SATB2 defect promotes colitis and colitis-associated colorectal cancer by impairing Cl -/HCO3 - exchange and homeostasis of gut microbiota.

BACKGROUND SATB2 is a diagnostic biomarker and a favorable prognostic marker for colorectal cancer (CRC), but its role in colitis and colitis-associated colorectal cancer (CAC) is unknown. METHODS Intestinal epithelial specific Satb2 knockout (Satb2 IEC-KO) and control mice was induced by DSS and AOM. RNA-seq analysis was performed on colonic tissues, and 16S rDNA-Seq on fecal bacterial DNA from Satb2 IEC-KO and control mice. Immunohistochemistry and flow cytometry were performed the reveal the proportion of different immune cells. ChIP and luciferase reporter were applied to show the regulatory role of SATB2 on SLC26A3, of which the Cl -/HCO3  - exchange activity was measured fluorometrically by the pHi-sensitive dye. Bacteroides was detected by FISH on colonic tissue. RESULTS Satb2 IEC-KO mice suffered from intestinal epithelial damage spontaneously, and developed more severe colitis and CAC. The expression of SLC26A3 correlated well with SATB2 revealed by RNA-seq and TCGA data, and was governed by SATB2 confirmed by ChIP and luciferase reporter experiments. Decreased intestinal flora diversity was seen in Satb2 IEC-KO mice. Bacteroides were more abundant and could colonize into the inner layer of colonic mucosa in Satb2 IEC-KO mice. Fecal microbiome transplantation from Satb2 IEC-KO mice aggregated colitis and M1 macrophages infiltration. CONCLUSION SATB2 plays a vital role in maintaining intestinal homeostasis and its deficiency promotes the development of colitis and CAC by influencing the intestinal luminal environment and gut flora.