{
  "abstract": "Background Depression frequently accompanies colorectal cancer (CRC) and worsens quality of life and outcomes, yet pathways translating peripheral tumour-derived metabolic cues into central affective dysfunction remain unclear. Enteroendocrine cells and vagal afferents provide a rapid gut–brain sensory route. We hypothesised that vagal afferent signalling is required to gate CRC-associated activation of the tryptophan–kynurenine (TRP–KYN) pathway into depressive-like behaviours.Methods CRC was induced in mice by syngeneic colon cancer cell implantation. Depressive-like behaviours were assessed using sucrose preference, forced swimming, and open field tests. Subdiaphragmatic vagotomy or pharmacological vagal blockade disrupted vagal afferent transmission. Plasma TRP, KYN, and KYN/TRP ratios were quantified by targeted liquid chromatography–mass spectrometry. Neuronal activation and neuroimmune markers were measured in the lateral habenula and prefrontal cortex.Results CRC-bearing mice developed pronounced anhedonia and behavioural despair, manifested by reduced sucrose preference and increased forced-swim immobility, while locomotor activity remained preserved. CRC robustly increased circulating KYN/TRP ratios. Disruption of vagal afferent signalling selectively restored sucrose preference, reduced immobility, and increased centre exploration in the open field, without normalising peripheral KYN/TRP, indicating that vagal transmission gates behavioural expression downstream of systemic metabolic perturbation. Vagal blockade markedly reduced c-Fos induction, Iba1/CD68-positive microglial activation, and Il1b and Tnf transcript expression within both regions. Tumour volume, body weight loss, and plasma CRP were not significantly altered by vagal manipulation, supporting a communication-specific mechanism. These effects were reproduced consistently across both surgical and pharmacological approaches to vagal disruption.Conclusions Vagal afferent transmission constitutes a critical neural conduit translating CRC-associated TRP–KYN metabolic disturbances into central affective dysfunction by regulating neuroimmune engagement within mood circuits. By defining a gut–vagus–brain gating mechanism, this pathway emerges as a mechanistically grounded target for preventing or treating CRC-associated depression and related gastrointestinal malignancies.",
  "authors": [
    {
      "affiliations": [
        "Shaanxi Provincial People’s Hospital, China"
      ],
      "name": "Yuming Zhang"
    },
    {
      "affiliations": [
        "Shaanxi Provincial People’s Hospital, China"
      ],
      "name": "Fei Xue"
    },
    {
      "affiliations": [
        "Shaanxi Provincial People’s Hospital, China"
      ],
      "name": "Qifan Huo"
    }
  ],
  "title": "IDDF2026-ABS-0028 Vagal afferent transmission of tryptophan–kynurenine signals drives colorectal cancer-associated depressive behaviours",
  "uid": "24cc6401-e935-514c-b5e8-13e22e14facd"
}