Microbial metabolite p-cresol inhibits gut hormone expression and regulates small intestinal transit in mice

Abstract

p-cresol is a metabolite produced by microbial metabolism of aromatic amino acid tyrosine. p-cresol and its conjugated forms, p-cresyl sulfate and p-cresyl glucuronide, are uremic toxins that correlate positively with chronic kidney disease and diabetes pathogenesis. However, how p-cresol affects gut hormones is unclear. Here, we expose immortalized GLUTag cells to increasing concentrations of p-cresol and found that p-cresol inhibited Gcg expression and reduced glucagon-like peptide-1 (GLP-1) secretion in vitro. In mice, administration of p-cresol in the drinking water for 2 weeks reduced the transcript levels of Gcg and other gut hormones in the colon; however, it did not affect either fasting or glucose-induced plasma GLP-1 levels. Furthermore, it did not affect glucose tolerance but promoted faster small intestinal transit in mice. Overall, our data suggest that microbial metabolite p-cresol suppresses transcript levels of gut hormones and regulates small intestinal transit in mice.

Microbial dietary protein metabolism regulates GLP‐1 mediated intestinal transit

“…An alternate hypothesis is that the absence of protein-derived microbial metabolites might regulate Gcg expression in the colon. 22 An earlier report also showed that chow fed GF mice exhibited higher colonic Gcg expression, 4 which could be reversed by SCFAs administration. 8 GLP-1 secreting L-cells are scattered along the length of the intestine.…”

“…Due to gut microbiota depletion in Abx‐treated mice, dietary protein would remain intact in the colonic lumen, resulting in limited production of microbial metabolites. p‐cresol and its conjugates are among the metabolites produced by microbial dietary protein degradation and are associated with colonic and small intestinal transit 20–22 . Therefore, we hypothesized that administration of p‐cresol would reverse WSD‐ETPi‐mediated effects in microbiota‐depleted mice.…”

“…This is likely due to increased load of undigested proteins in the distal gut where density of L‐cells is higher, which may induce Gcg expression. An alternate hypothesis is that the absence of protein–derived microbial metabolites might regulate Gcg expression in the colon 22 . An earlier report also showed that chow fed GF mice exhibited higher colonic Gcg expression, 4 which could be reversed by SCFAs administration 8 …”

“…It has been shown previously that gut microbiota regulated metabolites, such as SCFAs, modulate GLP-1 levels, either as energy substrates 4 or as FFAR2/3 agonists. 30,31 Since the absence of gut microbiota also reduces the production of amino acid-derived microbial metabolites (e.g., indole and p-cresol), which are reported to modulate GLP-1 expression and secretion, and gut motility, 22,32 we investigated here whether p-cresol might be responsible for the changes in GLP-1 and small intestinal transit. Our study demonstrated that supplementing mice with the tyrosine-derived microbial metabolite p-cresol reversed the enteropeptidase inhibition mediated effects on Gcg expression and small intestinal transit.…”

“…p-cresol and its conjugates are among the metabolites produced by microbial dietary protein degradation and are associated with colonic and small intestinal transit. [20][21][22] Therefore, we hypothesized that administration of p-cresol would reverse WSD-ETPimediated effects in microbiota-depleted mice. To test this hypothesis, p-cresol was supplemented along with antibiotics in the drinking water of mice fed WSD-ETPi diet.…”