Kynurenic acid mitigates poststroke brain damage through the gut-brain neural circuit

BACKGROUND: Stroke induces complex pathophysiological responses that extend beyond the brain, yet the mechanisms through which peripheral signals influence stroke recovery remain largely unclear. OBJECTIVE: Here, we identify a novel gut-brain neural circuit that promotes stroke recovery via kynurenic acid (KYNA) signalling. DESIGN: In a training cohort (30 patients with acute ischaemic stroke (AIS) and 30 controls), untargeted metabolomics profiled intestinal metabolites and the key metabolite KYNA was validated in an independent cohort (100 patients with AIS and 100 controls) using targeted metabolomics and assessed for its 3-month prognostic value. In stroke mouse models, KYNA was administered to evaluate therapeutic effects. Mechanistic studies combined neuronal calcium imaging, enteric neuron receptor manipulation, vagotomy, neuronal tracing, electrophysiology and immunofluorescence to delineate the KYNA-mediated gut-brain neural circuit regulating stroke recovery. RESULTS: Our study demonstrates a significant reduction of intestinal KYNA in patients with AIS and validates its prognostic value for neurological recovery at 3 months poststroke in both the training and validation cohorts. Oral KYNA supplementation markedly improves poststroke cerebral injury by activating G protein-coupled receptor 35 (GPR35) on enteric neurons, initiating vagal nerve signalling. Mechanistically, KYNA-GPR35 interaction activates vagal afferents, transmitting signals through the nucleus tractus solitarius to hippocampal and hypothalamic regions. This GPR35-vagus nerve signalling pathway, further validated with the selective GPR35 agonist Zaprinast, confers neuroprotection by shifting microglial polarisation towards the anti-inflammatory M2 phenotype and enhancing neuronal α7 nicotinic acetylcholine receptor activity. CONCLUSION: KYNA acts through an intestinal GPR35-vagus neural pathway to influence stroke recovery, highlighting this gut-brain signalling axis as a promising therapeutic avenue.