Colitis-associated gut–vagus–brain signaling integrates tumorigenesis and neuroinflammation: comparative regulation by vagotomy and atropine

Colitis-associated cancer (CAC) is frequently accompanied by neuropsychiatric comorbidities, yet the underlying gut-brain signaling pathways remain elusive. Emerging evidence highlights the gut-brain axis, particularly the vagus nerve, as a pivotal mediator linking gastrointestinal pathology with neuropsychiatric dysfunction. This study aimed to dissect the dual roles of vagal signaling in a murine CAC model and to evaluate the therapeutic potential of the muscarinic antagonist atropine on CAC. The azoxymethane/dextran sulfate sodium (AOM/DSS) was adopted to induce CAC mice model. We employed unilateral vagotomy and pharmacological intervention with atropine, a muscarinic antagonist, in CAC mice. We assessed colon tumorigenesis, intestinal inflammation, anxiety/depression-like behaviors, and neuroinflammation of CAC mice under vagotomy and atropine treatment. Vagotomy and retrograde viral tracing were used to verify the essential role of vagus nerve signaling in activating neurons in brain regions linked to inflammation-induced depression and anxiety, thereby clarifying the gut-neuro-brain circuit mechanism. The findings revealed that CAC progression was associated with depression- and anxiety-like behaviors. Vagotomy significantly alleviated these behaviors, reduced c-fos expression in the NTS and lateral habenula/ midbrain-hindbrain boundary (LHb/MHb), and retrograde tracing confirmed a functional gut–NTS–LHb/MHb circuit activated by intestinal inflammation. Moreover, vagotomy improved CAC-induced behavioral deficits by reducing GFAP expression, alleviating neuroinflammation, though it failed to inhibit tumor growth or intestinal inflammation. In contrast, atropine treatment not only improved behavioral deficits but also reduced tumor number, downregulated cholinergic signaling and tumor markers, suppressed intestinal pro-inflammatory cytokines, and markedly ameliorated depression- and anxiety-like behaviors. These findings demonstrate the vagus nerve as a key gut-brain pathway linking CAC to depression and anxiety. Vagotomy disrupts inflammation-driven signaling, whereas atropine preserves anti-inflammatory vagal activity, positioning it as a promising therapeutic strategy for CAC-related anxiety and depression.