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Gut microbial composition and metabolites influence serum IgA homeostasis

Xiaobo Zhang^a, Han Xiao^a, Yan Wang^a, Zhifeng Pan^b, Guangshu Hao^b,?

 
ABSTRACT:     Immunoglobulin A (IgA) is a key regulator of gut microbiota homeostasis, shaping both microbial community composition and metabolic output to maintain host-microbe symbiosis. However, the detailed mechanisms underlying how IgA modulates microbial diversity and coordinates the production of metabolites critical for immune and metabolic fitness remain poorly investigated. We combined clinical sampling, murine models, and multi-omics analyses to dissect these interactions. Specifically, fresh fecal samples were collected from adult volunteers and analyzed for gut microbiota diversity using 16S rDNA sequencing, while serum IgA concentrations were measured via ELISA. Subsequently, a high-IgA (HIgA) mouse model was established to validate the association between Prevotella and serum IgA level, which confirmed that metabolites derived from Prevotella, rather than viable bacteria or culture medium components, dominantly reduce serum IgA concentrations. Furthermore, metabolomics and proteomics analysis identified critical metabolites influencing IgA expression. Gut microbiota diversity was significantly reduced in the HIgA group, with a robust inverse correlation between Prevotella abundance and serum IgA levels. Metabolomic analysis further identified 596 differentially expressed microbial metabolites, with fatty alcohols, purines, and their derivatives emerging as key regulators of IgA levels. Additionally, pathways related to penicillin metabolism and cholinergic drugs, as well as the key neural signaling proteins UNC13B and CNTNAP1, were implicated in IgA modulation. These findings highlight the strong link between gut microbiota composition and serum IgA regulation, particularly the negative correlation with abundance of Prevotella, which suggests considerable potential for developing targeted immunotherapies based on microbiota-driven immune modulation.

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* Corresponding author, E-mail: hgs199099@126.com

Received 27 Oct 2025, Accepted 12 Jul 2026