Butyrate mitigates multi-organ damage in urosepsis: associated changes in the renal NOX4/ROS/NF-κB axis and gut microbiota.

Introduction: Urosepsis is a kind of sepsis resulting from urogenital infections, marked by a significant prevalence of organ failure and mortality. This study sought to examine the preventive effect and possible mechanism of butyrate against multi-organ damage caused by urosepsis. Methods: This work utilized a ureteral obstruction model complicated by infection to more precisely replicate acute kidney injury and the systemic inflammatory response associated with urosepsis. Rats received butyrate supplementation or antibiotic therapy following modeling, multi-organ function, histopathology, inflammatory markers, renal oxidative stress levels, and gut microbiota composition were comprehensively assessed. Results: The findings indicated that in rats with urosepsis generated by ureteral obstruction, renal NOX4 was markedly elevated, the inflammatory response was exacerbated, and various organ dysfunction was compromised. Butyrate intervention markedly diminished blood levels of TNF-α, IL-6, and MCP-1, and dramatically downregulated kidney expression of KIM-1 and NGAL, as well as macrophage infiltration. Moreover, butyrate significantly mitigated cardiac mitochondrial injury and raised liver transaminases, enhanced the expression of intestinal ZO-1 and occludin proteins, and restructured the gut microbiota. Mechanistic studies demonstrated that butyrate treatment was associated with reduced renal NOX4 expression, reduced ROS levels, and decreased phosphorylation of IκBα and p65, together with attenuated renal inflammation and multi-organ injury. These effects may help restrain the spread of kidney-derived inflammation and, in turn, alleviate multi-organ injury. Concurrently, by altering the gut microbiota and enhancing the growth of beneficial intestinal bacteria, it further elevates the synthesis of short-chain fatty acids in the gastrointestinal tract. Furthermore, by incorporating a combined butyrate and antibiotic treatment group, we observed that multiple physiological indicators were substantially improved in the combination therapy group compared with either the butyrate monotherapy group or the antibiotic monotherapy group, confirming that the concomitant administration of butyrate and antibiotics exerts a synergistic therapeutic effect. Conclusions: In a urosepsis model caused by urinary tract obstruction and infection, butyrate attenuated renal and systemic inflammation and multi-organ injury, accompanied by reductions in renal NOX4 expression, ROS levels, and NF-κB activation, consistent with modulation of the renal NOX4/ROS/NF-κB pathway. These findings highlight the potential therapeutic value of butyrate as an adjunct to antibiotic therapy.