Comorbid depression exacerbates Gelsemium elegans toxicity via disruption of the Clostridium-LCA-PXR-CYP3A11 metabolic axis

Abstract

Gelsemium elegans (G. elegans) is a toxic medicinal plant traditionally used to treat chronic pain, with its toxicity linked to indole alkaloids such as gelsemine and humantenmine (HMT). Chronic pain often co-occurs with depression, a condition known to disrupt host-microbiota interactions, potentially affecting drug metabolism and toxicity. However, the impact of comorbid depression on the toxicity of G. elegans remains unclear. This study investigates how depression exacerbates the neurotoxicity of G. elegans and explores the role of the gut microbiota−host metabolic axis in this process. Depression-model mice were treated with G. elegans aqueous extract, gelsemine and HMT. Multi-omics approaches, including 16S rRNA sequencing and shotgun metagenomics, were used to analyze microbiota changes under depressive conditions. Functional validation was performed using pseudo-germ-free mice, fecal microbiota transplantation, and supplementation with Clostridium species and lithocholic acid (LCA), as well as pregnane X receptor (Pxr) knockout models. The results showed that depression significantly heightened the neurotoxicity of G. elegans, gelsemine and HMT. Mechanistically, depression reduced Clostridium abundance and LCA levels, impairing PXR activation and downregulating hepatic CYP3A11 expression. This disruption of the Clostridium-LCA-PXR-CYP3A11 axis hindered the detoxification of indole alkaloids, leading to increased systemic exposure and exacerbated neurotoxicity. Restoration of this pathway through Clostridium or LCA supplementation alleviated the toxicity. These findings highlight the role of the Clostridium-LCA-PXR-CYP3A11 axis in the altered toxicity of G. elegans in a depressive state, and suggest that Clostridium species and their metabolites may serve as a potential strategy for mitigating toxicity.

Keywords

Gelsemium elegans / Humantenmine / Gut microbiota / Pregnane X receptor / Depression / Neurotoxicity

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82422077 and 82274193) and Guangdong Basic and Applied Basic Research Foundation (No. 2024B1515020093).

Acknowledgments

The Pxr knockout mice utilized in this study were generously provided by Prof. Fei Li (Sichuan University).

Data availability statement

The 16S rRNA and shotgun metagenomics sequencing datasets are available in the NCBI SRA database under the accession numbers PRJNA1073719 and PRJNA1077725, respectively. Supporting information for this study can be obtained by contacting the corresponding authors via E-mail.

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