{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Wen Zhang"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Shengnan Chen"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Xiaoqi Huang"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Jie Li"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Siqi Yang"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Yisi Liu"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Peibo Yuan"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Jiaxuan Wang"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Yonghui Guo"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Zhuang Li"
    },
    {
      "affiliations": [
        "Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China"
      ],
      "name": "Jia Yin"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Shenzhen Key Laboratory of Gastrointestinal Microbiota and Disease, Department of Gastroenterology and Department of Neurology, Shenzhen Hospital, Southern Medical University, Shenzhen, China",
        "State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen University, Shenzhen, China"
      ],
      "name": "Hongwei Zhou"
    },
    {
      "affiliations": [
        "Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China",
        "Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China"
      ],
      "name": "Kaiyu Xu"
    }
  ],
  "title": "Kynurenic acid mitigates poststroke brain damage through the gut-brain neural circuit",
  "uid": "58078721-e6ca-5507-ab50-c90dec64b093"
}