Circadian and gut-brain axis modulation is associated with neuroimmune and symptom recovery after rectal cancer surgery: An exploratory randomized controlled trial.

BACKGROUND

Disruption of circadian and neuroimmune regulation after rectal cancer surgery contributes to psychological distress, inflammation, and impaired recovery. This exploratory randomized controlled trial evaluated whether a perioperative multicomponent behavioral program targeting circadian and gut-brain processes was associated with improvements in neuroimmune profiles and symptom outcomes.

METHODS

A total of 184 patients with stage I-III low rectal cancer undergoing ultra-low anterior resection were randomized to receive either standard ERAS care or an integrative perioperative intervention that combined emotion-regulation strategies (mindfulness-based stress reduction, heart-rate-variability biofeedback, neurofeedback) with structured sleep and circadian therapy (cognitive behavioral therapy for insomnia, controlled-release melatonin, circadian scheduling). Co-primary outcomes were depressive symptoms (Beck Depression Inventory-II) and sleep quality (Pittsburgh Sleep Quality Index) at 6 months. Secondary outcomes included inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α), gastrointestinal recovery indices, and skeletal muscle index (SMI). Disease-free and overall survival were examined as pre-specified exploratory endpoints.

RESULTS

Compared with standard care, the integrative intervention was associated with greater 6-month improvements in depressive symptoms and sleep quality (both p < 0.01), lower postoperative inflammation (e.g., POD7 interleukin-6: 39.7 vs 52.3 pg/mL; p < 0.001), and faster gastrointestinal recovery. Preservation of SMI at 12 months was associated with improved disease-free survival (hazard ratio 0.51, 95 % CI 0.29-0.92; p = 0.027). Two-year disease-free survival showed an exploratory signal favoring the intervention (89.7 % vs 74.0 %; hazard ratio 0.46, 95 % CI 0.23-0.93), although survival analyses were not powered for definitive inference.

CONCLUSIONS

Perioperative modulation of circadian and gut-brain processes was associated with improvements in depressive symptoms, sleep quality, postoperative inflammatory profiles, and functional recovery. Survival findings represent preliminary exploratory signals and require confirmation in larger, adequately powered randomized trials.