Engineered commensals for metabolic modulation of the gut-liver-brain axis.

The gut-liver-brain axis is central to metabolic and neurological homeostasis and is mediated by host- and microbiota-derived metabolites. Disruptions in this axis contribute to complex disorders, underscoring the need for targeted, multi-metabolite interventions. Here, we engineered commensal Lactobacillus plantarum WCFS1 strains to specifically modulate metabolites dysregulated in hepatic encephalopathy (HE), a disorder driven by hyperammonemia and amino acid imbalance. One strain couples ammonia assimilation with branched-chain amino acid (BCAA) biosynthesis, whereas the other enhances L-glutamine utilization to suppress ammonia generation. In two preclinical HE models, these strains reduced systemic ammonia by up to 10-fold, restored BCAA and L-glutamine balance, and improved anxiety-like and cognitive behaviors. Notably, they outperformed rifaximin, a clinically used HE therapy, while preserving gut microbiota diversity. These findings establish engineered commensals as a modular, responsive platform for multi-metabolite modulation of host-microbiota metabolism, offering a programmable strategy to restore metabolic homeostasis in disorders of the gut-liver-brain axis.