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.