Human gut bacterial metabolism drives Th17 activation and colitis

Alexander, Margaret; Ang, Qi Yan; Nayak, Renuka R.; Bustion, Annamarie E.; Sandy, Moriah; Zhang, Bing; Upadhyay, Vaibhav; Pollard, Katherine S.; Lynch, Susan V.; Turnbaugh, Peter J.

doi:10.1016/j.chom.2021.11.001

Cited by 103 publications

(95 citation statements)

References 75 publications

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“…IL-17 has been shown to promote the development of colon cancer 37. Previous study showed that E. lenta was enriched in patients with IBD and it could induce IL-17a, by the cardiac glycoside reductase 2 enzyme,38 supporting our finding that E. lenta may activate the proinflammatory cytokine IL-17 pathways to induce tumourigenesis. Activation of TNF-α pathway induces colitis and colorectal carcinogenesis 39.…”

Section: Discussionsupporting

confidence: 91%

Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites

Bai

Wei

Liu

et al. 2022

Gut

102

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ObjectiveCigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites.DesignAzoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice.ResultsMice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal‑regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium.ConclusionThe gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.

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Section: Discussionsupporting

confidence: 91%

Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites

Bai

Wei

Liu

et al. 2022

Gut

102

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“…Eggerthella lenta also possesses 3α- and one 3β-HSDH for converting DCA to isoDCA to reduce gut bacteria toxicity [ 56 ]. These HSDHs also convert LCA to 3-exoLCA and isoLCA, both of which modulate Th17 populations in mice [ 57 , 58 ].…”

Section: Ba Biosynthesismentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

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Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

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“…Gut microbiota is one of the major components of the intestinal mucosal barrier (13,14). A large body of evidence suggests that changes in the composition and function of gut microbes are key factors directly contributing to the onset and progression of IBD (15), and therefore targeting the gut microbiota may be a novel strategy for the treatment of IBD.…”

Section: Introductionmentioning

confidence: 99%

Moringa oleifera Lam. Peptide Remodels Intestinal Mucosal Barrier by Inhibiting JAK-STAT Activation and Modulating Gut Microbiota in Colitis

et al. 2022

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Ulcerative colitis is a chronic inflammatory bowel disease (IBD), but progress in exploring its pathogenesis and finding effective drugs for its prevention and treatment has stalled in recent years. The seeds of Moringa oleifera Lam. are rich in proteins known to have multiple physiological activities. In our earlier work, we had isolated and purified a peptide (MOP) having the sequence KETTTIVR, from M. oleifera seeds; however, its anti-inflammatory activity and mechanism in vivo were unclear. Here we used the dextran sulfate sodium (DSS)-induced colitis model to study the anti-inflammatory activity and mechanism of this MOP. Our results are the first to show that MOP can ameliorate the pathological phenotype, inflammation, and intestinal barrier disruption in mice with colitis. Furthermore, RNA sequencing revealed that MOP inhibits the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway activation. Next, by using 16s rRNA gene sequencing, we found that MOP can ameliorate DSS-induced gut microbiota dysbiosis. In addition, an untargeted metabolomics analysis suggested that MOP is able to modulate the level of lipid and amino acid metabolites in IBD-stricken mice. Altogether, these results indicate that MOP ameliorates colitis by remodeling intestinal mucosal barrier by inhibiting JAK-STAT pathway’s activation and regulating gut microbiota and its metabolites, thus providing a basis for further processing and design of bioactive foods from M. oleifera seeds.

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Human gut bacterial metabolism drives Th17 activation and colitis

Cited by 103 publications

References 75 publications

Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites

Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Moringa oleifera Lam. Peptide Remodels Intestinal Mucosal Barrier by Inhibiting JAK-STAT Activation and Modulating Gut Microbiota in Colitis

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