SCFAs strongly stimulate PYY production in human enteroendocrine cells

P Larraufie,F M Gribble,C Martin-Gallausiaux,F Reimann,N Lapaque,H M Blottiere,J Dore

doi:10.1038/s41598-017-18259-0

Abstract

Peptide-YY (PYY) and Glucagon-Like Peptide-1 (GLP-1) play important roles in the regulation of food intake and insulin secretion, and are of translational interest in the field of obesity and diabetes. PYY production is highest in enteroendocrine cells located in the distal intestine, mirroring the sites where high concentrations of short chain fatty acids (SCFAs) are produced by gut microbiota. We show here that propionate and butyrate strongly increased expression of PYY but not GCG in human cell line and intestinal primary culture models. The effect was predominantly attributable to the histone deacetylase inhibitory activity of SCFA and minor, but significant contributions of FFA2 (GPR43). Consistent with the SCFA-dependent elevation of PYY gene expression, we also observed increased basal and stimulated PYY hormone secretion. Interestingly, the transcriptional stimulation of PYY was specific to human-derived cell models and not reproduced in murine primary cultures. This is likely due to substantial differences in PYY gene structure between mouse and human. In summary, this study revealed a strong regulation of PYY production by SCFA that was evident in humans but not mice, and suggests that high fibre diets elevate plasma concentrations of the anorexigenic hormone PYY, both by targeting gene expression and hormone secretion.

Highlights

The gut represents one the most important endocrine organs, secreting more than 20 different hormones from a scarce and heterogeneous enteroendocrine cell (EEC) population
Incubation of NCI-h716 cells with short chain fatty acids (SCFAs) for 24 h increased PYY expression to different extents depending on the SCFA chain length (Fig. 1b)
All three agents induced a similar strong effect on PYY expression in NCI-h716 cells (Fig. 2b). These results suggested that K/Histone Deacetylase (HDACs) inhibition, an extensively described GPCR-independent activity of butyrate and propionate, underlies the observed strong increase of PYY expression. These results suggested that SCFAs modulated PYY expression by two different but additive pathways: stimulation of FFA2 by all three SCFAs induced a small increase in PYY mRNA levels, whereas HDAC inhibition by propionate and butyrate induced a very large increase in PYY mRNA levels

Summary

Introduction

The gut represents one the most important endocrine organs, secreting more than 20 different hormones from a scarce and heterogeneous enteroendocrine cell (EEC) population Among these hormones, Peptide-YY (PYY) and Glucagon-like-peptide-1 (GLP-1) are of specific interest in the field of obesity and diabetes as they have been implicated in the regulation of food intake and insulin secretion, even though their precise physiological significance in healthy and pathological states is still debated[1,2,3,4,5,6]. As SCFAs seem capable to alter PYY and GLP-1 plasma levels in humans[29], other mechanisms may be involved and need to be assessed

Methods

Results

Conclusion