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

In the paper

“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).”

What the sources say

• Partly supported

  The Discussion (page unavailable) identifies epithelial adhesion as a shared characteristic of the Th17-inducing microbes studied, including SFB and 20 human-derived strains. Our copy does not state that the ATP-producing ability of other Th17-inducing gut bacteria remains undetermined; a search for ATP found only a cited reference about ATP and Th17 differentiation. (LLM, conf=0.85)

  cites Atarashi et al., 2015 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) report that B. adolescentis, like SFB, closely associated with the ileal epithelium and suggest that tight epithelial association may be a conserved feature of Th17-inducing microbes. Our copy does not address whether other Th17-inducing bacteria produce ATP, so it does not establish the claim about their ATP-production status. (LLM, conf=0.85)

  cites Tan et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Turnbaugh et al., 2008; 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Vrieze et al., 2012 source

In the paper

“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.”

What the sources say

• Not checked yetcites Human Microbiome Project Consortium, 2012
• Not checked yetcites Kurokawa et al., 2007 source
• Not checked yetcites Qin et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Everard et al., 2013 source

In the paper

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

What the sources say

• Not checked yetcites Cani et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites Turnbaugh et al., 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Cox and Blaser, 2013
• Not checked yetcites Shapiro et al., 2017 source

In the paper

“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.”

What the sources say

• Not checked yetcites Sonnenburg and Bäckhed, 2016 source

In the paper

“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”

What the sources say

• Not checked yetcites De Filippo et al., 2010 source
• Not checked yetcites Wu et al., 2011

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Karlsson et al., 2013 source
• Not checked yetcites Qin et al., 2012 source

In the paper

“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)).”

What the sources say

• Not checked yetcites Donath et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Fändriks, 2016
• Not checked yetcites Jonsson and Bäckhed, 2017
• Not checked yetcites Khan et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Kiss et al., 2011 source
• Not checked yetcites Lee et al., 2011 source
• Not checked yetcites Y. Li et al., 2011

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Arpaia et al., 2013 source
• Not checked yetcites Smith et al., 2013 source

In the paper

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

What the sources say

• Not checked yetcites Stockinger et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Venkatesh et al., 2014 source
• Not checked yetcites Wikoff et al., 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Atarashi et al., 2013 source
• Not checked yetcites Fu et al., 2004

In the paper

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

What the sources say

• Not checked yetcites Arpaia et al., 2013 source

In the paper

“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)”

What the sources say

• Not checked yetcites Kiss et al., 2011 source
• Not checked yetcites Lee et al., 2011 source
• Not checked yetcites Y. Li et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Zelante et al., 2013 source

In the paper

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

What the sources say

• Not checked yetcites Singh et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Levy et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Mardinoglu et al., 2015 source
• Not checked yetcites Matsumoto et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Ridlon et al., 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Z. Qiu et al., 2016 source
• Not checked yetcites Venkatesh et al., 2014 source

In the paper

“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.”

What the sources say

• Not checked yetcites Martinez-Augustin and Sanchez de Medina, 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Thomas et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites O'Neill et al., 2016

In the paper

“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).”

What the sources say

• Not checked yetcites M. Zhang et al., 1999 source
• Not checked yetcites M. Zhang et al., 1997 source

In the paper

“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).”

What the sources say

• Not checked yetcites Kawamata et al., 2003 source
• Not checked yetcites Maruyama et al., 2002 source

In the paper

“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).”

What the sources say

• Not checked yetcites Martinez-Augustin and Sanchez de Medina, 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Gadaleta et al., 2011 source
• Not checked yetcites Vavassori et al., 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Levy et al., 2015 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Miller-Fleming et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Martinez-Augustin and Sanchez de Medina, 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Kusu et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites C. Guo et al., 2015 source
• Not checked yetcites Kawamata et al., 2003 source
• Not checked yetcites Keitel et al., 2008 source

In the paper

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

What the sources say

• Not checked yetcites Faas et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Allard et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Cipriani et al., 2011 source
• Not checked yetcites Duboc et al., 2013 source
• Not checked yetcites Lenz et al., 1976 source

In the paper

“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).”

What the sources say

• Not checked yetcites Martinot et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Atarashi et al., 2008 source
• Not checked yetcites Hironaka et al., 2013 source
• Not checked yetcites Iwase et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Marques et al., 2014 source
• Not checked yetcites Neves et al., 2014 source

In the paper

“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.”

What the sources say

• Not checked yetcites Cobb et al., 2004 source
• Not checked yetcites Dasgupta et al., 2014 source
• Not checked yetcites Mazmanian et al., 2005 source

In the paper

“Mice deficient for P2X7 (P2rx7−/−) have elevated Tfh cell numbers in the intestinal mucosa, presumably because they are resistant to ATP-induced cell death.”

What the sources say

• Not checked yetcites Proietti et al., 2014 source

In the paper

“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.”

What the sources say

• Not checked yetcites Atarashi et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites Faas et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Ivanov et al., 2009 source

In the paper

“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.”

What the sources say

• Not checked yetcites Cobb et al., 2004 source
• Not checked yetcites Dasgupta et al., 2014 source
• Not checked yetcites Mazmanian et al., 2005 source

In the paper

“intestinal ATP has also been implicated in the development of IBD, likely due to the generally pro-inflammatory properties of ATP.”

In the paper

“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).”

What the sources say

• Not checked yetcites Mariathasan et al., 2006 source
• Not checked yetcites Sutterwala et al., 2014 source
• Not checked yetcites Yaron et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Faas et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Friedman et al., 2009 source
• Not checked yetcites Neves et al., 2014 source

In the paper

“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.”

What the sources say

• Not checked yetcites Proietti et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Geva-Zatorsky et al., 2017 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Dasgupta et al., 2014 source
• Not checked yetcites Mazmanian et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites Jiang et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Cobb et al., 2004 source
• Not checked yetcites Dasgupta et al., 2014 source
• Not checked yetcites Johnson et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Telesford et al., 2015 source

In the paper

“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.”