[4S00m] 01. ASBA - Part 10

11:15 AM - 11:30 AM JST(2:15 AM - 2:30 AM UTC)

[4ASBA-05] Engineered commensals for metabolic modulation of the gut-liver-brain axis

○Nikhil Aggarwal^1,2,3, Haosheng Shen^1,2,3, Li Ting Lee^1,2,3, Lei Zhou⁴, Meng Tong Zhu⁴, Xiu Qi Koh⁴, Anna Xin Yi Ng⁴, Ming Li⁴, Nur Halisah Binte Jumat⁴, Wai Yuen Cheah⁴, Shengjie Lie^1,3, Mukesh Saini^1,2,3, Jonathan Wei Jie Lee^1,3,4,5, Jee Loon Foo^1,2,6, Kwok Soon Wun^1,2,3,6, In Young Hwang^1,3,6, Chun Loong Ho^1,3,6,7, Yung Seng Lee^1,3,8, Yock Young Dan^1,3,4,5, Matthew Chang^1,2,3,6,7 (1. NUS Synthetic Biology for Clinical and Technological Innovation, National University of Singapore (Singapore), 2. National Centre for Engineering Biology (Singapore), 3. Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (Singapore), 4. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore (Singapore), 5. Division of Gastroenterology and Hepatology, National University Hospital (Singapore), 6. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (Singapore), 7. Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences (China), 8. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (Singapore))

Keywords:

Gut–liver–brain axis,Engineered commensals,Synthetic Biology,Metabolic Disorders

The gut–liver–brain axis is central to metabolic and neurological homeostasis, mediated by host–microbiota metabolic interactions. Disruption of this axis contributes to complex disorders such as hepatic encephalopathy (HE), characterized by hyperammonemia and amino acid imbalance, highlighting the need for targeted multi-metabolite interventions. Here, we engineered commensal Lactobacillus plantarum WCFS1 strains to selectively modulate key metabolites dysregulated in HE. Two strains were developed: Lp-NH3, which couples ammonia assimilation with branched-chain amino acid (BCAA) biosynthesis, and Lp-Q, designed to enhance L-glutamine utilization and suppress ammonia production. In hyperammonemic and bile duct ligation mouse models, these engineered strains significantly reduced systemic and brain ammonia levels, restored BCAA and L-glutamine balance, and improved anxiety-like and cognitive behaviors. Transcriptomic analysis of brain tissue revealed normalization of neuronal signaling pathways and reduced neuroinflammatory signatures, supporting a mechanistic link between gut metabolic modulation and central nervous system function. Importantly, these strains outperformed rifaximin, a clinically used therapy for HE, while preserving gut microbiota diversity and demonstrated favorable safety profiles without long-term colonization. Together, our findings establish engineered commensals as a modular and programmable platform for multi-metabolite intervention, offering a novel therapeutic strategy to restore metabolic homeostasis in disorders of the gut–liver–brain axis.