Megasphaera Elesdenii Dysregulates Colon Epithelial Homeostasis, Aggravates Colitis‐Associated Tumorigenesis

Abstract Altered gut microbiota has evidenced to be associated with colitis and colonic tumorigenesis, however bacteria‐driven mechanism underlying inflammation‐related colon pathologies remains undetermined. This study identifies a previously overlooked genus, Megasphaera , is highly abundant in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) cohorts. A Megasphaera species, M. elsdenii reshapes colonic immunity by triggering dendritic cell (DC)‐mediated Th1 and Th17 inflammation. Mechanistically, M. elsdenii and its lipopolysaccharide triggers DC activation via TLR4/NF‐κB/IRF4 pathway. Accordingly, in Tlr4 −/− mice, M. elsdenii colonization cannot expand colonic infiltration of DCs and fails to induce Th1 and Th17 responses in. In a Shanghai CRC cohort with a 100% detective rate for Megasphaera , the species of Megasphaera significantly dominated in early onset CRC patients (<50 years old) rather than late‐onset CRC (≥50 years old). M. elsdenii and M. elsdenii ‐enriched microbiota exacerbate colonic inflammation and tumorigenesis in azoxymethane (AOM)/dextran sodium sulfate (DSS)‐induced murine colitis‐associated cancer model. Taken together, this study uncovers a pathogenic role of Megasphaera in developing colonic tumorigenesis via activating DC‐mediated inflammation.