Multimodal brain-gut-sleep phenotypes predict delirium, long-term cognitive decline, and survival after colorectal cancer surgery.

BACKGROUND

Neuroimmune, circadian, autonomic, and gut-brain processes jointly shape vulnerability to postoperative delirium and long-term cognitive decline, yet their integrated contribution remains unclear.

METHODS

In this prospective cohort (n = 300), preoperative assessments included circadian actigraphy, gut microbial diversity and short-chain fatty acids, inflammatory cytokines (IL-6, CRP), nocturnal heart rate variability, sleep-wake characteristics, and psychological symptoms. Unsupervised clustering identified multimodal phenotypes. Outcomes included postoperative delirium, 36-month cognitive, fatigue, and sleep trajectories, and 3-year survival. Analyses used mixed-effects models, Cox regression, and gradient boosting.

RESULTS

Four biobehaviorally coherent phenotypes emerged. Delirium incidence increased from 4.7 % in Phenotype A to 21.6 % in Phenotype D. Cognitive decline over 36 months followed the same gradient, with Phenotypes C-D showing progressive deterioration. Fatigue and sleep recovery displayed parallel phenotype-dependent stratification. Three-year disease-free survival ranged from 86.7 % (A) to 69.3 % (D), and overall survival from 91.2 % to 78.8 %. Relative to the resilient reference phenotype (A), phenotypes characterized by convergent multidomain dysregulation were independently associated with worse survival (HR 2.11 for DFS; HR 1.96 for OS). Machine-learning models ranked circadian amplitude, microbial diversity, SCFA concentrations, IL-6, and nocturnal heart rate variability as dominant contributors.

CONCLUSIONS

Multimodal brain-gut-sleep phenotypes strongly predict delirium, long-term cognition, and survival after colorectal cancer surgery. These findings support a systems-based model in which perioperative resilience reflects coordinated regulation of circadian, microbial, autonomic, inflammatory, and psychological pathways.