Gut Microbiota Influences Sleep Deprivation-Induced Colorectal Cancer Progression

BACKGROUND: Sleep deprivation (SD) is common among cancer patients and a known disruptor of immune regulation and microbiota balance. We hypothesize that SD-induced bacterial dysbiosis promotes carcinogenesis and reduces 5-Fluorouracil (5-FU) efficacy by creating an immunosuppressive tumor-microenvironment (TME). METHODS: Chronic SD and fecal microbiota transplant (FMT, 5*107 CFU single oral gavage) mouse models were used to evaluate murine colorectal cancer using MC38 cancer cells. Tumor growth and 5-FU response were assessed. TME immune cell infiltration, tumor gene expression of circadian rhythm (CR) genes, inflammatory, and immune markers were compared between SD and controls. RESULTS: Chronic SD exposure increased PER2, CRY1, CRY2 and decreased BMAL1 CR gene expression compared to non-SD mice. Chronic SD mice experienced a significant increase in tumor volume (endpoint mean 734 mm3 SD vs 476 mm3 non-SD, p=0.0002), remodeled TME via a significant increase in Ly6G+ Neutrophils (0.0366) and CD19+ B cells (0.0163). This was associated with a decrease in TNFα, IL1β and IL17A gene expression. FMT from SD mice to recipient non-SD mice conferred greater MC38 tumor volume (endpoint mean 1086 mm3 SD vs 618 mm3 non-SD, p=0.0092) and a pro-inflammatory TME via increase in IL6+ producing Ly6G+ Neutrophils and IL-6 mRNA accumulation in the tumor (p < 0.0001). Interestingly, SD mice exhibited larger tumor volumes (endpoint mean 2241 mm3 SD vs 1033 mm3 non-SD, p=0.0059), and fewer cytotoxic and effector immune cells and markers following 5-FU treatment. Gene expression analysis revealed altered IL17a (p=0.0195), IL6 (p<0.0001), IFNγ (p=0.0366), and CD27 (p=0.0228) mRNA accumulation. FMT from SD donor mice to recipient non-SD mice exhibited impaired 5-FU response as seen with higher tumor volume (endpoint mean 1055 mm3 SD vs 630 mm3 non-SD, p=0.0033), decreased infiltration of CD4 and CD8+ T cells in the TME along with decreased gene expression of TNFα (p= 0.0296) and IL6 (p=0.0485) in the tumor. CONCLUSION: Chronic SD promotes carcinogenesis, disrupts circadian rhythm regulation, and weakens chemotherapy efficacy through microbiota-driven immune dysregulation. These findings identify SD as a modifiable factor influencing cancer outcomes and highlight the gut microbiota as an important mediator of this pathology. Citation Format: Maria Carolina Hernandez, Ye Yang, Christian Jobin. The gut microbiota influences chronic sleep deprivation-induced colorectal cancer progression and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4082.