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

“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., 2006, 2008).”

“Conversely, a plant-based diet promotes the enrichment of microbial species that efficiently ferment fiber (Bacteroidetes) (De Filippo et al., 2010; Wu et al., 2011).”

“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).”

“Members of the phylum Proteobacteria are also represented frequently but far less prominently (Eckburg et al., 2005; Hold et al., 2002; Human Microbiome Project Consortium, 2012).”

“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).”

“Interestingly, mice chronically exposed to low levels of LPS for 4 weeks gained weight and became resistant to insulin (Cani et al., 2007).”

“Cipriani et al., 2011; Guo et al., 2015; Kawamata et al., 2003; Mencarelli et al., 2009; Sayin et al., 2013; Vavassori et al., 2009; Wang et al., 2011a ty bile l Enhances epithelial barrier function and maintenance by promoting epithelial production of IL-18 Levy et al., 2015 (Continued on next…”

“Conversely, a plant-based diet promotes the enrichment of microbial species that efficiently ferment fiber (Bacteroidetes) (De Filippo et al., 2010; Wu et al., 2011).”

“…concentration of 150 mM with drinking water, while Arpaia et al. detected no significant changes at a concentration of 36 mM, likely because this lower quantity of butyrate was largely absorbed by the upper gastrointestinal tract before reaching the colon (Arpaia et al., 2013; Smith et al., 2013).”

“This effect is mediated through several different mechanisms: acetate and propionate, but not butyrate, stimulate the expansion of pre-existing colonic Tregs (cTregs), whereas propionate and butyrate, but not acetate, increase the de novo differentiation of naive T cells into Tregs (Arpaia et al., 2013; Furusawa et al…”

“4 Cell Metabolism 26, July 5, 2017 of SCFA-producing microbial species in the gut, and dietary changes that promote production of SCFAs by the microbiome can ameliorate symptoms (Frank et al., 2007; Kanauchi et al., 2002; Machiels et al., 2014; Sokol et al., 2009).”

“Interestingly, 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).”

“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).”

“Propionate and acetate travel largely intact across the epithelium to the liver, where a substantial portion of propionate is degraded while acetate is released into systemic circulation (Bloemen et al., 2009; Morrison and Preston, 2016).”

“A technique that dates back to the 4th century CE, FMTs have most recently been used as experimental treatments for recurrent infection with Clostridium difficile, with promising results (Rao and Safdar, 2016; van Nood et al., 2013; Zhang et al., 2012).”

“…gut microbiota appears to influence nearly every aspect of host physiology, including energy balance, cardiovascular health, chronic inflammation, development of adaptive immune cells, andmany more systems that fall outside of the scope of this review (Rooks and Garrett, 2016; Sharon et al., 2014).”

“These observations were further corroborated and extended by subsequent studies from the same group and others (Li et al., 2017; Mente et al., 2015; Tang et al., 2013, 2014, 2015; Trøseid et al., 2015; Wang et al., 2014b).”

“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).”

“Acetate (C2), propionate (C3), and butyrate (C4) are by far the most abundant of the intestinal SCFAs (Cummings et al., 1987; Morrison and Preston, 2016).”

“Atarashi et al., 2008; Kusu et al., 2013; Mariathasan et al., 2006; Nuttle and Dubyak, 1994; Perruzza et al., 2017; Sutterwala et al., 2006 Polysaccharide A (PSA) Activation of TLR2 on DCs and Tregs.”

“…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; Wang et al., 2006).”

“This effect is mediated through several different mechanisms: acetate and propionate, but not butyrate, stimulate the expansion of pre-existing colonic Tregs (cTregs), whereas propionate and butyrate, but not acetate, increase the de novo differentiation of naive T cells into Tregs (Arpaia et al., 2013; Furusawa et al…”

“This involves multiple steps and typically begins with the initial deconjugation of glycine or taurine, followed by dehydrox- 10 Cell Metabolism 26, July 5, 2017 ylation (Ridlon et al., 2006).”

“Both receptors can be activated by primary and secondary bile acids alike (Kawamata et al., 2003; Makishima et al., 1999; Maruyama et al., 2002; Parks et al., 1999; Wang et al., 1999).”

“This destabilizes the entire plaque, facilitating rupture and subsequent formation of an embolus that may result in myocardial infarction, stroke, or other forms of cardiovascular disease (Brophy et al., 2017; Frostegård, 2013; Moore et al., 2013).”

“Outside of the cell, they function as agonists for several G-protein-coupled receptors (GPCRs), namely the free fatty acid receptors 2 (FFAR2, also known as GPR43) and 3 (FFAR3 or GPR41) (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003).”

“…of NLRP6 inflammasome activation Derived from hos produced primar salts by intestina microbiota interestingly, expresses OR51E2) (Brown et al., 2003; Fleischer et al., 2015; Le Poul et al., 2003; Nilsson et al., 2003; Shi et al., 2017; Tolhurst et al., 2012; Tunaru et al., 2003; Wise et al., 2003).”

“…levels of short-chain fatty acids (SCFAs, discussed in detail below), which have been shown in vitro and in vivo to support the integrity of the intestinal mucosa in a variety of ways (Fukuda et al., 2011; Gaudier et al., 2004; Macia et al., 2015; Willemsen et al., 2003; Wrzosek et al., 2013).”

“A tentative connection between expression of HCAR2 on microglia and Parkinson’s disease Cellulose Tryptophan Arginine Acetate SCFAs Propionate Butyrate Indoles R Polyamines H2N NH H N NH2 H2N H N NH2 NH H2N 2 Putrescine Spermidine Spermine Intestinal microbiota ECGC DC Treg NΦ B cell MΦ ILC3 IL-18 Repair Integrity Muc…”

“…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; Wang et al., 2006).”

“While a comprehensive species inventory of SCFA producers remains elusive, studies investigating individual species have uncovered interesting microbial cross-feeding dynamics (recently reviewed by Flint et al., 2015, and Rı́os-Covián et al., 2016).”

“Recently, Plovier et al. reported that much of this effect could be replicated by administration of a membrane protein purified from A. muciniphila, suggesting the appealing possibility of a novel therapeutic application (Plovier et al., 2017).”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“Beyond a direct effect on atherosclerosis, TMAO has also been reported to increase platelet responsiveness by enhancing intracellular Ca2+ release, thus increasing the likelihood of thrombotic events and thereby cardiovascular disease (Zhu et al., 2016).”

“…is associated with a decrease 4 Cell Metabolism 26, July 5, 2017 of SCFA-producing microbial species in the gut, and dietary changes that promote production of SCFAs by the microbiome can ameliorate symptoms (Frank et al., 2007; Kanauchi et al., 2002; Machiels et al., 2014; Sokol et al., 2009).”

“Members of the Bacteroidetes provide most of the acetate and propionate, whereas Firmicutes, which tend to utilize polysaccharides less efficiently, are believed to be the primary producers of butyrate (Flint et al., 2015; El Kaoutari et al., 2013; Levy et al., 2016; Louis et al., 2010).”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“Both receptors can be activated by primary and secondary bile acids alike (Kawamata et al., 2003; Makishima et al., 1999; Maruyama et al., 2002; Parks et al., 1999; Wang et al., 1999).”

“…Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE) (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012; Rothhammer et al., 2016; Shi et al., 2007; Veldhoen et al., 2008; Zelante et al., 2013).”

“…species, explaining the rapid changes in the composition of the microbiome upon dietary modifications described a century ago and studied in great detail more recently (Cannon, 1921; Cotillard et al., 2013; David et al., 2014; Herter and Kendall, 1910; Koeth et al., 2013; Walker et al., 2011).”

“Receptor-specific regulation of ERK1/2 activation by members of the ‘‘free fatty acid receptor’’ family.”

“…Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE) (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012; Rothhammer et al., 2016; Shi et al., 2007; Veldhoen et al., 2008; Zelante et al., 2013).”

“Host genetic variation has been shown to be associated with variation in the microbiome composition, but genome-wide approaches to identify individual genes and their role in shaping the microbiome are only beginning to emerge (Blekhman et al., 2015; Spor et al., 2011).”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“…reports on whether or not butyrate directly inhibits activation of the transcription factor NF-kB (nuclear factor kappa-light-chain enhancer of activated B cells), likely due to varying experimental methodologies and cell types (Chang et al., 2014; L€uhrs et al., 2002; Segain et al., 2000).”

“Similarly, lactate, which is produced by many members of the human gut microbiome, has been shown to serve as substrate for bacterial production of propionate (e.g., Coprococcus catus) and butyrate (e.g., Eubacterium hallii andAnaerostipes caccae) (Duncan et al., 2004b; Reichardt et al., 2014).”

“The regulation of T cell biology may be even more complex, however, as SCFAs have also been reported to promote generation of both effector and regulatory T cells, depending on the immunological context (Park et al., 2015).”

“This results in a significant decrease in the expression of pro-inflammatory cytokines (Pascual et al., 2005; Vavassori et al., 2009).”

“…is associated with a decrease 4 Cell Metabolism 26, July 5, 2017 of SCFA-producing microbial species in the gut, and dietary changes that promote production of SCFAs by the microbiome can ameliorate symptoms (Frank et al., 2007; Kanauchi et al., 2002; Machiels et al., 2014; Sokol et al., 2009).”

“A fourth SCFA-responsive GPCR, the olfactory receptor 51E2 (OR51E2, also known as Olfr78 in mice), is expressed by some cells of the intestinal epithelium but has not been connected to the immune system (Fleischer et al., 2015; Pluznick et al., 2013).”

“Similarly, lactate, which is produced by many members of the human gut microbiome, has been shown to serve as substrate for bacterial production of propionate (e.g., Coprococcus catus) and butyrate (e.g., Eubacterium hallii andAnaerostipes caccae) (Duncan et al., 2004b; Reichardt et al., 2014).”

“For instance, intraperitoneal injection of ATP exacerbated experimental colitis in mice (Atarashi et al., 2008).”

“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).”

“…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 (Qiu et al., 2016; Venkatesh et al., 2014).”

“Similarly, Chang et al. demonstrated that butyrate limits the secretion of pro-inflammatory cytokines from LPS-stimulated macrophages in the colonic lamina propria.”

“This destabilizes the entire plaque, facilitating rupture and subsequent formation of an embolus that may result in myocardial infarction, stroke, or other forms of cardiovascular disease (Brophy et al., 2017; Frostegård, 2013; Moore et al., 2013).”

“A direct relevance of this interaction for the immune system has not been described yet, but exposure to bacterial strains present in the healthy gut microbiome has been shown to affect PPAR-g activity (Are et al., 2008; Kelly et al., 2004).”

“Receptor-specific regulation of ERK1/2 activation by members of the ‘‘free fatty acid receptor’’ family.”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“This mechanism is quite different from the previously reported general hypo-responsiveness of intestinal macrophages that was based on starkly reduced expression of several innate response receptors (Smythies et al., 2005).”

“This includes cells of the immune system: bile acids reduce the expression of pro-inflammatory cytokines from monocytes, macrophages, DCs, and the hepatic macrophages known as Kupffer cells (Brestoff and Artis, 2013; Martinot et al., 2017).”

“ENTPD1 converts ATP to AMP, which is then quickly metabolized to the anti-inflammatory adenosine by 50-nucleotidase (also known as CD73) (Allard et al., 2017).”

“Interestingly, a recent study found that TMAO induced the transcription of several genes encoding pro-inflammatory, atherosclerosis-promoting proteins in endothelial and smooth-muscle cells (but not peritoneal macrophages) through an unknown mechanism (Seldin et al., 2016).”

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

“…but is also consistent with a model of transcriptional competition between NF-kB and the cAMP-activated transcription factor cAMP response element binding protein (CREB) (Guo et al., 2015; Kawamata et al., 2003; Keitel et al., 2008; Pols et al., 2011; Wang et al., 2011a; Wen et al., 2010).”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“…Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE) (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012; Rothhammer et al., 2016; Shi et al., 2007; Veldhoen et al., 2008; Zelante et al., 2013).”

“Correspondingly, 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).”

“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).”

“A few years later, four groups independently discovered that 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; Li et al., 2011; Qiu et al., 2012).”

“Dietary tryptophan, for instance, is processed to several different indole derivatives, which can act as ligands for the aryl hydrocarbon receptor (AhR) in host cells (Wikoff et al., 2009).”

“Members of the Bacteroidetes provide most of the acetate and propionate, whereas Firmicutes, which tend to utilize polysaccharides less efficiently, are believed to be the primary producers of butyrate (Flint et al., 2015; El Kaoutari et al., 2013; Levy et al., 2016; Louis et al., 2010).”

“…as the fungus Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE) (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012; Rothhammer et al., 2016; Shi et al., 2007; Veldhoen et al., 2008; Zelante et…”

“…of NLRP6 inflammasome activation Derived from hos produced primar salts by intestina microbiota interestingly, expresses OR51E2) (Brown et al., 2003; Fleischer et al., 2015; Le Poul et al., 2003; Nilsson et al., 2003; Shi et al., 2017; Tolhurst et al., 2012; Tunaru et al., 2003; Wise et al., 2003).”

“Interestingly, the same strains did not produce TMA from L-carnitine under the same experimental conditions (Romano et al., 2015).”

“monocolonized germ-free mice separately with 53 different bacterial species resident in the human intestine (less than 5% 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).”

“Well over a century ago, studies demonstrated that dietary changes can alter the type of metabolites produced by bacteria living in the healthy intestine (Hirschler, 1886), and that the composition of the intestinal microbiome itself depends on the composition of the consumed diet (Cannon, 1921; Herter and Kendall, 19…”

“Host genetic variation has been shown to be associated with variation in the microbiome composition, but genome-wide approaches to identify individual genes and their role in shaping the microbiome are only beginning to emerge (Blekhman et al., 2015; Spor et al., 2011).”

“…of the NLRP3 inflammasome in LPS-stimulated macrophages, which causes secretion of IL-18 (but also of the pro-inflammatory cytokine IL-1b) and may thus promote maintenance and function of the epithelial barrier (Mariathasan et al., 2006; Sutterwala et al., 2006, 2014; Yaron et al., 2015).”

“Indeed, the composition of bile acids varies dramatically between germ-free and control animals in feces, liver, heart, kidney, and plasma (Duboc et al., 2013; Sayin et al., 2013; Swann et al., 2011).”

“These observations were further corroborated and extended by subsequent studies from the same group and others (Li et al., 2017; Mente et al., 2015; Tang et al., 2013, 2014, 2015; Trøseid et al., 2015; Wang et al., 2014b).”

“Second, microbiota-derived LPS has been suggested to traverse the mucosal barrier of the intestine on chylomicrons, lipoprotein complexes that transport long-chain fatty acids from the gut lumen to the lymph and blood (Ghoshal et al., 2009; Khan et al., 2014; Sonnenburg and B€ackhed, 2016).”

“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).”

“Dietary tryptophan, for instance, is processed to several different indole derivatives, which can act as ligands for the aryl hydrocarbon receptor (AhR) in host cells (Wikoff et al., 2009).”

“This has been linked to direct inhibition of NF-kB activation but is also consistent with a model of transcriptional competition between NF-kB and the cAMP-activated transcription factor cAMP response element binding protein (CREB) (Guo et al., 2015; Kawamata et al., 2003; Keitel et al., 2008; Pols et al., 2011; Wang…”

“A technique that dates back to the 4 century CE, FMTs have most recently been used as experimental treatments for recurrent infection with Clostridium difficile, with promising results (Rao and Safdar, 2016; van Nood et al., 2013; Zhang et al., 2012).”

“…gut microbiota appears to influence nearly every aspect of host physiology, including energy balance, cardiovascular health, chronic inflammation, development of adaptive immune cells, andmany more systems that fall outside of the scope of this review (Rooks and Garrett, 2016; Sharon et al., 2014).”

“Outside of the cell, they function as agonists for several G-protein-coupled receptors (GPCRs), namely the free fatty acid receptors 2 (FFAR2, also known as GPR43) and 3 (FFAR3 or GPR41) (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003).”

“Cipriani et al., 2011; Guo et al., 2015; Kawamata et al., 2003; Mencarelli et al., 2009; Sayin et al., 2013; Vavassori et al., 2009; Wang et al., 2011a ty bile l Enhances epithelial barrier function and maintenance by promoting epithelial production of IL-18 Levy et al., 2015 (Continued on next…”

“Nr1h4 / mice also develop spontaneous hepatic inflammation and liver tumors (Kim et al., 2007; Yang et al., 2007).”

“These observations were further corroborated and extended by subsequent studies from the same group and others (Li et al., 2017; Mente et al., 2015; Tang et al., 2013, 2014, 2015; Trøseid et al., 2015; Wang et al., 2014b).”

“Members of the Bacteroidetes provide most of the acetate and propionate, whereas Firmicutes, which tend to utilize polysaccharides less efficiently, are believed to be the primary producers of butyrate (Flint et al., 2015; El Kaoutari et al., 2013; Levy et al., 2016; Louis et al., 2010).”

“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).”

“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).”

“Members of the phylum Proteobacteria are also represented frequently but far less prominently (Eckburg et al., 2005; Hold et al., 2002; Human Microbiome Project Consortium, 2012).”

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

“Propionate and acetate travel largely intact across the epithelium to the liver, where a substantial portion of propionate is degraded while acetate is released into systemic circulation (Bloemen et al., 2009; Morrison and Preston, 2016).”

“Instead, presentation of SFB-derived antigens by intestinal APCs was shown to be sufficient for TH17 cell development (Goto et al., 2014; Panea et al., 2015).”

“…levels of short-chain fatty acids (SCFAs, discussed in detail below), which have been shown in vitro and in vivo to support the integrity of the intestinal mucosa in a variety of ways (Fukuda et al., 2011; Gaudier et al., 2004; Macia et al., 2015; Willemsen et al., 2003; Wrzosek et al., 2013).”

“Chemical structure of PSA subunit based on (Mazmanian and Kasper, 2006).”

“Nr1h4 / mice also develop spontaneous hepatic inflammation and liver tumors (Kim et al., 2007; Yang et al., 2007).”

“4 Cell Metabolism 26, July 5, 2017 of SCFA-producing microbial species in the gut, and dietary changes that promote production of SCFAs by the microbiome can ameliorate symptoms (Frank et al., 2007; Kanauchi et al., 2002; Machiels et al., 2014; Sokol et al., 2009).”

“…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; Wang et al., 2006).”

“Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”

“Of those 48 metabolites, 35 had altered concentrations in the colon of germ-free mice compared to controls, as did 88 metabolites that were also present in the food (Matsumoto et al., 2012).”

“These observations were further corroborated and extended by subsequent studies from the same group and others (Li et al., 2017; Mente et al., 2015; Tang et al., 2013, 2014, 2015; Trøseid et al., 2015; Wang et al., 2014b).”

“Indeed, spermine administration exhibits protective anti-inflammatory effects in mouse models of both localized and systemic inflammation (ter Steege et al., 1999; Zhang et al., 1997; Zhu et al., 2009).”

“Finally, intracellular butyrate can act as an agonist for the peroxisome proliferator-activated receptor gamma (PPAR-g) (Alex et al., 2013).”

“Microbially derived metabolites signal not only to the host but also to other gut bacteria, and multiple interacting communities may influence the host in an additive, synergistic, redundant, or even subtractive fashion (Adair and Douglas, 2016).”

“Consequently, Ffar2 / mice are significantly more susceptible to colitis induced by dextrane sodium sulfate (DSS) (Le Poul et al., 2003; Maslowski et al., 2009; Sina et al., 2009; Venkatraman et al., 2003; Vinolo et al., 2011a, 2011b).”

“Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.”

“Entpd1 / mice, which cannot remove extracellular ATP through this mechanism, were highly susceptible to experimental colitis (Friedman et al., 2009).”

“Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.”

“…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; Wang et al., 2006).”

“Unexpectedly, the gutmicrobiome 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).”

“…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; Wang et al., 2006).”

“Given the anti-inflammatory effects described for PPAR-g, future studies are likely to further explore this topic (Croasdell et al., 2015).”

“Nr1i2 / mice exhibit impaired epithelial barrier function, and administration of synthetic NR1I2 agonists exerts protective effects in mouse models of colitis (Dou et al., 2013; Garg et al., 2016; Shah et al., 2007; Terc et al., 2014; Venkatesh et al., 2014).”

“In general, SCFAs have anti-inflammatory properties in the intestinal mucosa (Ferreira et al., 2014).”

“…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; Wang et al., 2006).”

“…Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a, 2009b ary ferent AhR activation…”

“Dietary supplementation with L-carnitine has also been associated with a significant decrease in the risk of cardiovascular disease, in apparent contradiction to the reported association of elevated plasma L-carnitine with increased risk (DiNicolantonio et al., 2013; Ussher et al., 2013).”

“On a biochemical level, 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).”

“Importantly, 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-1b) and may thus promote maintenance and function of the epithelial barrier (Mariathasan et al., 2006; Sutterwala et al., 2006, 20…”

“Once inside the cell, butyrate broadly affects transcriptional regulation by directly inhibiting nuclear class I histone deacetylases (HDACs) and activating histone acetyltransferases (HATs) (Donohoe et al., 2012; Koh et al., 2016; Steliou et al., 2012).”

“Under homeostatic conditions, IL-22 is primarily produced by a specialized subset of intraepithelial lymphocytes, the type 3 innate lymphoid cells (ILC3s) (Melo-Gonzalez and Hepworth, 2017).”

“4 Cell Metabolism 26, July 5, 2017 of SCFA-producing microbial species in the gut, and dietary changes that promote production of SCFAs by the microbiome can ameliorate symptoms (Frank et al., 2007; Kanauchi et al., 2002; Machiels et al., 2014; Sokol et al., 2009).”

“Cell Metabolism 26, July 5, 2017 15 Review Ghoshal, S., Witta, J., Zhong, J., de Villiers, W., and Eckhardt, E. (2009).”

“sepsis (Proietti et al., 2014).”

“The highly reactive polyamines putrescine (a diamine, N2), spermidine (N3), and spermine (N4) all are arginine derivatives produced and secreted by intestinal bacteria (Michael, 2016).”

“Cipriani et al., 2011; Guo et al., 2015; Kawamata et al., 2003; Mencarelli et al., 2009; Sayin et al., 2013; Vavassori et al., 2009; Wang et al., 2011a ty bile l Enhances epithelial barrier function and maintenance by promoting epithelial production of IL-18 Levy et al., 2015 (Continued on next…”

“Dietary supplementation with L-carnitine has also been associated with a significant decrease in the risk of cardiovascular disease, in apparent contradiction to the reported association of elevated plasma L-carnitine with increased risk (DiNicolantonio et al., 2013; Ussher et al., 2013).”

“Oral administration of polyamines enhances the development and maintenance of the intestinal mucosa and resident immune cells (Buts et al., 1993; Dufour et al., 1988; Löser et al., 1999; Pérez-Cano et al., 2010).”

“Long-term activation of P2X7, however, results in formation of a large membrane pore and cell death (Nuttle and Dubyak, 1994; Smart et al., 2003).”

“Atarashi et al., 2008; Kusu et al., 2013; Mariathasan et al., 2006; Nuttle and Dubyak, 1994; Perruzza et al., 2017; Sutterwala et al., 2006 Polysaccharide A (PSA) Activation of TLR2 on DCs and Tregs.”

“…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).”

“Dufour et al., 1988; Levy et al., 2015; Pérez-Cano et al., 2010; Wang et al., 1997; Zhang et al., 1999 Gut Bacteria ty bile l Inhibit NF-kB-dependent transcription of proinflammatory genes in monocytes, macrophages, dendritic cells.”