Exploring the antidepressant mechanisms of Guipi pill: A focus on gut-brain axis and immunity modulation

doi:10.5498/wjp.v16.i6.114553

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World Journal of Psychiatry

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2220-3206

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Psychiatry. Jun 19, 2026; 16(6): 114553
Published online Jun 19, 2026. doi: 10.5498/wjp.v16.i6.114553

Exploring the antidepressant mechanisms of Guipi pill: A focus on gut-brain axis and immunity modulation

Jing Zhong, Wei Chen, Sen Li, Dong-Lin Zheng, Yi-Dan Wang, Jia-Hui Huang, Xing-Qiu Liang, Ming-Kun Liang

Jing Zhong, Wei Chen, Sen Li, Jia-Hui Huang, Department of Basic Medical Sciences, Guangxi University of Chinese Medicine, Nanning 530021, Guangxi Zhuang Autonomous Region, China

Dong-Lin Zheng, Department of Gastroenterology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China

Yi-Dan Wang, Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China

Xing-Qiu Liang, Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China

Ming-Kun Liang, Traditional Chinese Medicine Specialty Office, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China

Co-first authors: Jing Zhong and Wei Chen.

Co-corresponding authors: Xing-Qiu Liang and Ming-Kun Liang.

Author contributions: Zhong J, Chen W, Li S, Zheng DL, Wang YD, and Huang JH contributed to investigation; Zhong J and Chen W were responsible for conceptualization, methodology, and writing-draft, they contributed equally to this article, they are the co-first authors of this manuscript; Li S handled software-related work; Liang XQ and Liang MK provided conceptualization, supervision, and writing review and editing, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors have read and approved the final manuscript.

AI contribution statement: Only DeepL was used for language polishing in manuscript revision; ChatGPT and Grammarly were not employed. All core scientific content, including study design, data analysis, results interpretation, and figures, was independently created by the authors without AI involvement. No AI-generated images were included, and all charts were manually produced using professional tools.

Supported by National Natural Science Foundation of China, No. 81960807; Guangxi Natural Science Foundation, No. 2023GXNSFAA026237; Guangxi Xinglin Young Talents Project of Guangxi University of Traditional Chinese Medicine, No. 2022C026 and No. 2022C042; and Guangxi Zhuang Autonomous Region’s First Batch of Medical Young Reserve Talent Training Program.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Guangxi University of Traditional Chinese Medicine.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Corresponding author: Xing-Qiu Liang, PhD, Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, No. 10 Huadong Road, Nanning 530011, Guangxi Zhuang Autonomous Region, China. 121308213@qq.com

Received: September 23, 2025
Revised: November 14, 2025
Accepted: February 2, 2026
Published online: June 19, 2026
Processing time: 248 Days and 0.1 Hours

Abstract

BACKGROUND

Depression is a multifactorial neuropsychiatric disorder involving genetic, neuroendocrine, and environmental factors. Traditional Chinese medicine offers holistic treatments, such as Guipi pill (GPP), which tonifies the spleen, nourishes the heart, and calms the mind, aligning with patterns like heart-spleen deficiency. The gut-brain axis, modulated by immune dysregulation and inflammation, is implicated in depression. However, the molecular mechanisms of GPP’s antidepressant effects via this axis remain unclear. We hypothesize that GPP exerts antidepressant effects by regulating immune-related targets in the gut-brain axis.

AIM

To investigate the mechanism by which GPP exerts antidepressant effects via gut-brain axis regulation.

METHODS

This basic study integrated bioinformatics and animal experiments. Transcriptomic data from patients with inflammatory bowel disease and depression were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified, and shared genes defined gut-brain axis dysregulation. A chronic unpredictable mild stress rat model assessed depressive-like behaviors and transcriptomic changes. Expression quantitative trait loci analysis evaluated genetic associations at bulk and single-cell levels. Statistical methods included t-tests and odds ratio (OR) calculations.

RESULTS

GPP significantly ameliorated depressive-like behaviors in chronic unpredictable mild stress rats (P < 0.01). Transcriptomic analysis identified 1349 differentially expressed genes post-intervention. Intersection analysis revealed seven gut-brain axis-related targets, with granzyme A (GZMA) as the key gene associated with reduced depression risk (OR < 1, P < 0.05). At the single-cell level, GZMA expression positively correlated with CD8+ effector T cells (OR > 1, P < 0.05) and negatively with CD8+ naïve cells (OR < 1, P < 0.05). GPP modulated GZMA expression in these CD8+ T cell subsets.

CONCLUSION

GPP alleviates depression by modulating the gut-brain axis through GZMA regulation in CD8+ T cell subsets, highlighting an immune-mediated pathway for traditional Chinese medicine.

Keywords: Guipi pill; Depression; Gut-brain axis; Traditional Chinese medicine; Immune regulation; Transcriptomics; Granzyme A; Chronic unpredictable mild stress; Inflammatory bowel disease; Expression quantitative trait loci

Core Tip: This study demonstrates that the traditional formula Guipi pill (GPP) alleviates depression by modulating the gut-brain axis via immune regulation. GPP significantly improved depressive-like behaviors in a chronic unpredictable mild stress rat model and altered the expression of 1349 genes, with GZMA playing a key role. Mechanistically, GPP enhanced GZMA expression in CD8+ T-cell subsets, promoting effector T cells while reducing naïve T cells. These results suggest a novel immune-mediated pathway for GPP’s antidepressant effect.