Ko, Haeun Kim, Chan Johng Choi, Seungyeon Noh, Jaegyun Kim, Seung Won Lee, Juhun Byun, Seohyun Lee, Haena Park, John Chulhoon Park, Hye Eun Sharma, Amit Park, Minhyuk Park, Junghwan Lee, Choong-Gu Cha, Kwang Hyun Im, Sin-Hyeog 2026-01-30T08:30:13Z 2026-01-30T08:30:13Z 2026-01-30 2026-01 https://pubs.kist.re.kr/handle/201004/154080 Background The gut microbiota plays an essential role in mucosal immunity, with secretory immunoglobulin A (IgA) acting as a key effector in neutralizing pathogens and maintaining host-microbiota homeostasis. IgA production occurs via T cell-dependent (TD) and -independent pathways, with T follicular helper (Tfh) cells driving high-affinity, antigen-specific IgA responses. However, the specific microbial taxa and metabolites that regulate Tfh-mediated IgA responses under steady-state conditions remain poorly understood. This study investigated how gut microbiota-derived signals shape Tfh responses and IgA production, with implications for enhancing mucosal vaccine efficacy. Results We demonstrate that Peyer’s patches (PP)-derived Tfh cells exhibit superior IgA-inducing capacity compared to splenic Tfh cells. RNA sequencing revealed distinct transcriptional profiles in PP-Tfh cells, including upregulation of the genes associated with Tfh differentiation and activation (Bcl6, Cd40lg, Maf), T-B cell interactions (Il21, Sh2d1a, Fyn), and migration (Ccr6, Cxcr5). Functionally, PP-Tfh cells formed larger T-B cell contact areas and induced significantly higher IgA secretion in co-culture than their splenic counterparts. Microbiota depletion experiments revealed that eliminating neomycin-depleted bacteria reduced fecal IgA levels and diminished PP-Tfh cell frequencies. Fecal microbiota transplantation from neomycin-treated mice restored both IgA production and Tfh responses in germ-free (GF) mice. Bioinformatic analysis (PICRUSt2 and LEfSe) identified butyrate-producing Lachnospiraceae and Ruminococcaceae as key drivers of the Tfh-IgA axis. Butyrate supplementation enhanced Tfh differentiation and IgA⁺ germinal center B cell development in vitro and increased fecal IgA levels in vivo. Mechanistically, butyrate promoted IgA production via GPR43 signaling, as its effect was lost in co-cultures with Gpr43⁻/⁻ Tfh cells. Moreover, treatment with tributyrin, a butyrate prodrug, enhanced vaccine-induced IgA and protected mice against Salmonella Typhimurium infection, reducing bacterial burden and tissue damage. These findings define a functional microbiota-Tfh-IgA axis sustained by neomycin-depleted, butyrate-producing bacteria. Conclusions Our study underscores the crucial role of the gut microbiota, particularly neomycin-depleted butyrate producing taxa, in regulating PP-Tfh cell function and IgA production. Butyrate emerges as a metabolite linking microbial metabolism to Tfh differentiation and IgA class switching. Together, these findings establish a microbiota-metabolite-Tfh cell axis essential for mucosal immune homeostasis and suggest novel strategies for enhancing vaccine efficacy and protection against enteric infections. English BioMed Central Commensal microbe-derived butyrate enhances T follicular helper cell function to boost mucosal vaccine efficacy Article 10.1186/s40168-025-02284-7 1 Microbiome, v.14, no.1 Microbiome 14 1 N scie scopus 001667061400001 Microbiology Microbiology Article CHAIN FATTY-ACIDS GUT MICROBIOTA INFLAMMATORY RESPONSES EPITHELIAL-CELLS IGA METABOLITES BARRIER HEALTH DIFFERENTIATION BACTERIA Gut microbiota Mucosal immunity Immunoglobulin A T follicular helper cell Peyer&apos s patches Butyrate <italic>Salmonella</italic> Typhimurium