Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog

  • Cell Host Microbe. 2026 Jun 10;34(6):1000-1017.e5. doi: 10.1016/j.chom.2026.05.003.
Liang Bian  1 ,  Yang Cai  1 ,  Yuan Zhang  1 ,  Ling Shen  1 ,  Huijuan Wang  1 ,  Feng Gao  1 ,  Ningbo Cai  1 ,  Wenbo Chen  2 ,  Conghui You  2 ,  Yurui Yang  1 ,  Fang Wang  3 ,  Yonggui Yuan  4 ,  Bing Han  5 ,  Honghong Yao  6
Affiliations
  • 1. Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
  • 2. Department of Pathogen Biology and Immunology, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
  • 3. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 4. Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 5. Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu, China; Liangjiang Hospital of Southeast University, Nanjing Pukou People's Hospital, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 6. Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu, China; Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu, China. Electronic address: [email protected].
PMID: 42269582 DOI: 10.1016/j.chom.2026.05.003
Abstract

Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for Metabolic Disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1r-/- mice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii, which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression.

Keywords
2-AG; GLP-1 analog; Lactobacillus delbrueckii; depression; neuronal hyperactivation.
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