Engineered Chiral Probiotics Ameliorate MASH via Gut-Liver Axis.

Abstract

The global epidemic of metabolic dysfunction-associated steatohepatitis (MASH) is escalating without effective therapies. This study identified a significant depletion of the gut commensal bacterium Faecalibacterium duncaniae (F. duncaniae) as a core feature of MASH. To overcome the poor colonization by traditional probiotics in inflammatory environments, we engineered a living microbial therapeutic by incorporating chiral gold nanozymes onto F. duncaniae. We discovered that biological performance is enantiomer-dependent: the right-handed nanozyme (D-Au) serves as a superior ROS-scavenging shield, protecting the probiotic from oxidative assault and enhancing its colonization in the inflamed gut. In mouse models of MASH, this engineered probiotic (F@D-Au) reversed disease progression, ameliorating steatosis, inflammation, and fibrosis. It further restored systemic homeostasis, rectifying dysbiosis, metabolic disturbances, and-notably-MASH-associated cognitive impairment. Metabolomic analyses revealed that this multi-organ benefit was linked to the restoration of key microbial metabolites, including kynurenic acid and linoleic acid. Our work establishes a new class of chirality-enhanced living therapeutics that precisely remodel the gut-liver axis, offering a transformative strategy for treating MASH and its complications.