Dual modulation of the NLRP3/CASPASE-1 inflammasome pathway and gut microbial metabolism: the antidepressant mechanism of puerarin.

Overview

1. Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China
2. Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan, Guangdong, China
3. Institute of Biomedical Translational Research, Jinan University, Guangzhou, China
4. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Ministry of Education, School of Medicine, Jinan University, Guangzhou, China
5. Department of Food Science and Engineering, Jinan University, Guangzhou, China
6. School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
7. School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China

Abstract

Background: Post-stroke depression (PSD) is the most common neuropsychiatric complication following stroke. Puerarin (PU), the principal bioactive compound extracted from the medicinal and edible plant Pueraria lobata, has shown beneficial therapeutic effects in both depression and stroke. However, the therapeutic effect of PU on PSD and its underlying mechanisms remain unclear. This study investigates the therapeutic efficacy of PU in ameliorating abnormal behaviors in PSD mice and elucidates the roles of intestinal microbiota disorder, intestinal barrier damage, activation of the NLRP3/CASPASE-1 inflammasome in the hippocampus, and dysregulated inflammatory cytokine production in the pathogenesis of PSD.

Methods: To investigate the ameliorative effect of PU on behavioral abnormalities and to clarify the role of intestinal microbiota regulation in the therapeutic effects of PU in PSD mice, various methodologies were employed, including a PSD model, behavioral tests, network pharmacology, hematoxylin-and-eosin staining, ultrastructural morphology, enzyme-linked immunosorbent assay, western blotting, 16S rRNA sequencing, metabolomic analyses, and fecal microbiota transplantation (FMT).

Results: Oral administration of PU could effectively alleviate depressive-like behaviors in PSD mice, repair the damaged colonic mucosa, and increase the expression of occludin and ZO-1. Network pharmacology analysis indicated that the NLRP3/CASPASE-1 inflammasome pathway was a potential therapeutic target of PU, and PU inhibited activation of the hippocampal NLRP3/CASPASE-1 inflammasome. Additionally, PU suppressed pro-inflammatory cytokines in both the hippocampus and serum. PU restored the intestinal microbiota and regulated the microbial metabolism of PSD mice. More importantly, fecal microbiota transplantation from PSD mice reproduced depressive-like behaviors, while fecal microbiota transplantation from PU-treated mice (PU-FMT) prominently relieved depressive-like behaviors in PSD mice.

Conclusion: Our findings indicate that PU reduces depressive-like behaviors in PSD mice by modulating the intestinal microbiota and microbial metabolism and inhibiting the NLRP3/CASPASE-1 inflammasome.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• bioproject:PRJNA1501384 — at NCBI BioProject; found in “Data availability statement”

Data availability statement

The data presented in this paper are stored in NCBI SRA database under accession number PRJNA1501384: https://www.ncbi.nlm.nih.gov/sra/PRJNA1501384.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 16 authors, 5 keywords, 57 references.

Cite

This paper

Lu, Y.-t., Chen, Y.-y., Ding, N.-n., Meng, L.-w., Yuan, J.-j., Huang, Z.-x., Hu, J.-b., Tong, J.-x., Zhang, Y.-r., Nan, N., Liu, D.-d., Tang, K.-r., Luo, X., Li, X., Hao, W.-z., & Chen, J.-x. (2026). Dual modulation of the NLRP3/CASPASE-1 inflammasome pathway and gut microbial metabolism: the antidepressant mechanism of puerarin. Frontiers in microbiology, 17, 1907120. https://doi.org/10.3389/fmicb.2026.1907120

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