High humidity reprograms the gut mycobiome to promote Meyerozyma caribbica-derived syringic acid and attenuate sepsis-induced acute kidney injury.

Sepsis-induced acute kidney injury (SAKI) remains a major contributor to mortality, yet the impact of environmental factors-particularly humidity-on disease progression is poorly understood. Here, we investigated how short-term high-humidity exposure shapes host susceptibility to SAKI and explored the underlying microbiota- and metabolite-mediated mechanisms. Mice pre-exposed to high humidity exhibited markedly attenuated renal injury and improved survival following cecal ligation and puncture (CLP). Notably, this protective effect persisted after bacterial depletion, but was abolished by amphotericin B treatment, indicating a fungus-dependent mechanism. Internal transcribed spacer sequencing and microbiota manipulation experiments identified Meyerozyma caribbica (M. caribbica) as a humidity-enriched commensal fungus essential for renal protection. Metabolomic profiling further revealed syringic acid (SA) as a key M. caribbica-derived metabolite responsible for the observed benefits. SA suppressed MAPK and NF-κB activation, reduced inflammatory cytokine release, and inhibited macrophage pyroptosis in vitro. Together, these findings demonstrate that high humidity confers protection against SAKI through an M. caribbica-SA axis that modulates macrophage inflammation and pyroptosis, highlighting a previously unrecognized environment-microbiota-host interaction in septic immunoregulation.IMPORTANCESepsis outcomes are traditionally attributed to host immunity and microbial infection, whereas environmental influences remain largely overlooked. This study reveals that short-term environmental humidity profoundly shapes septic kidney injury through a commensal fungus-derived metabolite, establishing M. caribbica and its product syringic acid as key mediators of renoprotection. These findings challenge the conventional bacteria-centered view of sepsis-microbiota interactions and uncover humidity-driven mycobiota remodeling as a critical regulator of immune responses. By defining an environment-fungus-host axis that mitigates macrophage inflammation and pyroptosis, this work provides a conceptual framework for leveraging environmental modulation or fungal metabolites as novel therapeutic strategies for sepsis.