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

Sep 5, 2025Pharmacological research

Limosilactobacillus reuteri and butyrate as a key pathway in depression treatment found using a new animal model with human gut bacteria

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Abstract

The human flora-associated depression rat (HFADR) model demonstrates conserved microbial-host interactions that may enhance the relevance of preclinical studies to clinical depression.

The HFADR model replicates key characteristics of clinical depression as observed in patients and other animal models.
Alterations in microbial composition and inflammatory biomarkers were validated as indicators of depression in the HFADR model.
Geniposide treatment restored the abundance of Limosilactobacillus reuteri, which is linked to improved gut-brain axis function.
L. reuteri supplementation and butyrate administration both showed potential to reverse depression-like behaviors in the HFADR model.
The study suggests that the L. reuteri-butyrate axis could serve as a new target for depression therapies.

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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 butyrate administration reversed depression-like behavior, mechanistically confirming the axis by reduced hippocampal astrocyte activation and elevated Nrf2 expression. This study established the HFADR model as a translational tool for evaluating microbiota-targeted therapies and identified the L. reuteri-butyrate axis as a novel therapeutic target. Our findings provide a theoretical and practical framework for refining preclinical models and advancing antidepressant development using microbiome-based strategies.

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

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