Gut-derived Helicobacter rodentium aggravates Tfh/Tfr imbalance and neuroinflammation via PI3K/AKT activation in anti-NMDAR encephalitis mice

Background The gut microbiota is essential for the bidirectional communication between the gut and the brain. However, its specific role and underlying mechanisms in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain largely unclear. Methods An anti-NMDAR encephalitis model was induced by GluN1 peptide immunization, and brain histopathology was assessed by hematoxylin-eosin staining. Behavioral performance was assessed through the Y-maze and open field tests. Flow cytometry was employed to quantify T follicular helper (Tfh) and T follicular regulatory (Tfr) cell populations. Enzyme-linked immunosorbent assay and western blot were used to assess inflammatory cytokines and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway-related protein levels, respectively. 16S rRNA sequencing and Helicobacter rodentium gavage (1.5   mL, 1×10¹¹ CFU/mL) were used to assess microbiota composition and bacterial function. Results 16S rRNA sequencing revealed a trend toward reduced gut microbial diversity in anti-NMDAR encephalitis mice. Helicobacter rodentium colonization further exacerbated behavioral deficits and inflammatory cell infiltration in the cerebral cortex. This was accompanied by a marked increase in tumor necrosis factor alpha (TNF-α) and interleukin (IL)-21 levels and a reduction in IL-10 concentrations in both cerebrospinal fluid and serum. Moreover, the Tfh/Tfr cell ratio was further elevated following Helicobacter rodentium exposure. Targeted suppression of the PI3K/AKT pathway with LY294002 significantly restored Tfh/Tfr balance and alleviated neurobehavioral impairments and cortical inflammation. Conclusion Helicobacter rodentium exacerbates anti-NMDAR encephalitis by inducing PI3K/AKT-mediated Tfh/Tfr imbalance, highlighting a potential therapeutic target in autoimmune encephalitis.