Potential Modulatory Roles of Gut Microbiota and Metabolites in the Associations of Macronutrient‐to‐Physical Activity Ratios With Dyslipidemia

Background Lifestyle factors toward diet and physical activity (PA) may directly influence the pathophysiology of dyslipidemia. However, the associations of the specific macronutrient‐to‐PA ratio with dyslipidemia, and the underlying mechanisms regarding gut microbiota and metabolites, remain largely unexplored. Methods Dietary and PA information from 273 participants with or at risk of metabolic syndrome was collected via a food frequency questionnaire and the International Physical Activity Questionnaire. Gut microbial genera and fecal metabolites were profiled through 16S rRNA sequencing and untargeted LC–MS metabolomics, respectively. Machine‐learning algorithms were applied to identify gut microbiome features of macronutrient‐to‐PA ratios and to construct microbiome risk score. Results Higher macronutrient‐to‐PA ratios, especially for high saturated fatty acid intake, were associated with increased risks of dyslipidemia, with adjusted odds ratio (95% CIs) of 2.87 (1.41–5.99) for hypercholesteremia, 2.21 (1.11–4.48) for hypertriglyceridemia, and 2.52 (1.26–5.16) for high low‐density lipoprotein cholesterol. Microbiome risk scores were significantly associated with elevated levels of total cholesterol, triglycerides, and low‐density lipoprotein cholesterol. Additionally, for each macronutrient‐to‐PA ratio, a core group of gut microbial genera were identified (eg, Phocaeicola , Lachnoclostridium , Limosilactobacillus , and Tyzzerella ), exhibiting positive associations with lipid disorders and superior discrimination capacities for hypercholesterolemia, hypertriglyceridemia, and high low‐density lipoprotein cholesterol. Furthermore, we identified 9 metabolites (eg, acetyl phosphate, glycerol, and pyruvic acid), predominantly enriched in dyslipidemia‐related pathways and associated with both core gut microbial taxa and macronutrient‐to‐PA ratios. Conclusions This study identified varied associations between macronutrient‐to‐PA ratios and dyslipidemia and depicted the potential modulatory roles of gut microbiota and fecal metabolites.