Limosilactobacillus reuteri-butyrate axis in depression therapy: A key pathway discovered through a novel preclinical human flora-associated animal model

作者：Xiaojing Liu, Jing He, Li-Xun Cui, Ying Ye, Miaomiao Luo, Haoran Xu, Yujia Zhai, Zixin Zhao, Taohong Huang, Yunxia Li, Jianlin Wu, Jun Wen, Yong Wang, Tingting Zhou · 发表于：Pharmacological Research · 年份：2025 · DOI：10.1016/j.phrs.2025.107941 · 被引用次数：7 · 研究领域：Tryptophan and brain disorders、Gut microbiota and health、Medicinal Plants and Bioactive Compounds

The transition from preclinical to clinical drug development is critically impeded by interspecies disparities, which limit the predictive validity of preclinical efficacy for human outcomes. To address this limitation, we established a human flora-associated depression rat (HFADR) model through fecal microbiota transplantation (FMT). The HFADR model bridges the preclinical-clinical translation by recapitulating conserved microbial-host interactions identified through multi-omics analysis in a chronic unpredictable mild stress (CUMS) rat model and in patients with major depressive disorder. The HFADR model simulated the pathophysiological characteristics of clinical depression validated by gut-brain axis indices, including microbial composition, inflammatory biomarkers, brain-derived neurotrophic factor (BDNF), and monoamine neurotransmitters. Employing geniposide, a bioactive iridoid compound derived from medicinal plants, as a therapeutic prototype, the HFADR model revealed the novel Limosilactobacillus reuteri-butyrate axis as a conserved regulatory hub for the treatment of depression. Geniposide administration restored L. reuteri abundance in the HFADR model, which significantly correlated with improved gut-brain axis homeostasis. Metabolomics confirmed that L. reuteri exerts antidepressant effects via butyrate restoration in CUMS mice, with parallel butyrate level alterations observed in geniposide-treated HFADR model. Both L. reuteri supplementation and exogenous butyra...