Positive Effect And Mechanism Of Akkermansia Muciniphila On Celiac Disease In Mice

Celiac disease is an autoimmune bowel disorder caused by the ingestion of gluten or its related products in genetically susceptible individuals.Gluten is difficult for the digestive tract to fully digest it into amino acids,leaving a gliadin peptide.Gliadin peptides enter the lamina propria through the tight junction gap of the intestine,causing mucosal immune response,damaging the structure of the villi of the small intestine,resulting in nutritional malabsorption,and leading to functional disorders of the body or even other complications in serious cases.At present,there is no treatment and medicine for celiac disease in the world.The only recognized treatment is that patients adhere strictly to a gluten-free diet for life.Therefore,it is necessary to develop new treatments or medicine for celiac disease.Akkermansia muciniphila is the next generation probiotics attracting much attention at present.Resent studies have proved that A.muciniphila has a protective effect on obesity and type 2 diabetes,and has an ability to improve inflammation in some inflammatory bowel diseases.In addition,pasteurized A.muciniphila has been demonstrated to replicate all the protective effects of live A.muciniphila.Interestingly,a negative correlation between the abundance of A.muciniphila and the development of celiac disease has been found in clinical patients.However,the effect of A.muciniphila on celiac disease is not known.Therefore,in this study,we investigated the effect of A.muciniphila and its mechanism on celiac disease by constructing a mouse model of celiac disease and intervening with A.muciniphila.The main results and conclusions are as follows:(1)By repeating stimulation of gliadin in BALB/c mice raised with a gluten-free diet for more than three generations,we established a mouse model of celiac disease.And then the feasibility of this model was evaluated by examining celiac disease-related diagnostic indicators.The results demonstrated that the mice in the model group showed shortened duodenal villi,increased crypt hyperplasia and a significant increase in various inflammatory factors,immune cells,and transglutaminase 2(TG2)expression,as well as the disruption of the intestinal barrier.In conclusion,these data indicate that the animal model of celiac disease remarkably mimics the key clinical features of celiac disease clinically.(2)Mice were administrated with live or pasteurized A.muciniphila standard strain ATCC BAA-835 respectively to investigate the effect of A.muciniphila on celiac disease.The results showed that A.muciniphila could significantly improve the growth rate of body mass and improve the tissue morphological damage of duodenum induced by celiac disease,indicating that A.muciniphila could alleviate the pathogenic process of celiac disease.(3)The effect of A.muciniphila on the intestinal barrier of mice with celiac disease were investigated.The results show that A.muciniphila significantly reduced intestinal permeability and restored intestinal barrier function in mice by increasing the expression of mucin,decreasing the expression of zonulin and enhancing the expression of tight junction proteins including ZO-1,ZO-2 and occludin,indicating that A.muciniphila could restore the damaged intestinal barrier in celiac disease mice.(4)The effects of A.muciniphila on mucosal immune response in celiac disease were investigated.The results showed that A.muciniphila significantly reduced the expression of pro-inflammatory factors and TG2 in duodenum and inhibited the infiltration of TG2-specific plasma cells and TG2-specific B cells,indicating that A.muciniphila could inhibit the mucosal immune response in celiac disease mice.(5)The potential mechanism of A.muciniphila in celiac disease was revealed.The results showed that A.muciniphila increased the content of short-chain fatty acids(SCFAs)in the duodenal contents and activated G-protein-coupled receptors(GPCR)-41 and GPR43,while A.muciniphila also increased the expression of pro-form and cleaved-form of the cathelicidinrelated antimicrobial peptidesin peptides(CRAMP)in duodenum.The results suggest that A.muciniphila alleviates the pathogenesis of celiac disease in mice by upregulating SCFAs and activating their receptors GPR41 and GPR43 in duodenum,while restoring the expression of CRAMP.The study is the first time to confirm that A.muciniphila has a protective effect on celiac disease and provides new ideas for the future research of A.muciniphila as well as the development of new therapeutic strategy for celiac disease.