| Summary: | Abstract Background The prevalence of dyslipidemia has increased in recent years; however, it remains a modifiable condition through diet and gut microbiome modulation. Yet, evidence from population-based studies remains limited. This study aimed to investigate the relationships among a low-carbohydrate diet (LCD), macronutrient intake, and the gut microbiome, and to evaluate their interaction effects on dyslipidemia in a Korean population. Methods Data were drawn from two population-based studies: the Korean Microbiome Study (KMS) and the Korea National Health and Nutrition Examination Survey (KNHANES). We included 2,178 participants aged 20–80 years from the KMS (2017–2019) and 12,938 participants from the KNHANES (2017–2019). The LCD score and percentage of energy intake from macronutrients were calculated using either a food frequency questionnaire or a 24-hour dietary recall. Dyslipidemia was assessed based on fasting blood tests. Gut microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene in the KMS. Multivariate logistic regression models including interaction terms were used to evaluate the joint effects of diet and the gut microbiome on dyslipidemia. Results A higher LCD score was associated with lower odds of atherogenic dyslipidemia and low high–density lipoprotein (HDL) cholesterolemia in both studies. Although both studies showed a positive trend for fat intake and a negative trend for carbohydrate intake in relation to hypercholesterolemia, the level of significance differed slightly. We identified 38 microbial genera associated with LCD score and macronutrient intake. Notably, fat intake showed beneficial associations with triglyceride and HDL cholesterol levels in individuals carrying Bifidobacterium (p for interaction = 0.0017) and Lachnospiraceae UCG–004 (p for interaction = 0.0482), respectively. In contrast, low carbohydrate intake was associated with increased odds of hypercholesterolemia in individuals harboring Lachnoclostridium (odds ratio: 3.79; 95% confidence interval: 2.01–7.17; p for interaction < 0.0001). No significant associations were observed in individuals lacking these genera. Similar interaction effects were observed at the amplicon sequence variant level for Bifidobacterium and Lachnospiraceae UCG–004. Conclusions These findings provide population-based evidence for the interactive role of fat and carbohydrate intake with gut microbiota in influencing dyslipidemia among Koreans.
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