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Cited by 876Gut microbiota and healthOral microbiology and periodontitis researchGastrointestinal motility and disorders

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

Open access
Postler, Thomas Siegmund, Ghosh, Sankar·2017·Cell Metabolism
DOI 10.1016/j.cmet.2017.05.008PMC PMC5535818
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Abstract

SUMMARY The human gastrointestinal tract is populated by a diverse, highly mutualistic microbial flora, which is known as the microbiome. Disruptions to the microbiome have been shown to be associated with severe pathologies of the host including metabolic disease, cancer and inflammatory bowel disease. Mood and behavior are also susceptible to alterations in the gut microbiota. A particularly striking example of the symbiotic effects of the microbiome is the immune system, whose cells depend critically on a diverse array of microbial metabolites for normal development and behavior. This includes metabolites that are produced by bacteria from dietary components; metabolites that are produced by the host and biochemically modified by gut bacteria; and metabolites that are synthesized de novo by gut microbes. In this review, we highlight the role of the intestinal microbiome in human metabolic and inflammatory diseases and focus in particular on the molecular mechanisms that govern the gut-immune axis.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that gut microbes and their metabolites form a composite holobiont with the host, influencing metabolic and inflammatory disease as well as immune cell development. It surveys mechanisms by which dietary-, host-, and microbe-derived metabolites shape the intestinal immune system, while emphasizing unresolved mechanistic and ecological questions.

Key findings

  • Microbiome composition and function are linked to obesity, type 2 diabetes, and atherosclerosis. Obesity associates with increased Firmicutes relative to Bacteroidetes; transferring obese microbiota to germ-free mice causes greater weight gain than lean transfer. Type 2 diabetes microbiota produces fewer short-chain fatty acids, increasing mucosal permeability and LPS-driven inflammation; TMAO from phosphatidylcholine and l-carnitine predicts cardiovascular risk and promotes atherosclerosis in mice, though fish/TMAO and l-carnitine contradictions remain.
  • Short-chain fatty acids are major anti-inflammatory mediators. Acetate, propionate, and butyrate signal via FFAR2/FFAR3/HCAR2 and HDAC inhibition; they support epithelial barrier, neutrophils, macrophages, dendritic cells, B cells, and regulatory T cells. Different short-chain fatty acids have distinct effects: acetate/propionate expand existing colonic regulatory T cells, while propionate/butyrate promote de novo regulatory T cell differentiation. In vivo concentrations varied from 36 to 300 mM; butyrate at 150 mM in drinking water increased colonic regulatory T cells, 36 mM did not, and 50 mM by enema did.
  • Other metabolites include indole derivatives activating AhR and PXR to support IL-22/ILC3 and barrier function; polyamines modulating NLRP6/IL-18 and macrophage cytokines; bile acids signaling through BAR/FXR and GPBAR1/TGR5 to reduce pro-inflammatory cytokines; microbially derived ATP driving TH17 and P2X7-dependent IgA regulation; and polysaccharide A from Bacteroides fragilis inducing IL-10 and Treg/TH1 responses.
  • Reported quantities include: average male colonized by about 3.8×10^13 microbes versus 3.0–3.7×10^13 host cells; female about 4.4×10^13 bacteria versus 2.1×10^13 host cells; metagenomic catalog of 3.3×10^6 nonredundant microbial genes from up to 1,150 species, about 150-fold human protein-coding genes; each person hosts at least 160 species; about 10% of blood metabolites are microbiota-derived. In mouse colonic lumen, 179 metabolites were detected, 48 absent from food, 35 of those altered in germ-free mice, plus 88 food-present metabolites altered. Of 79 human intestinal strains screened, 9 (11.4%) produced TMA from choline.

Methods

  • Narrative review, not primary research; synthesizes prior human, animal, in vitro, and metagenomic/metabolomic studies.
  • Covers microbiome links to metabolic disease and immune modulation by three metabolite classes: bacterial products from diet, host metabolites modified by bacteria, and de novo microbial products.
  • Main analysis is conceptual synthesis and mechanistic discussion; no systematic search, inclusion criteria, or meta-analysis described.

Limitations

  • The paper states many mechanisms remain unresolved: most intestinal bacterial metabolome is unidentified, many known metabolites are functionally uncharacterized, bioavailability and epithelial crossing are poorly understood, TMAO mechanisms are elusive, bile-acid causality in IBD is not established, and short-chain fatty acid dosing/route effects are unclear.
  • The paper notes functional studies mostly examine single species or metabolites, whereas real gut communities may interact additively, synergistically, redundantly, or subtractively; up to 1,150 species and at least 160 per person make network complexity enormous.
  • Evident from the text: as a narrative review, it does not systematically assess study quality or bias, and many conclusions rest on mouse models, in vitro systems, or small human studies, such as the small FMT study in type 2 diabetes.

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

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2017.05.008

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation

    The same weight-increasing effect is observed when microbiota from obese or lean humans is transferred to germ-free mice.

    “This observation also holds true when the microbiota from obese or lean humans is transferred to germ-free mice (Ridaura et al., 2013; Tremaroli et al., 2015).”
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  • Findingreasoning

    When a germ-free mouse receives microbiota from an obese individual, the ability to utilize high-caloric nutrients is transferred, resulting in obesity of the recipient.

    “When a germ-free mouse receives the microbiota of an obese individual, the ability to effectively utilize high-caloric nutrients is transferred along with it, resulting in obesity of the recipient.”
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  • Findingcitation

    Obesity is associated with a relative increase in Firmicutes at the expense of Bacteroidetes in humans and animal models.

    “The composition of the microbiome differs between obese and lean individuals in humans and in animal models: obesity is associated with a relative increase in Firmicutes at the expense of Bacteroidetes (Ley et al., 2005; 2006).”
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    • cites Ley et al., 2005; 2006

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  • Findingcitation

    Obesity is linked to deterioration of the intestinal mucosa and resultant chronic systemic inflammation.

    “In addition to changes in energy metabolism, obesity has also been linked to a deterioration of the intestinal mucosa and resultant chronic, systemic inflammation, analogous to type 2 diabetes (see below) (Boutagy et al., 2016).”
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  • Findingcitation

    l-carnitine and its metabolite γ-butyrobetaine promoted atherosclerosis in mice.

    “They found that l-carnitine and its metabolite γ-butyrobetaine also promoted atherosclerosis in mice, and that elevated plasma levels of l-carnitine were associated with increased risk of cardiovascular disease in individuals with elevated TMAO plasma levels (Koeth et al., 2013; 2014).”
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    Findingcitation

    Transfer of microbiota from obese mice to germ-free animals causes a significantly larger weight increase than transfer from lean mice, demonstrating that body weight is partly controlled by the microbiome.

    “Crucially, the transfer of the microbiota from obese mice to germ-free animals results in a significantly larger weight increase than an equivalent transfer from lean mice, clearly demonstrating that body weight is in part controlled by the microbiome (Turnbaugh et al., 2008; 2006).”
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    Findingcitation

    A small study of FMTs from lean healthy donors to obese recipients with type 2 diabetes found no weight reduction but a significant increase in insulin sensitivity six weeks after transplantation.

    “Interestingly, a small study of FMTs from lean, healthy donors to obese recipients with type 2 diabetes found no reduction in weight but a significant increase in insulin sensitivity in the recipient population six weeks after transplantation (Vrieze et al., 2012).”
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    Findingcitation

    The representation of biochemical pathways in the collective genome of the gut microbiome is remarkably similar between healthy individuals, whereas species composition varies significantly.

    “Consistent with this model of microbial selection based on biochemical capacity, the representation of biochemical pathways in the collective genome of the gut microbiome is remarkably similar between healthy individuals, whereas the composition of the microbiome on a species level varies significantly.”
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    • cites Human Microbiome Project Consortium, 2012

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    • cites Kurokawa et al., 2007 source

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    Findingcitation

    Abundance of A. muciniphila is decreased in obese and diabetic mice, and reintroduction by oral gavage improves epithelial barrier function and reduces diet-induced obesity.

    “Abundance of A. muciniphila is decreased in obese (and diabetic) mice, while reintroduction of the bacterium by oral gavage improves epithelial barrier function and reduces diet-induced obesity (Everard et al., 2013).”
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    Findingcitation

    Mice chronically exposed to low levels of LPS for four weeks gained weight and became insulin-resistant.

    “Interestingly, mice chronically exposed to low levels of LPS for four weeks gained weight and became insulin-resistant (Cani et al., 2007).”
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    Findingcitation

    Obese individuals share a functionally similar gut microbiome, with reduced but still considerable species diversity.

    “Obese individuals share a functionally similar gut microbiome between them, with reduced but still considerable species diversity (Human Microbiome Project Consortium, 2012; Kurokawa et al., 2007; Qin et al., 2010; Turnbaugh et al., 2009).”
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    Premisecitation

    The gut microbiome can actively drive obesity, either together with diet and genetic predisposition or independently.

    “Unexpectedly, the gut microbiome can be an active driver of obesity, either in combination with the interrelated factors of diet and genetic predisposition, or by itself (Cox and Blaser, 2013; Shapiro et al., 2017).”
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    Interpretationcitation

    The microbiota extracts energy from dietary components not digested by the host and converts it to absorbable nutrients, altering host energy balance.

    “the microbiota extracts energy from dietary components that are not digested by the host and converts that energy to nutrients the host can absorb, thereby altering the overall energy balance of the host.”
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    Interpretationcitation

    A Western-style diet selects for a less diverse microbiota that efficiently extracts energy (mostly Firmicutes), while a plant-based diet promotes fiber-fermenting species (Bacteroidetes).

    “An obesity-inducing, Western-style diet, which is typically low in fiber and high in caloric content from sucrose and unsaturated fat, thus selects for a less diverse microbiota that efficiently extracts energy from these nutrients (mostly members of the Firmicutes). Conversely, a plant-based diet promotes the enrichment of microbial species that efficiently ferment fiber (Bacteroidetes) (De”
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    Premisenone given

    The human gastrointestinal tract hosts a diverse, highly mutualistic microbial community known as the microbiome.

    “The human gastrointestinal tract is populated by a diverse, highly mutualistic microbial flora, which is known as the microbiome.”
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    Premisenone given

    Microbial metabolites affecting the gut-immune axis fall into three categories: those produced by bacteria from dietary components, those produced by the host and modified by gut bacteria, and those synthesized de novo by gut microbes.

    “These can broadly be grouped into three categories: (i) metabolites that are produced by bacteria directly from dietary components; (ii) metabolites that are produced by the host and biochemically modified by gut bacteria; and (iii) metabolites that are synthesized de novo by gut microbes (Table 1).”
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    Interpretationreasoning

    In the absence of adequate SCFA production, intestinal permeability increases, allowing gut bacteria to cross into the bloodstream.

    “In the absence of adequate SCFA production, the permeability of the intestinal mucosa increases, allowing gut bacteria to cross and enter the bloodstream.”
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    Premisecitation

    The microbiome of T2D patients is markedly different from healthy individuals and is believed to promote inflammatory events by two distinct mechanisms.

    “The microbiome of patients suffering from T2D, which is also markedly different from healthy individuals, is believed to promote these inflammatory events by two distinct mechanisms (Karlsson et al., 2013; Qin et al., 2012).”
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    Premisecitation

    T2D is associated with inflammation of insulin-producing β cells and white adipose tissue, resulting in decreased insulin production and increased insulin resistance.

    “T2D is associated with inflammation of the insulin-producing β cells of the pancreatic islets and the white adipose tissue itself, which results in decreased insulin production and increased insulin resistance, respectively (comprehensively reviewed by (Donath et al., 2013)).”
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    Premisecitation

    The gut microbiome is implicated directly in the development of type 2 diabetes and cardiovascular disease.

    “In addition to obesity, the gut microbiome has also been implicated directly in the development of the two primary complications of Metabolic Syndrome, type 2 diabetes (T2D) and cardiovascular disease (Fändriks, 2016; Jonsson and Bäckhed, 2017; Khan et al., 2014).”
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    Premisecitation

    AhR is required for postnatal maintenance of IL-22-producing ILC3s and for formation of isolated lymphoid follicles.

    “the AhR is in fact required for postnatal maintenance of IL-22-producing ILC3s, as well as the formation of isolated lymphoid follicles (Kiss et al., 2011; Lee et al., 2011; Y. Li et al., 2011; J. Qiu et al., 2012).”
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    Premisecitation

    SCFAs promote regulatory T cells, which suppress effector T-cell activity.

    “Perhaps the most potent anti-inflammatory property of SCFAs is their promotion of regulatory T cells (Tregs), which suppress the activity of effector T cells.”
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    Premisecitation

    The expansion and de novo differentiation effects operate independently, as cTreg numbers in germ-free mice are reduced and can be rescued by separate provision of acetate, propionate, or butyrate.

    “Each of these functions operates independently, as numbers of cTregs in germ-free mice, which are starkly reduced in the absence of treatment, can be rescued by separate provision of acetate, propionate or butyrate (Arpaia et al., 2013; Smith et al., 2013).”
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    Premisecitation

    AhR is a ligand-activated transcription factor with a central role in the intestinal mucosa.

    “The AhR is a ligand-activated transcription factor with a central role in the intestinal mucosa (Stockinger et al., 2014).”
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    Premisecitation

    IPA is produced in mice monocolonized with Clostridium sporogenes but is absent in the gut of germ-free mice.

    “which is produced in mice monocolonized with Clostridium sporogenes but absent in the gut of germ-free mice (Venkatesh et al., 2014; Wikoff et al., 2009).”
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    Premisecitation

    Exposure of a colorectal cancer cell line to a mixture of SCFAs can elicit TGF-β production, which promotes differentiation of naive T cells into Tregs.

    “Atarashi et al. showed that exposure of a colorectal cancer cell line to a mixture of SCFAs could elicit the production of transforming growth factor beta (TGF-β), which promotes the differentiation of naive T cells into Tregs (Atarashi et al., 2013; Fu et al., 2004).”
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    Interpretationcitation

    Administration route and SCFA concentration are important for in vivo experiments.

    “emphasizing the importance of administration route and SCFA concentration for in vivo experiments (Arpaia et al., 2013).”
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    Premisecitation

    Ahr−/− mice have multiple immunological deficits, including reduced resistance to Listeria monocytogenes, Citrobacter rodentium, and Candida albicans, exacerbated DSS-induced colitis, and altered susceptibility to EAE.

    “Ahr−/− mice suffer from multiple immunological deficits, including reduced resistance to infection with the bacteria Listeria monocytogenes or Citrobacter rodentium, as well as the fungus Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE)”
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    Premisecitation

    Indole derivatives produced by these bacteria can compensate for the lack of endogenous AhR ligands, reflecting a mutualistic balance between microbiome and host.

    “Indole derivatives produced by these bacteria can then compensate for the lack of endogenously produced AhR ligands, reflecting an interesting mutualistic balance between the needs of microbiome and host (Zelante et al., 2013).”
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    Premisecitation

    The inhibition of dendritic cell maturation by butyrate and propionate is primarily mediated by HDAC inhibition and depends on the SCFA transporter SLC5A8.

    “This appears to be primarily mediated by HDAC inhibition, as the effect is dependent on the SCFA transporter SLC5A8 (Singh et al., 2010).”
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    Premisecitation

    Free taurine generated by deconjugation can enhance NLRP6 inflammasome activation and increase IL-18 production by the intestinal epithelium, supporting barrier function and maintenance.

    “free taurine generated by deconjugation can enhance the activation of the NLRP6 inflammasome and thereby increase production of IL-18 by the intestinal epithelium, which supports epithelial barrier function and maintenance (Levy et al., 2015).”
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    Interpretationreasoning

    The microbiome metabolizes substantial quantities of dietary arginine and may regulate arginine availability to the immune system to some extent.

    “This indicates that the microbiome metabolizes substantial quantities of dietary arginine and may thus regulate the availability of arginine to the immune system to a certain extent (Mardinoglu et al., 2015; Matsumoto et al., 2012).”
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    Premisecitation

    Primary bile acids are converted to secondary bile acids by the local microbiota, partly in the small intestine and predominantly in the colon, beginning with deconjugation and followed by dehydroxylation.

    “Primary bile acids are converted to secondary bile acids by the local microbiota, partly in the small intestine and predominantly in the colon. This involves multiple steps and typically begins with the initial deconjugation of glycine or taurine, followed by dehydroxylation (Ridlon et al., 2006).”
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    Premisecitation

    Combined knockout of Nr1i2 and Tlr4 can rescue the phenotype of Nr1i2−/− mice, possibly by counteracting accelerated cell death of inflammatory monocytes.

    “the combined knockout of Nr1i2 and the gene encoding the LPS sensor toll-like receptor 4 (Tlr4) can rescue the phenotype of Nr1i2−/− mice, possibly because it counteracts the accelerated cell death of inflammatory monocytes observed in NR1I2-deficient mice (Z. Qiu et al., 2016; Venkatesh et al., 2014).”
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    Premisecitation

    About 95% of bile acids are reabsorbed in the terminal ileum by active transport, mostly in conjugated form, and recycled by the host.

    “After passage through the small intestine, about 95% of bile acids are reabsorbed in the terminal ileum by active transport, mostly in their conjugated form, and recycled by the host.”
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    Premisecitation

    Bile acids have also been reported to act as agonists at additional receptors, but the physiological relevance of these pathways remains incompletely understood.

    “Bile acids have also been reported to function as agonists to additional receptors, but the physiological relevance of these pathways remains incompletely understood (Thomas et al., 2008).”
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    Premisecitation

    Arginine is an important modulator of macrophage and T-cell immunometabolism and affects their effector functions.

    “Arginine itself is an important modulator of the immunometabolism of macrophages and T cells and thus affects their effector functions (O'Neill et al., 2016).”
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    Premisecitation

    Extraneous spermine is taken up by monocytes and macrophages and selectively inhibits LPS-induced expression of pro-inflammatory cytokines.

    “Extraneous spermine is taken up by monocytes and macrophages and selectively inhibits the LPS-induced expression of pro-inflammatory cytokines (M. Zhang et al., 1999; 1997).”
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    Premisecitation

    GPBAR1 is a Gs-protein-coupled receptor; bile acid binding triggers an increase in intracellular cAMP and activation of ERK.

    “GPBAR1, as the name suggests, is a Gs-protein-coupled receptor. Binding by bile acids triggers an increase in intracellular cAMP levels and the activation of ERK (Kawamata et al., 2003; Maruyama et al., 2002).”
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    Premisecitation

    Primary bile acids are more readily absorbed in the small intestine, whereas secondary bile acids are more hydrophobic and are taken up more efficiently in the colon.

    “Primary bile acids are more readily absorbed in the small intestine, whereas secondary bile acids are more hydrophobic and can thus be taken up more efficiently in the colon (Martinez-Augustin and Sanchez de Medina, 2008).”
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    Premisecitation

    Treatment with a synthetic BAR agonist has protective effects in mouse colitis models, whereas BAR-deficient mice exhibit exacerbated pathology.

    “treatment with a synthetic agonist of BAR has protective effects in mouse models of colitis, whereas BAR-deficient (Nr1h4−/−) mice exhibit exacerbated pathology (Gadaleta et al., 2011; Vavassori et al., 2009).”
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    Premisecitation

    Taurine counteracts the effects of spermine and histamine, indicating a finely tuned balance of opposing bacterial stimuli.

    “taurine, another microbial metabolite that derives from host-produced bile acids (see below), counteracts the effects of spermine and histamine, indicating a finely tuned balance of opposing bacterial stimuli (Levy et al., 2015).”
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    Premisenone given

    Primary bile acids such as cholic acid and chenodeoxycholic acid are synthesized in the liver from cholesterol and conjugated to glycine or taurine before secretion.

    “Primary bile acids, such as cholic acid and chenodeoxycholic acid, are synthesized in the liver from cholesterol and conjugated to glycine or taurine prior to secretion.”
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    Premisecitation

    Polyamines are present in every living cell and have important roles in gene expression and proliferation; their endogenous production in eukaryotic cells is strictly regulated.

    “Polyamines are present in every living cell and fulfill important roles in gene expression and proliferation; therefore their endogenous production in eukaryotic cells is strictly regulated (Miller-Fleming et al., 2015).”
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    Premisecitation

    About half of the remaining bile acids are taken up in the colon by passive absorption, and the rest is excreted in feces.

    “About half of the remaining bile acids are taken up in the colon by passive absorption, the rest is excreted with the feces (Martinez-Augustin and Sanchez de Medina, 2008).”
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    Premisecitation

    Mice deficient for ENTPD7 have higher luminal ATP and an increase in TH17 cells in the small-intestinal lamina propria.

    “mice deficient for the epithelial ATP-degrading enzyme ectonucleoside triphosphate diphosphohydrolase 7 (ENTPD7) exhibit higher levels of luminal ATP and an increase in TH17 cells in the lamina propria of the small-intestinal epithelium (Kusu et al., 2013).”
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    Premisecitation

    This inhibition has been linked to direct inhibition of NF-κB activation but is also consistent with transcriptional competition between NF-κB and CREB.

    “This has been linked to direct inhibition of NF-κB activation, but is also consistent with a model of transcriptional competition between NF-κB and the cAMP-activated transcription factor cAMP response element binding protein (CREB) (C. Guo et al., 2015; Kawamata et al., 2003; Keitel et al., 2008; Pols et al., 2011; Y.-D. Wang et al., 2011; Wen et al., 2010).”
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    Within the host, ATP is released passively from necrotic cells and actively from stressed or stimulated cells, such as during an inflammatory response.

    “Within the host, ATP is released passively from necrotic cells and actively from stressed or stimulated cells, e.g. during an inflammatory response.”
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    • cites Faas et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ENTPD1/CD39 converts ATP to AMP, which is then quickly metabolized to anti-inflammatory adenosine by 5'-nucleotidase/CD73.

    “ENTPD1 converts ATP to AMP, which is then quickly metabolized to the anti-inflammatory adenosine by 5’-nucleotidase (also known as CD73) (Allard et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Allard et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes in bile acid pool composition, increased colonic GPBAR1 expression, and decreased ileal BAR activity have been detected in IBD patients.

    “changes in the composition of the bile acid pool, an increase in colonic expression of GPBAR1 and a decrease in ileal activity of BAR have all been detected in patients suffering from IBD (Cipriani et al., 2011; Duboc et al., 2013; Lenz et al., 1976; Nijmeijer et al., 2011; Rutgeerts et al., 1979).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cipriani et al., 2011 source

      Not checked in the free run.

    • cites Duboc et al., 2013 source

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    • cites Lenz et al., 1976 source

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  • May combine two claims.

    Premisecitation

    Bile-acid recycling efficiency depends on microbial biotransformation, while de novo bile-acid synthesis is subject to strict feedback that may limit the effect of increased bile-acid excretion when the microbiota is not fully functional.

    “The efficiency of bile-acid recycling depends on their biotransformation by the microbiome; however, the de novo synthesis of bile acids is subject to a strict feedback mechanism, which may limit the effect of increased excretion of bile acids in the absence of a fully functional microbiota (Martinot et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Martinot et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some but not all intestinal bacteria actively secrete ATP, and germ-free mice have lower gut ATP concentrations than controls.

    “some, but not all, intestinal bacteria actively secrete ATP, and germ-free mice have lower ATP concentrations in their gut than controls (Atarashi et al., 2008; Hironaka et al., 2013; Iwase et al., 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Atarashi et al., 2008 source

      Not checked in the free run.

    • cites Hironaka et al., 2013 source

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    • cites Iwase et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist.

    “P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist (Marques et al., 2014; Neves et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Marques et al., 2014 source

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    • cites Neves et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-10 production is primarily mediated by dendritic cells, which internalize PSA and present fragments to CD4+ T cells with MHC-II, stimulating activation and clonal expansion.

    “The production of IL-10 is primarily mediated by DCs, which internalize PSA and present fragments to CD4+ T cells in conjunction with the major histocompatibility complex class II (MHC-II), thus stimulating activation and clonal expansion of T cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cobb et al., 2004 source

      Not checked in the free run.

    • cites Dasgupta et al., 2014 source

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    • cites Mazmanian et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    P2rx7−/− mice have elevated Tfh cell numbers in the intestinal mucosa, presumably because they are resistant to ATP-induced cell death.

    “Mice deficient for P2X7 (P2rx7−/−) have elevated Tfh cell numbers in the intestinal mucosa, presumably because they are resistant to ATP-induced cell death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Proietti et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Germ-free mice show a severe reduction of TH17 lymphocytes in the colonic lamina propria, which can be rescued by direct ATP administration.

    “Germ-free mice show a severe reduction of TH17 lymphocytes in the lamina propria of the colonic epithelium, which can be rescued by the direct administration of ATP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Atarashi et al., 2008 source

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  • May combine two claims.

    Premisecitation

    Extracellular ATP is the sole agonist for P2X family receptors, which are ligand-activated ion channels expressed by various tissues including innate and adaptive immune cells.

    “extracellular ATP is the sole agonist for receptors of the P2X family, which are ligand-activated ion channels expressed by a variety of tissues including innate and adaptive immune cells (Faas et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Faas et al., 2017

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  • May combine two claims.

    Premisecitation

    Segmented filamentous bacteria induce TH17 cells in the murine small intestine but do not produce high levels of ATP.

    “segmented filamentous bacteria (SFB), which have been shown to induce TH17 cells in the lamina propria of the murine small intestine, do not produce high levels of ATP (Ivanov et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ivanov et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ability of other TH17-inducing gut bacteria to produce ATP has not been determined, but a common property appears to be their ability to adhere to the intestinal epithelium.

    “The capability of other TH17-inducing gut bacteria to produce ATP has not been determined yet, but a common property appears to be their ability to adhere to the intestinal epithelium (Atarashi et al., 2015; Tan et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Atarashi et al., 2015 source

      Not checked in the free run.

    • cites Tan et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSA induces IL-10 secretion by CD4+ T cells and promotes differentiation of naive CD4+ T cells into TH1 over TH2 cells.

    “PSA induces secretion of the potent anti-inflammatory cytokine IL-10 by CD4+ T cells and promotes the differentiation of naive CD4+ T cells into TH1 cells over TH2 cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cobb et al., 2004 source

      Not checked in the free run.

    • cites Dasgupta et al., 2014 source

      Not checked in the free run.

    • cites Mazmanian et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Intestinal ATP has been implicated in the development of IBD, likely because of the generally pro-inflammatory properties of ATP.

    “intestinal ATP has also been implicated in the development of IBD, likely due to the generally pro-inflammatory properties of ATP.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Extracellular ATP primarily has pro-inflammatory properties.

  • May combine two claims.

    Premisecitation

    This binding elicits activation of the NLRP3 inflammasome in LPS-stimulated macrophages, causing secretion of IL-18 and IL-1β, and may promote maintenance and function of the epithelial barrier.

    “this has been shown to elicit activation of the NLRP3 inflammasome in LPS-stimulated macrophages, which causes secretion of IL-18 (but also of the pro-inflammatory cytokine IL-1β) and may thus promote maintenance and function of the epithelial barrier (Mariathasan et al., 2006; Sutterwala et al., 2014; 2006; Yaron et al., 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mariathasan et al., 2006 source

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    • cites Sutterwala et al., 2014 source

      Not checked in the free run.

    • cites Yaron et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATP serves as an endogenous danger-associated molecular pattern that can drive chemotaxis and cytokine release by immune cells, while low ATP concentrations tend to have the opposite effect.

    “As such, it serves as an endogenous danger-associated molecular pattern (DAMP) that can drive chemotaxis of and cytokine release by immune cells (interestingly, low concentrations of ATP tend to have the opposite effect) (Faas et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Faas et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, polymorphisms of ENTPD1 are associated with IBD, and P2X7 expression is increased in the intestinal epithelium and lamina propria of IBD patients.

    “In humans, polymorphisms of ENTPD1 were shown to be associated with IBD, and expression of P2X7 was increased in the intestinal epithelium and lamina propria of IBD patients (Friedman et al., 2009; Neves et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Friedman et al., 2009 source

      Not checked in the free run.

    • cites Neves et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This results in an increase in high-affinity IgA specific for intestinal bacteria secreted into the lumen and a depletion of the gut microbiota.

    “This results in an increase in high-affinity IgA specific for intestinal bacteria secreted into the intestinal lumen and thereby a depletion of the gut microbiota.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Proietti et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Geva-Zatorsky et al. monocolonized germ-free mice separately with 53 different bacterial species resident in the human intestine and found that each had some immunomodulatory effect on the host.

    “Geva-Zatorsky et al. monocolonized germ-free mice separately with 53 different bacterial species resident in the human intestine (less than five percent of the estimated total!) and found that each one of them had some sort of immunomodulatory effect on the host (Geva-Zatorsky et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Geva-Zatorsky et al., 2017 source

      Not checked in the free run.

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

    Premisereasoning

    Virtually all functional studies of the microbiome have been limited to single bacterial species or metabolites.

    “Virtually all functional studies of the microbiome have been limited to single bacterial species or metabolites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PSA-induced IL-10 inhibits mucosal effector T cells, particularly TH17 cells, and protects mice in experimental colitis models.

    “The PSA-induced production of IL-10 inhibits the activity of mucosal effector T cells, in particular of TH17 cells, and thereby protects mice in experimental models of colitis (Dasgupta et al., 2014; Mazmanian et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dasgupta et al., 2014 source

      Not checked in the free run.

    • cites Mazmanian et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fetal enterocytes exposed to PSA produce lower levels of IL-1β-induced IL-8, which may play a role in the development of necrotizing enterocolitis in prematurely born infants.

    “Jiang et al. recently reported that fetal enterocytes exposed to PSA produce lower levels of the IL-1β-induced, pro-inflammatory cytokine IL-8, which may play a role in the development of necrotizing enterocolitis in prematurely born infants (Jiang et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jiang et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSA activates TLR2 on dendritic cells, triggering release of cytokines that promote IL-10 production by T cells.

    “Importantly, PSA also activates toll-like receptor (TLR) 2 expressed on the surface of DCs, which triggers the release of cytokines that promote IL-10 production by T cells (Cobb et al., 2004; Dasgupta et al., 2014; Johnson et al., 2015; Mazmanian et al., 2005; 2008; Telesford et al., 2015; Q. Wang et al., 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cobb et al., 2004 source

      Not checked in the free run.

    • cites Dasgupta et al., 2014 source

      Not checked in the free run.

    • cites Johnson et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSA exposure increases ENTPD1 expression on FoxP3+ Tregs, suggesting a potential intersection between PSA and extracellular ATP in immune regulation.

    “PSA exposure increases expression of ENTPD1 on FoxP3+ Tregs, thus suggesting a potential intersection between PSA and (microbially derived) extracellular ATP in the regulation of the immune system (Telesford et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Telesford et al., 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Most known bacterially derived metabolites in the intestinal tract remain functionally uncharacterized, and it is unclear how many unidentified metabolites exist.

    “most of the known bacterially derived metabolites in the intestinal tract remain functionally uncharacterized, and it is unclear how many other, hitherto unidentified metabolites are yet to be discovered.”
    Quote in the paperSubstantial claim
67 of 67

  • The paper relies on this without support.

    Extracellular ATP primarily has pro-inflammatory properties.

    “Unlike the other microbiota-derived compounds discussed so far, extracellular ATP primarily exhibits pro-inflammatory properties.”

  • The paper relies on this without support.

    IL-22 supports intestinal mucosa integrity by inducing antimicrobial peptide secretion from epithelial cells, mucin production, and intestinal goblet cell proliferation.

    “Protection against these pathologies is mediated by expression of IL-22, a cytokine that supports the integrity of the intestinal mucosa by inducing the secretion of antimicrobial peptides from epithelial cells, production of mucins and proliferation of intestinal goblet cells.”

  • The paper relies on this without support.

    Protection against the immunological pathologies of AhR deficiency is mediated by IL-22 expression.

    “Protection against these pathologies is mediated by expression of IL-22”

  • The paper relies on this without support.

    T follicular helper cells in Peyer's patches foster development of B cells that produce immunoglobulins specific for intestinal bacteria, which can be secreted across the epithelium as IgA.

    “T follicular helper (Tfh) cells in the Peyer’s patches foster the development of B cells that produce immunoglobulins with specificity for intestinal bacteria, which can be secreted across the epithelium as IgA.”

  • The paper relies on this without support.

    The human intestinal tract is believed to contain up to 1,150 bacterial species, with at least 160 present in any given individual.

    “Considering that up to 1,150 different bacterial species are believed to reside in the human intestinal tract, and at least 160 of them are present in any given individual”
5 of 5

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?

  • Bile acids regulate metabolism and anti-inflammatory signals.

    “Considering that bile acids regulate metabolism and anti-inflammatory signals 40 and that they are depleted in Lmna G609G/G609G mice 28 , the restoration of secondary bile acidsand other metabolites (arabinose, ribose, inosine)by FMT might contribute to extend healthspan and lifespan in progeroid mice (Fig. 4g).”

    From Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice (2019) · cites this paper as [40]

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Authors
Postler, T. S., & Ghosh, S.
Affiliations
  • Columbia University (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Ghosh, Sankar
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2017-07
Volume
26
Issue
1
Pages
110-130
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2017.05.008
PMC
PMC5535818
OpenAlex
W2625068954
Semantic Scholar
75cf85d5fe820ba74946018ee4d760637d128aae
Cited by
876
References
252
Citations by year
2026: 89 · 2025: 91 · 2024: 120 · 2023: 113 · 2022: 97 · 2021: 102 · 2020: 106 · 2019: 92 · 2018: 52 · 2017: 14
FWCI
6.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102180)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
gut microbiota, microbial metabolites, host-microbe interactions, gut-immune axis, immune system development, metabolic disorders, inflammatory bowel disease, cancer, mood and behavior, dietary metabolites
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Humans, Immune System, Inflammation, Metabolic Diseases, Inflammatory Bowel Diseases, 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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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