{
  "abstract": "Background Depression is a frequent and disabling comorbidity in colorectal cancer (CRC), yet how tumour-associated metabolic disturbances are converted into persistent central affective dysfunction remains unclear. Dysregulation of the tryptophan–kynurenine pathway has been implicated in both cancer biology and depression, but its downstream neural effectors in CRC are poorly defined. We hypothesised that CRC-induced kynurenine pathway activation drives depressive-like behaviours through microglial-mediated synaptic dysfunction.Methods CRC was induced in mice using syngeneic colon cancer cell implantation. Depressive-like behaviours were assessed using sucrose preference, forced swimming, and open field paradigms. Targeted liquid chromatography–mass spectrometry quantified tryptophan, kynurenine, and downstream kynurenine metabolites in plasma and brain tissue. Microglial activation and synaptic integrity were examined by immunohistochemistry and immunoblotting in the prefrontal cortex and lateral habenula. Pharmacological inhibition of key kynurenine pathway enzymes was applied to test causal involvement.Results CRC-bearing mice developed robust anhedonia and behavioural despair, characterised by reduced sucrose preference and increased forced-swim immobility, while locomotor activity remained intact. CRC selectively increased circulating kynurenine-to-tryptophan ratios and promoted accumulation of neuroactive kynurenine metabolites within the brain. These metabolic alterations were accompanied by pronounced microglial activation, elevated inflammatory signalling, and significant reductions in synaptic proteins, including PSD95 and synapsin, within emotion-related brain regions. Pharmacological inhibition of the kynurenine pathway selectively reversed anhedonia and behavioural despair, suppressed microglial activation, normalised synaptic marker expression, and reduced local inflammatory transcripts, without substantially affecting tumour burden or body weight. Together, these findings identify a microglia–synapse execution axis linking peripheral metabolic dysregulation to central affective impairment in CRC.Conclusions Dysregulated tryptophan–kynurenine metabolism mediates CRC-associated depressive behaviours through microglial activation and synaptic impairment within mood-regulating circuits. By defining a brain immune–synaptic execution pathway downstream of tumour-associated metabolic signals, this work highlights kynurenine pathway enzymes as mechanistically grounded and potentially targetable nodes for treating depression in colorectal cancer and related gastrointestinal malignancies characterised by chronic metabolic inflammation.",
  "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": "Jing Zhao"
    }
  ],
  "title": "IDDF2026-ABS-0029 Microglial and synaptic mechanisms linking tryptophan–kynurenine metabolism to depression in colorectal cancer",
  "uid": "25e03abc-0cc1-5ae2-a03b-ac6cdec94686"
}