Short Chain Fatty Acids Signaling through the G Protein-Coupled Receptor GPR41 in the Intestine.




Shaito, Abdullah

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There are more than 100 Trillion microflora that inhabit the gastrointestinal tract of animals. The resident microflora modulate thephysiology of the gastrointestinal tract in several ways, from shaping the villi vasculature to regulation of epithelial cell proliferation and differentiation. Of more relevance to this study is the fact that, microflora help the host extract energy from the otherwise indigestible polysaccharides. The microflora ferment the polysaccharides to produce short chain fatty acids (SCFAs). SCFAs constitute around 70% of the energy source in ruminants and 10-15% in non-ruminants. Recently, SCFAs have been shown to be ligands fortwo G protein-coupled receptors (GPCRs), Gpr41 and Gpr43. We show that Gpr41 is expressed in the intestinal enteroendocrine cells. The localization of Gpr41 to enteroendocrine cells suggests that SCFAs signaling through Gpr41 induces the enteroendocrine cells to release a soluble mediator. In this study we sought to study the effects of SCFAs signaling on animal physiology and how this signaling is related to energy balance. For this purpose Gpr41 knock out mice were generated and rederived as germ free mice. Gpr41 knock out and wild type germ free mice were recolonized as young adults with 2 prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methano-brevibacter smithii. We find that Gpr41 -/- mice are leaner than their wild type littermates. This observation is also seen in the recolonization model, where germ free Gpr41 -/- and +/+ mice are of equal weight, however recolonization of these mice with microflora induces a weight increase in the Gpr41+/+ mice and not in the Gpr41 -/- mice. This is despite equal consumption of chow. Further studies demonstrated that recolonized Gpr41 -/- germ free mice; as compared to recolonized Gpr41 +/+ littermates, fail to induce the release of PYY, an enteroendocrine cell derived hormone that limits food intake and inhibits gut motility, into plasma. We also show that an acute oral administration of SCFAs increases circulating PYY levels in the wild type but not the Gpr41 knock out mice. Additional studies showed that recolonized Gpr41 -/- mice have increased intestinal transit rate and reduced harvest of energy (SCFAs) from the diet. These results show that Gpr41 is a regulator of host energy balance through pathways that are dependent on the presence of the microflora. These results also point to the possibility of the development of a Gpr41 based drug that can be used to slow down energy extraction and treat certain kinds of obesity.

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