Systemic Oxidative Stress and Oxidized Albumin Mediate the Pathogenic Kidney-to-Gut Crosstalk by Disrupting...

Deleterious crosstalk between the gut and distant organs is a key factor behind disease progression. Currently, the molecular signals mediating this communication remain elusive. We hypothesized that systemic oxidative stress and oxidatively modified serum proteins transmit injury signals from extraintestinal sites to the gut. In various murine models of organ injury, primary damage was consistently associated with systemic oxidative stress and intestinal damage. Specifically, ischemia/reperfusion (I/R)-induced acute kidney injury caused profound colonic barrier defects. Depleting the microbiota with antibiotics markedly improved survival and attenuated both renal and colonic injury, implicating translocated microbes in exacerbating pathology. Mechanistically, these changes were linked to systemic oxidative stress and were largely prevented by the antioxidant N-acetylcysteine. Furthermore, serum from I/R mice disrupted epithelial barrier integrity and induced cell death in vitro, effects that were recapitulated by exposure to oxidized serum proteins. Characterization of serum components identified albumin as the predominantly oxidized protein, which displayed potent cytotoxicity toward cultured intestinal epithelial cells. Our findings establish oxidative stress and oxidized serum albumin as key pathogenic factors mediating the detrimental interaction between remote organs and the gut. These data suggest that targeting oxidative modifications offers a promising therapeutic strategy to disrupt this pathological loop in critical illness.