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.