Activation of GABA receptor attenuates intestinal inflammation by modulating enteric glial cells function through inhibiting NF-KB pathway

Aims: Emerging research indicates that & gamma;-aminobutyric acid (GABA) provides substantial benefits during enteritis. Nevertheless, GABA signaling roles on enteric glial cells (EGCs) remain unknown. The study's objective was to evaluate the underlying mechanisms of GABA signaling on EGCs in vitro and in vivo. Main methods: We established LPS-induced mouse models and stimulated EGCs with LPS to mimic intestinal inflammation, and combined GABA, GABAA receptor (GABAAR) or GABAB receptor (GABABR) agonists to explore the exact mechanisms of GABA signaling. Key findings: EGCs were immunopositive for GAD65, GAD67, GAT1, GABAAR & alpha;1, GABAAR & alpha;3, and GABABR1, indicating GABAergic and GABAceptive properties. GABA receptor activation significantly inhibited the high secretions of proinflammatory factors in EGCs upon LPS stimulation. Interestingly, we found that EGCs express immune-related molecules such as CD16, CD32, CD80, CD86, MHC II, iNOS, Arg1, and CD206, thus establishing their characterization of E1 and E2 phenotype. EGCs exposed to LPS mainly acted as E1 phenotype, whereas GABABR activation strongly promoted EGCs polarization into E2 phenotype. Transcriptome analysis of EGCs indicated that GABA, GABAAR or GABABR agonists treatment participated in various biological processes, however all of these treatments exhibit inhibitory effects on NF-KB pathway. Notably, in LPS-induced mice, activation of GABABR mitigated intestinal damage through modulating inflammatory factors expressions, strengthening sIgA and IgG levels, inhibiting NF-KB pathway and facilitating EGCs to transform into E2 phenotype. Significance: These data demonstrate that the anti-inflammatory actions of GABA signaling system offer in enteritis via regulating EGCs-polarized function through impeding NF-KB pathway, thus providing potential targets for intestinal inflammatory diseases.