The Role Of Akkermansia Muciniphilia In Irradiation-induced Intestinal Injury

High dosages of irradiation(IR)lead to acute radiation syndrome.The intestine is extremely sensitive to IR.After IR,intestinal epithelial cells(IECs)undergo degeneration,necrosis,and shedding,and integrity of the mucosal barrier is disrupted,leading to infection,multiple organ insufficiency,and failure of rescue in acute radiation syndrome.In addition,as radiation therapy is widely used in the treatment of malignant tumors,intestinal damage occurs frequently.Thus,it is of great significance to elucide the mechanisms by which intestinal injury is induced and identify new agents to protect the intestine from IR-induced injury.There are more than 1000 types of microorganisms in the gut,most of which are commensal bacteria.Mounting evidence indicates that the gut microbiota is a key regulator of host health and plays a crucial role in the maintenance of physiological functions such as nutrition,immunity,and digestion.The intestinal flora includes mucus layer bacteria and intestinal lumen microbiota.As compared with the mucous layer flora intestinal lumen microbiota is attracting much more attentions due to its availability and abundance.Akkermansia Muciniphilia(A.muciniphila)is a newly identified gram-negative anaerobic probiotic,which colonizes in the intestinal mucus layer.A.muciniphila degrades mucins and stimulates goblet cells to continuously secrete new mucins,maintaining the dynamic of intestinal mucus layer.The role of A.muciniphila in abdominal IR-induced enteritis remains unknown.Herein,we reported that gut microbiota was severely disrupted in abdominal radiotherapy patients as compared with that in healthy subjects.IR led to the reduction of the diversity and abundance of the gut microbiota and altered its composition in IR patients.Similar results were obtained in a mouse model of radiation injury.We identified that A.muciniphila was strikingly reduced in fecal samples from radiotherapy patients and in intestinal contents of abdominal IR mice.Administration of A.muciniphila to IR mice substantially mitigated intestinal damage and increased the survival of IR mice,indicating that reduction of A.muciniphila might play a critical role in IR-induced intestinal injury.Analyzing metabolites of A.muciniphila revealed that propionate,a short-chain fatty acid secreted by the microorganism,mediated the protective effect of A.muciniphila on the intestine of abdominal IR mice.Propionate bound to G-protein coupled receptor43(GPR43)on the surface of IECs,increased 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 intestinal damage.Metformin,a first line agent for the treatment of type II diabetes,increased the abundance of A.muciniphila in intestine,promoted intestinal epithelial barrier integrity,and reduced radiation intestinal damage.Together,we demonstrated that reduction of A.muciniphila in intestinal contents promoted the development of abdominal IR-induced intestinal damage in mice.Corrections of abnormal gut microbiota by administration of A.muciniphila or elevation of the probiotic by metformin maintained intestinal epithelial barrier integrity and protected IR mice from intestinal injury.