The aldehyde dehydrogenase 2 (ALDH2) gene variant rs671 (G>A; Glu487Lys), common in East Asian populations, is linked to metabolic disease susceptibility. However, its clinical effects vary across regions, suggesting that environmental factors, particularly the gut microbiota, may influence its impact. We aimed to investigate if gut microbial composition contributes to the metabolic differences associated with rs671.

We studied 562 adults from northeastern Taiwan, combining rs671 genotyping, full-length 16S rRNA-based gut microbiota profiling, and blood-based metabolic measurements. We examined associations between rs671, microbial taxa and metabolic traits and applied moderation analysis to assess whether gut microbial composition modified the genetic effects of rs671.

Prevotellaceae abundance showed a clear gene-dosage pattern, increasing with the number of rs671 “A” alleles, indicating a potential genetic influence on gut microbial composition. Higher levels of Prevotellaceae were positively associated with markers of insulin resistance, including the insulin-to-glucose ratio and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Moderation analysis revealed that Prevotellaceae abundance altered the effect of rs671 on the insulin-to-glucose ratio, suggesting that the variant’s impact on insulin-glucose balance is context-dependent on gut microbial composition.

Prevotellaceae may act as a context-dependent modifier of rs671’s metabolic effects, which could help explain regional variability in the clinical impact of this variant. These findings highlight the possibility that dietary interventions targeting Prevotellaceae may serve as a precision nutrition strategy for rs671 carriers to improve insulin sensitivity and reduce the risk of glucose dysregulation.