppressants such as azathioprine and mesalamine that are used in the clinic to treat ulcerative colitis and Crohn's disease.188”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Khare, 2019, Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMT was reported to decrease antibiotic, chemotherapy, and injury-induced gut permeability and increased the prevalence of specific microbiota strains exhibiting anti-inflammatory properties.

    “FMT was reported to decrease antibiotic, chemotherapy, and injury-induced gut permeability and increased the prevalence of specific microbiota strains exhibiting anti-inflammatory properties.195,196”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [195] Le Bastard, 2018, Fecal microbiota transplantation reverses antibiotic and chemotherapy-induced gut dysbiosis in mice, Sci Rep source

      Not checked in the free run.

    • cites [196] Schmidt, 2020, Fecal transplant prevents gut dysbiosis and anxiety-like behaviour after spinal cord injury in rats, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Beneficial activities of microbial metabolites in regulating gut barrier function have been shown in animal models, but no microbial metabolites or their analogues are in clinical use.

    “Though beneficial activities of microbial metabolites in regulating gut barrier function have been shown in animal models, thus far, no microbial metabolites or their analogues are in clinical use.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Probiotic strains such as L. plantarum elevate the levels of host defense peptides such as pBD2, PG1-5 and pBD2 and improve gut barrier function.

    “Furthermore, probiotic strains such as L. plantarum also elevate the levels of host defense peptides such as pBD2, PG1-5 and pBD2 and improve gut barrier function.83”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Feng, 2018, Short-chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy, Cell Physiol Biochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxyberberine ameliorated gut barrier dysfunction via inhibition of the TLR4, MyD88, and NF-κB signaling pathways and downregulated inflammatory cytokines such as TNFα, IL-6, and IL-1β.

    “Oxyberberine, another microbial metabolite derived from berberine ameliorated gut barrier dysfunction via inhibition of the TLR4, MyD88, and NF-κB signaling pathways197 and downregulated inflammatory cytokines such as TNFα, IL-6, and IL-1β.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Li, 2020, Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-kappaB pathway, Pharmacol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary cellulose supplements can ameliorate LPS-mediated intestinal barrier damage and protect against gut epithelial apoptosis.

    “Dietary cellulose supplements also can ameliorate LPS-mediated intestinal barrier damage and protect against gut epithelial apoptosis.205”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Di Caro, 2019, Effect of dietary cellulose supplementation on gut barrier function and apoptosis in a murine model of endotoxemia, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Curcumin supplementation reduced high fat diet induced hepatic steatosis by modulating the gut-liver axis and by enhancing ZO-1 and OCLN expression in the intestines.

    “Dietary component such as curcumin supplementation reduced high fat diet induced hepatic steatosis by modulating the gut-liver axis and by enhancing ZO-1 and OCLN expression in the intestines.203”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Yang, 2019, Ellagic acid and its microbial metabolite urolithin a alleviate diet-induced insulin resistance in mice (OR24-03-19), Curr Dev Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Increasing recognition of the association between gut microbes, gut barrier dysfunction, and intestinal diseases highlights the importance of understanding microbial metabolite production and function.

    “Moreover, increasing recognition of the association between gut microbes, gut barrier dysfunction, and intestinal diseases highlights the importance of understanding microbial metabolite production and function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The influence of gut microbiota on intestinal barrier permeability and subsequent host cellular homeostasis is indisputable.

    “The influence of gut microbiota on intestinal barrier permeability and subsequent host cellular homeostasis is indisputable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Emerging knowledge of host-microbiota interactions allows for the development of new therapeutic strategies to restore a healthy gut ecosystem and prevent a variety of intestinal diseases.

    “Emerging knowledge of host-microbiota interactions allows for the development of new therapeutic strategies to restore a healthy gut ecosystem and prevent a variety of intestinal diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A deeper understanding of intestinal microbiota dynamics with respect to gut barrier function provides translational opportunities for therapeutic discovery, including drug design, microbe transplantation, and a clearer perspective of host pathophysiology.

    “Furthermore, a deeper understanding of intestinal microbiota dynamics with respect to gut barrier function provides translational opportunities for therapeutic discovery, including drug design, microbe transplantation, and a clearer perspective of host pathophysiology.”
    Quote in the paperNot a substantial claim
86 of 86

  • The authors state this as an assumption.

    Gut microbial metabolites, produced in close proximity to gut epithelium, have significant impact on gut barrier function and immune responses.

    “Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses.”

  • The paper relies on this without support.

    Intestinal microbial homeostasis is required for maintenance of good health and disease prevention.

    “Intestinal microbial homeostasis is required for maintenance of good health and disease prevention.”

  • The paper relies on this without support.

    Reversal of gut dysbiosis is the key factor for any treatment utilizing gut microbiota.

    “Reversal of gut dysbiosis is the key factor for any treatment utilizing gut microbiota.”

  • The paper relies on this without support.

    A healthy life without stress, obesity, and diabetes and accompanied by an alcohol-free diet can reverse gut barrier dysfunction over time.

    “A healthy life without stress, obesity, and diabetes and accompanied by an alcohol-free diet can reverse gut barrier dysfunction over time.”
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?

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.

  • Goblet-cell location differs between the text and Table 1

    Minor

    The text says goblet cells are present in both the small intestine and colon, but Table 1 lists them only in the small intestine.

1 of 1

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Authors
Ghosh, S., Whitley, C. S., Haribabu, B., & Jala, V. R.
Affiliations
University of Louisville (US)
Corresponding author
Jala, Venkatakrishna Rao
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2021
Volume
11
Issue
5
Pages
1463-1482
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2021.02.007
PMC
PMC8025057
OpenAlex
W3129925389
Semantic Scholar
90f802cea558abb11387de76fdcedb31c6e57f46
Cited by
835
References
211
Citations by year
2026: 168 · 2025: 229 · 2024: 192 · 2023: 130 · 2022: 89 · 2021: 27
FWCI
11.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Nutrition and Physiology
Keywords
intestinal barrier function, gut microbiota, microbial metabolites, intestinal epithelium, host-microbe interactions, immune regulation, dietary metabolites, dysbiosis, probiotics
MeSH terms
Gastrointestinal Microbiome, Animals, Cell Membrane Permeability, Humans, Intestinal Mucosa, Metabolome

About these checks

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.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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