Butyrate attenuates SA-AKI by inhibiting pyroptosis via the STING-GSDMD axis

Sepsis-associated acute kidney injury (SA-AKI) is a common and serious complication with high morbidity and mortality. The pathophysiology of SA-AKI is complex. The underlying mechanisms of SA-AKI remain unclear, and effective therapeutic strategies are limited. Butyrate is a type of short-chain fatty acid (SCFA) derived from the gut microbiota that plays a key role in kidney disease. However, the effect of butyrate on SA-AKI and its underlying mechanisms remain unclear. In this study, LPS was used to establish an SA-AKI model in C57BL/6 mice. Our results indicated that butyrate levels were substantially reduced in SA-AKI model mice. Notably, butyrate intervention attenuated kidney injury and inflammation in SA-AKI model mice. Moreover, the levels of NLRP3, STING, and GSDMD (a marker of pyroptosis) were significantly decreased by butyrate intervention. An in vitro model induced by LPS was established using HK-2 cells. Butyrate mitigated pyroptosis and reduced NLRP3, STING, and GSDMD protein expression. Furthermore, STING overexpression abrogated the downregulation of several proteins (NLRP3 and caspase 1) invovled in NLRP3 inflammsome-mediated pyroptosis and weakened the protective effect of butyrate. Hence, butyrate may attenuate SA-AKI by inhibiting pyroptosis via the STING-GSDMD axis, which provides a potential therapeutic strategy for preventing SA-AKI progression.