Jianfeng Zheng, Zhihua Wu, Duxiang Lin, Minghui Fang, Pengxing Lin
Acute ischemic stroke is accompanied by marked peripheral and central immune imbalance, in which disruption of the Th17/Treg axis is considered an important driver of aggravated neuroinflammation and secondary injury, yet the upstream regulatory pathways amenable to intervention remain unclear. We hypothesised that the probiotic Akkermansia muciniphila (AKK) could be linked to post-stroke immune remodelling and neuroprotection by influencing intestinal epithelial signalling. Using a tMCAO mouse model combined with AKK intervention, SIRT1 inhibition, IL-17-deficient conditions, and IL-17 neutralisation/rescue experiments, we systematically assessed intestinal barrier integrity, peripheral and central immune responses, and neurological injury, together with single-cell transcriptomic and ATAC-seq analyses of the Th17/Treg axis. Complementary human and murine intestinal epithelial-T cell co-culture systems and a neuronal OGD model were used for functional mechanistic assessment. AKK was associated with activation of AMPK/SIRT1 signalling, decreased Th17 proportions, increased Treg levels, suppression of IL-17-associated inflammatory responses, and enhancement of IL-10 signalling, thereby improving systemic and intracerebral inflammatory environments. In the neuronal OGD model, IL-17 neutralisation alone provided partial protection, combined AKK and IL-17 blockade further enhanced neuroprotection, and recombinant IL-17 rescue attenuated, but did not fully define, the protective effects of AKK. AKK also protected intestinal barrier integrity, reduced infarct volume, and improved neurological function. Together, these findings support a contributory gut epithelial AMPK/SIRT1-associated immunoregulatory network in which AKK is linked to Th17/Treg immune remodelling and reduced post-stroke neuroinflammation through the gut-immune-brain axis, while IL-17 signalling appears to represent one important component rather than an exclusive pathway.