Microbial dietary protein metabolism regulates GLP-1 mediated intestinal transit
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Microbial dietary protein metabolism regulates GLP-1 mediated intestinal transit. / Toft, Pernille Baumann; Yashiro, Hiroaki; Erion, Derek M.; Gillum, Matthew Paul; Bäckhed, Fredrik; Arora, Tulika.
In: FASEB Journal, Vol. 37, No. 10, e23201, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Microbial dietary protein metabolism regulates GLP-1 mediated intestinal transit
AU - Toft, Pernille Baumann
AU - Yashiro, Hiroaki
AU - Erion, Derek M.
AU - Gillum, Matthew Paul
AU - Bäckhed, Fredrik
AU - Arora, Tulika
N1 - Publisher Copyright: © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2023
Y1 - 2023
N2 - Depletion of gut microbiota is associated with inefficient energy extraction and reduced production of short-chain fatty acids from dietary fibers, which regulates colonic proglucagon (Gcg) expression and small intestinal transit in mice. However, the mechanism by which the gut microbiota influences dietary protein metabolism and its corresponding effect on the host physiology is poorly understood. Enteropeptidase inhibitors block host protein digestion and reduce body weight gain in diet-induced obese rats and mice, and therefore they constitute a new class of drugs for targeting metabolic diseases. Enteroendocrine cells (EECs) are dispersed throughout the gut and possess the ability to sense dietary proteins and protein-derived metabolites. Despite this, it remains unclear if enteropeptidase inhibition affects EECs function. In this study, we fed conventional and antibiotic treated mice a western style diet (WSD) supplemented with an enteropeptidase inhibitor (WSD-ETPi), analyzed the expression of gut hormones along the length of the intestine, and measured small intestinal transit under different conditions. The ETPi-supplemented diet promoted higher Gcg expression in the colon and increased circulating Glucagon like peptide-1 (GLP-1) levels, but only in the microbiota-depleted mice. The increase in GLP-1 levels resulted in slower small intestinal transit, which was subsequently reversed by administration of GLP-1 receptor antagonist. Interestingly, small intestinal transit was normalized when an amino acid-derived microbial metabolite, p-cresol, was supplemented along with WSD-ETPi diet, primarily attributed to the reduction of colonic Gcg expression. Collectively, our data suggest that microbial dietary protein metabolism plays an important role in host physiology by regulating GLP-1-mediated intestinal transit.
AB - Depletion of gut microbiota is associated with inefficient energy extraction and reduced production of short-chain fatty acids from dietary fibers, which regulates colonic proglucagon (Gcg) expression and small intestinal transit in mice. However, the mechanism by which the gut microbiota influences dietary protein metabolism and its corresponding effect on the host physiology is poorly understood. Enteropeptidase inhibitors block host protein digestion and reduce body weight gain in diet-induced obese rats and mice, and therefore they constitute a new class of drugs for targeting metabolic diseases. Enteroendocrine cells (EECs) are dispersed throughout the gut and possess the ability to sense dietary proteins and protein-derived metabolites. Despite this, it remains unclear if enteropeptidase inhibition affects EECs function. In this study, we fed conventional and antibiotic treated mice a western style diet (WSD) supplemented with an enteropeptidase inhibitor (WSD-ETPi), analyzed the expression of gut hormones along the length of the intestine, and measured small intestinal transit under different conditions. The ETPi-supplemented diet promoted higher Gcg expression in the colon and increased circulating Glucagon like peptide-1 (GLP-1) levels, but only in the microbiota-depleted mice. The increase in GLP-1 levels resulted in slower small intestinal transit, which was subsequently reversed by administration of GLP-1 receptor antagonist. Interestingly, small intestinal transit was normalized when an amino acid-derived microbial metabolite, p-cresol, was supplemented along with WSD-ETPi diet, primarily attributed to the reduction of colonic Gcg expression. Collectively, our data suggest that microbial dietary protein metabolism plays an important role in host physiology by regulating GLP-1-mediated intestinal transit.
U2 - 10.1096/fj.202300982R
DO - 10.1096/fj.202300982R
M3 - Journal article
C2 - 37732618
AN - SCOPUS:85171783649
VL - 37
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 10
M1 - e23201
ER -
ID: 369085946