Akkermansia muciniphila exacerbates acute radiation–induced intestinal injury by depleting mucin and enhancing inflammation

Abstract Dysbiosis of gut microbiota plays a crucial role in acute radiation-induced intestinal injury. However, studies on the influence of gut microbiota on acute radiation-induced intestinal injury are inconsistent. In this study, we established an acute radiation-induced intestinal injury mouse model and performed fecal microbiota transplantation to explore the role of the gut microbiota in acute radiation-induced intestinal injury. We observed a significant increase in Akkermansia muciniphila following irradiation, whereas fecal microbiota transplantation effectively reduced A. muciniphila levels. Contrary to expectations, A. muciniphila supplementation increased acute radiation-induced intestinal injury and mortality. Mechanistically, postradiation A. muciniphila upregulates mucin metabolism genes and consumes mucin, thinning the mucosal barrier and promoting the adhesion and translocation of potential pathogens to epithelial cells, thus exacerbating acute radiation-induced intestinal injury. This enables A. muciniphila to use mucin as an energy source. Additionally, A. muciniphila increases the inflammatory macrophage changes and secretion of inflammatory cytokines, leading to a decrease in epithelial stem cell density and inhibition of goblet cell differentiation, further exacerbating acute radiation-induced intestinal injury. Our findings suggest that in certain intestinal environments, the addition of A. muciniphila may worsen radiation-induced intestinal damage; thus, alternative approaches to reverse the dysbiosis associated with radiotherapy should be explored.