Loss of Parietal Cell‐Expressed Sonic Hedgehog Results in Hypochlorhydria that is Associated with Altered Gastrointestinal Microbiota and Epithelial Morphology

Abstract

Sonic Hedgehog (Shh) regulates gastric epithelial cell function and differentiation. Mice expressing a parietal cell-specific deletion of Shh (HKCre/ShhKO) develop both hypochlorhydria and hypergastrinemia due to disruption of parietal cell function. Histological evaluation revealed that compared to control mice, HKCre/ShhKO mice developed atypical colonic crypts (aberrant crypt foci) and distortion of the small intestinal mucosa, with short, broad and irregular villi and inflammatory infiltrate. Bacterial changes were quantified in stomach, luminal flushes and mucosal scrapping of terminal ileum, cecum, proximal and distal colon using 16S ribosomal DNA bacterial primers by qRT-PCR. Total gastric bacterial load was increased 10 fold in HKCre/ShhKO mice. Intestinal flushes from HKCre/ShhKO mice showed increased total bacteria in ileum when compared to wild type littermates. HKCre/ShhKO mice displayed significant decreases in gamma-Proteobacteria in ileum and Bifidobacteria in distal colon. Increased Actinobacteria levels in both the proximal and distal colon were observed. Mucosal scrapings from HKCre/ShhKO mice also showed an increase in total bacteria of the ileum, while decreases occurred in Actinobacteria in ileum and in beta-Proteobacteria in the distal colon. These data suggest that hypochlorhydria due to loss of gastric Shh results in altered microbiota in stomach and small and large intestine which may contribute to disrupted gastrointestinal morphology and function. Supported by NIH DK079979.