<i>Akkermansia muciniphila</i> protects the intestine from irradiation-induced injury by secretion of propionic acid

Abstract

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of <i>A. muciniphila</i> in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of <i>A. muciniphila</i> was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of <i>A. muciniphila</i> in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of <i>A. muciniphila</i> substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of <i>A. muciniphila</i> revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of <i>A. muciniphila</i>. Together, our results demonstrated that <i>A. muciniphila</i> plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.