BUTYRATE AMELIORATES INFLAMMATION IN COLON BIOPSY SAMPLES OF IBD PATIENTS AND EXPERIMENTAL COLITIS IN MICE INVOLVING RNA BINDING PROTEIN, AUF1-IL-27 AXIS AND ACCELERATING B1a TO B10 POLARIZATION

The pathophysiology of Inflammatory Bowel Disease (IBD) is significantly influenced by the decline in B regulatory (B10) cells, which produce IL-10. Therefore, it is important to identify the key genes and pathways that regulate the B10 cell generation in order to develop more effective therapies. Here, we have shown that one of the short chain fatty acid, butyrate regulates the expression of RNA binding protein, AUF1 which is responsible for increasing the half-life of p28 mRNA, coding for p28 protein which associates with overexpressed EBI3 and forms functional IL-27. This effect is mediated through AUF1 binding to 3UTR of IL-27p28 mRNA. As a consequence, IL-27 signals splenic CD19+CD5+ (B1a) cells but not CD19+CD23+ (B2) cells to polarize to B10 cells. We proved the importance of AUF1 and the sequential downstream players in unique cell penetrating morpholino induced AUF1 knockdown (AUF1-KD) in mice, establishing the roster of events in splenic B1a cells: butyrate-AUF1-IL-27-IL-10. We showed that there was a significant decrease in AUF1, IL-27 and IL-10 expression in the colon biopsy of IBD patients compared to non-IBD control. We have used DSS induced colitis in mice as a surrogate of IBD in human and showed the reduction in AUF1 in spleen and colon could be correlated with the decrease in IL-27 and B10 cells in spleen and mesenteric lymph nodes which were reversed with butyrate treatment. We further established AUF1 as the role player by showing adoptive transfer of butyrate stimulated B1a cells from wild type mice conferring protection against colitis while adoptive transfer of butyrate stimulated B1a cells from AUF1 KD mice failed to suppress the disease. Finally, we propose that butyrate driven B1a cells as a glimmer of new hope of therapeutic possibility against colitis.