MLKL deficiency inhibits DSS-induced colitis independent of intestinal microbiota.

The maintenance of intestinal tissue homeostasis is vital for the resistance against inflammatory bowel diseases (IBDs). Necroptosis is identified as an alternative mode of regulated cell death, which plays a pivotal role in tissue homeostasis. Thus, the roles of RIP3-mediated necroptosis in intestinal inflammation have been extensively studied. However, the biological implications of the mixed lineage kinase-like protein (MLKL), a molecule downstream of RIP3 in gut remain unclear. In this study, the role of MLKL in DSS-induced colitis was examined, and the contribution of gut microbiota was also determined. Compared with non-littermate WT mice, the survival rate, clinical score, intestinal damage and intestinal mucosal barrier integrity of non-littermate MLKL-deficient mice are significantly improved. MLKL deficiency prevents inflammatory cytokines production and MAPK signaling activation. Hence, MLKL deficiency inhibits DSS-induced colitis. Moreover, we proved that DSS susceptibility difference between two genotypes is not driven by intestinal microbiota based on the co-housing of two non-littermate genotypes and qPCR detection of fecal dominant bacterial taxa.