Abstract Introduction Lung cancer remains the leading cause of cancer-related mortality worldwide. Recent studies implicate the gut microbiome as a systemic modulator of immunity and cancer progression. Given prior links between dietary fiber to immune modulation, this study investigates the gut-lung axis, focusing on low-fiber diet-mediated lung tumorigenesis. We explore mechanisms involving myeloid-derived suppressor cells (MDSCs) and dysregulated metabolites. Methods Using the inducible KrasLSL-G12D; Trp53flox/flox; Msh2flox/flox (KPM) lung adenocarcinoma model, lung tumorigenesis was induced via intranasal Adeno-Cre. Mice were fed one of two precisely formulated, isocaloric, and isobulking diets: a Low-Fiber diet (containing 8% non-fermentable cellulose, 0% soluble inulin) and a High-Fiber diet (containing 8% non-fermentable cellulose and 15% soluble inulin). Diets were administered prophylactically or therapeutically. Microbiome dependence was assessed using broad-spectrum antibiotics treatment. Lung tumor burden was quantified by digital histopathology, while immune profiling, plasma metabolomics, and systemic cytokine analyses characterized diet-related changes. Anti-Gr1 MDSC depletion was assessed to explore immunological effects on tumor growth. Results Low-fiber diet significantly increased lung tumor burden and reduced survival in both early and established disease settings. Antibiotic-mediated microbiome depletion mitigated tumor progression, demonstrating microbiota involvement. Immune profiling revealed marked expansion of lung MDSCs (CD11b+Gr1+) and monocytes (CD11b+Ly6C+CX3CR1+) in low-fiber-fed mice, alongside elevated systemic IL-6, IL-17A, and TNF-α levels. Adaptive immunity showed increased pro-inflammatory Th17 and γδT17 cells, with minimal changes in Th1 and Treg populations. Metabolomic analysis identified elevated plasma serine and fructose associated with tumor-promoting inflammation and immunosuppression. MDSCs depletion reduced lung tumor burden and enhanced CD8+ cytotoxic T-cell activity (CD107a) (Figure 1). Conclusion This study unveils a novel immunometabolic axis linking a low-fiber diet to gut microbiota-mediated lung tumorigenesis through MDSCs expansion and metabolite dysregulation. Targeting dietary patterns and gut microbiota composition may offer preventative strategies for lung cancer, especially in high-risk populations. Results further suggest potential avenues for improving immune checkpoint inhibitor responsiveness through metabolic interventions. This abstract is funded by: R37
Mccormick et al. (Fri,) studied this question.