Downregulation Of Farnesoid X Receptor Promotes Colorectal Tumorigenesis By Facilitating Enterotoxigenic Bacteroides Fragilis Colonization

Colorectal cancer（CRC）is considered as the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide.While scientific and clinical advances have found promising new treatment options,the five-year survival rate for metastatic CRC is still low at about 14%,promising targets are urgently needed.Farnesoid X receptor（FXR;NR1H4）,a member of the nuclear receptor（NR）superfamily,was considered as a master regulator of bile acids（BAs）synthesis and secretion,lipid and glucose metabolism,and it is expressed primarily in the gastrointestine tract,liver and kidney.FXR expression levels were downregulated in CRC tissues,as a main regulator of bile acids（BAs）,the down-regulation of FXR changes the profile of BAs in vivo.Bile acids are potent digestive surfactants that promote lipid absorption.They were synthesized from cholesterol by liver,and it is the main regulator of the intestinal flora.In this study,we first detected the expression level of FXR in CRC,then we used a colitis-associated cancer（CAC）mouse model induced by azoxymethane（AOM）/dextran sodium sulfate（DSS）and an Fxr null mouse model to figure out the role FXR played in CRC.BAs concentration were determined by LC-MS/MS and ELISA.Through 16S sequencing preliminary examination and RT-q PCR verification,we gained insight in to the composition and abundance of mice gut flora.Then we tested the effects of BAs and secretory immunoglobulin A（s Ig A）on the adhesion and biofilm formation of enterotoxigenic Bacteroides fragilis（ETBF）.According to the results,we observed increase in BA levels in serum of patients with CRC and feces of CAC mice.Through 16S sequence and RT-q PCR verification,we found the intestine of CAC mice harbors a unique gut flora and large quantities of cancer-promoting bacteria ETBF.Besides,the concentration of s Ig A was significantly higher in Fxr^-/-mice.Both in-vitro and in-vivo models showed BAs positively regulated s Ig A concentration in the intestinal lumen,and then s Ig A bound to bacteria and enhanced its adhesion to epithelial cells,which promoted biofilm formation of bile-tolerant bacteria such as ETBF.These effects eventually promoted tumorigenesis and development of colorectal cancer.In summary,our study detected the intestinal luminal concentration of bileacids and gut microbiota of CRC mice.We found BAs could positively regulate s Ig A,and both bile acids and s Ig A could facilitate the colonization of ETBF.Our research revealed the regulating mechanism of FXR-BAs-s Ig A axis on ETBF,which resulted in increased abundance of ETBF in the intestinal mucosa of CRC mice,and finally promoted the development of CRC.According to our research,BAs and s Ig A are risk factors of CRC,and which provides important clues and references for related studies.