Intestinal IL-17 family orchestrates microbiota-driven histone deacetylation and promotes Treg differentiation to mediate the alleviation of asthma by Ma-Xing-Shi-Gan decoction

Yanfei Hong; Jiaqi Cui; Guichuan Xu; Na Li; Guiying Peng

doi:10.1016/j.phymed.2025.156656

Intestinal IL-17 family orchestrates microbiota-driven histone deacetylation and promotes Treg differentiation to mediate the alleviation of asthma by Ma-Xing-Shi-Gan decoction

Phytomedicine. 2025 Jul:142:156656. doi: 10.1016/j.phymed.2025.156656. Epub 2025 Mar 17.

Authors

Yanfei Hong¹, Jiaqi Cui¹, Guichuan Xu¹, Na Li², Guiying Peng³

Affiliations

¹ Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, PR China.
² Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, PR China. Electronic address: nali@bucm.edu.cn.
³ Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, PR China. Electronic address: penggy@bucm.edu.cn.

PMID: 40311598
DOI: 10.1016/j.phymed.2025.156656

Abstract

Background: Gut microbiota imbalance is well-known as one important trigger of allergic asthma. Ma-Xing-Shi-Gan decoction (MXSG) is a traditional Chinese medicine prescription with ideal clinical efficacy on asthma. However, whether and how MXSG exerts its efficacy on asthma through gut microbiota remains unclear.

Purpose: To investigate the underlying mechanism of MXSG against asthma using multi-omics technologies.

Methods: An asthma model was established using 8-week-old C57BL/6 J mice, after which they were daily administrated with high-, medium- and low-dose MXSG for 7 days. Histopathological examinations and flow cytometry were performed to evaluate the effects of MXSG on lung immune injury. Key regulatory pathways were predicted via network pharmacology and verified using 16S rRNA sequencing, metagenomics, metabolomics, and in vivo experiments including the knockout of the targeting gene.

Results: MXSG alleviated asthma symptoms, elevated intestinal microbial diversities, and enriched potential beneficial microbes such as Lactococcus, Lactobacillus, and Limosilactobacillus. Network pharmacology and experimental validation highlighted the IL-17/Treg signaling as crucial for asthma treatment. IL-17 knockout experiments revealed its necessity for Treg differentiation during asthma. Moreover, IL-17-deficient asthmatic mice exhibited lower levels of Lactobacillus and significant changes in microbial genes involving histone deacetylases (HDAC) and short-chain fatty acids (SCFAs). Finally, MXSG significantly boosted SCFA production and reduced HDAC9 expression, which were correlated with Treg cell ratios.

Conclusion: Our study delineates a novel mechanism where MXSG synergizes with the IL-17 family to enrich intestinal beneficial microbes (e.g. Lactobacillus) and SCFAs. This inhibits the expression of SCFA-downstream HDAC9 to promote Treg differentiation, and thus potentially alleviates asthma.

Keywords: Asthma; Gut microbiota; Ma-Xing-Shi-Gan decoction; Treg cells; histone deacetylation.

MeSH terms

Acetylation
Animals
Asthma* / drug therapy
Asthma* / microbiology
Cell Differentiation / drug effects
Disease Models, Animal
Drugs, Chinese Herbal* / pharmacology
Gastrointestinal Microbiome* / drug effects
Histone Deacetylases / metabolism
Histones / metabolism
Interleukin-17* / genetics
Interleukin-17* / metabolism
Lung / drug effects
Lung / pathology
Male
Mice
Mice, Inbred C57BL
T-Lymphocytes, Regulatory* / drug effects

Substances

Drugs, Chinese Herbal
Interleukin-17
Histones
Histone Deacetylases