biostudies-literatureLiao YLaboratory of Lingnan Mordern Agriculture ProjectNational key R&D Program of ChinaNational Natural Science Foundation of Chinae2215921119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9636909biostudies-literatureUnknown119(44)Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA⁺ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as Proceedings of the National Academy of Sciences of the United States of AmericaGABA signaling enforces intestinal germinal center B cell differentiation.PMC96369092021YFD1300700NT202100531872365Duan JYin YLiao YCai QRen WChen QBin PHu XHan WZhu CDing SZhang YFan LCai YfalseGABA signaling enforces intestinal germinal center B cell differentiation.Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA⁺ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as 2022-01-01T00:00:00Z2022 Nov2026-07-14T16:57:37.642Z2025-04-06T08:02:52.008ZS-EPMC96369093627943210.1073/pnas.2215921119