Recovery from DSS‐induced intestinal colitis is mediated by MIP2‐dependent neutrophil recruitment

Conventionally raised mice successfully recover from the injury caused by DSS‐induced colitis. In contrast, bacteria‐depleted mice (BD mice), generated by treatment with broad‐spectrum oral antibiotics for two weeks, failed to recover from subsequent DSS‐induced injury, suggesting interactions between components of the normal gut microbiota of the host are required for recovery. Monocolonization by Bacteroides fragilis or commensal E. coli strain was able to prevent DSS‐induced mortality in BD mice. Since LPS is one component that is common to both these bacteria, we then determined if LPS alone would be sufficient to rescue BD mice from DSS‐induced mortality. Oral treatment with LPS with continuous antibiotic treatment was sufficient to reduce DSS‐induced mucosal injury and mortality in the wild type BD mice, but not in bacteria‐depleted TLR4 −/− mice or MyD88 −/− mice. The data suggest activation of TLR4‐dependent signals that enhance the recovery from DSS‐induced colitis in BD mice. We investigated the mechanistic basis for these observations and found that DSS treatment resulted in lower intestinal expression of MIP2 and correspondingly lower levels of neutrophil recruitment to the damaged mucosa. Administration of exogenous MIP2 eliminated DSS‐induced mortality in BD mice with a corresponding increase of neutrophils in the inflamed mucosa strongly suggesting a specific role for MIP2‐dependent neutrophil recruitment. These results support the idea that Gram‐negative commensal gut flora is necessary for the recovery from DSS‐induced colitis. The LPS‐mediated activation of TLR4‐MyD88 dependent signaling leads to up‐regulation of chemoattractants that recruit neutrophils, thereby enhancing the recovery from intestinal injury.