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.

Keywords: GLP-1; metabolic disease; microbial metabolite; p-cresol; small intestinal transit.

Figure 1

(A) Expression of proglucagon (Gcg) in GLUTag cells exposed to different concentrations of p-cresol and (B) GLP-1 secretion in GLUTag cells exposed to different concentrations of p-cresol in the absence and presence of 10 µM chemical TGR5 agonist MerckV. Each bar represents the mean of three independent measurements. Data were analyzed using nonparametric Kruskal–Wallis test followed by Dunn’s post-hoc analysis * p < 0.05.

Figure 2

Cumulative (A) food intake and (B) water intake, (C) body weight gain, (D) epididymal adipose tissue mass (expressed as the percentage of body weight) in control and p-cresol-supplemented mice (n = 6–7). (E) p-cresyl sulfate and (F) p-cresyl glucuronide (expressed as normalized peak area) in cecal contents, liver, and plasma of control and p-cresol-supplemented mice (n = 6–7). Data were analyzed using nonparametric Mann–Whitney U test, * p < 0.05.

Figure 3

RNA expression of proglucagon (Gcg), peptide YY (Pyy), neurotensin (Nts), and cholecystokinin (Cck) in (A) ileum (B) and proximal colon and (C) fasting plasma GLP-1 in control and p-cresol-supplemented mice (n = 6–7). (D) Oral glucose tolerance test, (E) GLP-1 pre- and post-glucose gavage, and (F) small intestinal transit (expressed as the percentage of the small intestine traveled by carmine red relative to total small intestinal length) in control and p-cresol-supplemented mice (n = 4–5). Data were analyzed using nonparametric Mann–Whitney U test, * p < 0.05. ns, not significant.