Formation of a reducing microenvironment and regulation of protein supersulfidation by gut microbial supersulfides.

Supersulfides, sulfur species containing catenated sulfur atoms, are potent reducing agents produced by diverse organisms. Although their intracellular functions are increasingly recognized, the ecological and physiological importance of gut microbial supersulfides remains poorly understood. In this study, we explored two complementary aspects of gut microbiota-derived supersulfide. First, by assessing the reducing activity, we found that bacterial supersulfides contribute to the enhancement of the extracellular reducing capacity. In particular, Dorea longicatena and Enterocloster bolteae exhibit strong cystine-dependent supersulfide production, which is associated with protection against oxidative stress. Second, beyond their ecological roles, supersulfides influence protein supersulfidation, which is a reversible post-translational modification. Supersulfidated proteins have been detected across multiple commensal taxa with species-specific profiles. This modification is redox-sensitive and modulated by extracellular supersulfides. Members of the Lactobacillaceae family are particularly susceptible to exogenous supersulfides. Supersulfidation involves proteins linked to core microbial processes, including bile acid metabolism, suggesting their potential role in tuning bacterial functions. Together, these findings suggest that microbial supersulfides act as dual regulators: (i) contributing to a protective reducing milieu and (ii) modulating bacterial protein function through supersulfidation. By highlighting post-translational control in gut bacteria and their sensitivity to the local redox environment, this work broadens the current models of microbial redox biology and provides a basis for linking bacterial sulfur metabolism with gut ecosystem stability and host-microbe interactions.