High-fat diet, triglyceride glucose index, and gastrointestinal cancer: integrative insights from human and animal studies

Background: High-fat diet (HFD) exposure has been associated with an increased risk of gastrointestinal (GI) cancers; however, the metabolic and inflammatory mechanisms underlying this association remain incompletely understood. Identifying clinically accessible biomarkers that capture diet-induced metabolic stress may improve early risk stratification and prevention strategies. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES, 2003-2020) and the Global Burden of Disease (GBD) 2021 dataset. HFD-related metabolic exposure was characterized using eight lipid-related obesity indices, including body mass index (BMI), waist-to-height ratio (WHtR), lipid accumulation product (LAP), visceral adiposity index (VAI), triglyceride-glucose index (TyG), TyG-WHtR, waist circumference (WC), and TyG-BMI. Threshold effects of TyG were evaluated, and mediation analyses were performed to assess the roles of the systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR). Complementary animal experiments were conducted to examine changes in TyG levels, gastrointestinal histopathology, and serum carbohydrate antigen 19-9 (CA19-9). Results: Elevated TyG levels were significantly associated with increased GI cancer risk. A nonlinear relationship was identified, with a threshold effect at TyG = 9.657; below this threshold, the association exhibited a dose-dependent pattern. Mediation analyses indicated that SII and NLR partially mediated the TyG-GI cancer association, accounting for 1.6 and 2.8% of the total effect, respectively. Stratified analyses revealed significant heterogeneity across demographic subgroups. In animal models, HFD exposure resulted in elevated TyG levels, gastrointestinal mucosal injury, and increased tumor-associated biomarkers, consistent with the development of precancerous lesions. Conclusion: The findings identify the TyG index as a practical and biologically relevant marker linking HFD-induced metabolic dysregulation to GI cancer risk, with systemic inflammation serving as a partial mediator. The integration of population-based analyses with experimental evidence underscores the potential utility of TyG in metabolic risk assessment and precision prevention strategies for GI cancers.