Gut Microbiota Responses to Isocaloric Macronutrient Modulation in Tissue-Specific Insulin Resistance: a secondary analysis of the PERSonalized glucose Optimization through Nutritional intervention (PERSON) randomized trial

BACKGROUND: Precision nutrition strategies can be effective in optimizing health outcomes. We previously showed that dietary macronutrient modulation targeting tissue-specific insulin resistance (IR) phenotypes induced pronounced improvements in cardiometabolic health. It remains unclear whether these improvements may partially be explained by gut microbiota-related mechanisms. OBJECTIVE: We investigated whether 12-week high-monounsaturated fatty acid (HMUFA) and low-fat, high-protein, high-fiber (LFHP) diets impact gut microbiota composition and functionality in people with predominant muscle (MIR) versus liver IR (LIR) in relation to cardiometabolic health improvements. METHODS: ), who followed either a 12-week isocaloric HMUFA or LFHP diet. A 7-point oral glucose tolerance test was performed to determine tissue-specific IR and cardiometabolic risk factors. Fecal microbiota composition was profiled using 16S rRNA amplicon sequencing (V3-V4 region), and GLP-1 and gut microbial products were determined in plasma and feces. RESULTS: The HMUFA diet induced significant shifts in overall gut microbial composition (p <0.05) and short-chain fatty acid-producing bacteria (q < 0.05) in the LIR phenotype, but not in MIR. The LFHP diet induced only modest changes in gut microbiota features. We found phenotype-specific correlations between specific baseline taxa abundance and change in metabolic outcomes (MIR-HMUFA: Barnesiela- ΔMISI (Spearman ρ = 0.45, p <0.001); LIR-HMUFA: Sutterella-Δplasma-CRP (Spearman ρ = 0.57, p = 0.0001) and a Rhodospirillales genus-ΔHOMA-IR (Spearman ρ = -0.58, p <0.001). CONCLUSION: Individuals with predominant LIR seem more prone to diet-induced gut microbiota-related improvements in cardiometabolic health than those with MIR, highlighting the importance of understanding heterogeneity in IR. Our findings support a role for the gut microbiota in precision nutrition targeting tissue-specific IR. CLINICALTRIALS: gov registration: This is a secondary analysis of the PERSonalized glucose Optimization through Nutritional intervention (PERSON) randomized trial. REGISTRATION NUMBER: NCT03708419, https://clinicaltrials.gov/study/NCT03708419.