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. Objectives: We investigated whether 12-wk high monounsaturated fatty acid (HMUFA) and low-fat, high-protein, high-fiber diets (LFHP) impact gut microbiota composition and functionality in people with predominant muscle IR (MIR) compared with liver IR (LIR) in relation to cardiometabolic health improvements. Methods: This 2-center, randomized, double-blind, dietary intervention trial included 179 individuals with LIR or MIR [40-75 y, body mass index (in kg/m2) 25-40], who followed either a 12-wk 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 ribosomal ribonucleic acid 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: Barnesiella-?MISI (Spearman ? = 0.45, P < 0.001); LIR-HMUFA: Sutterella-?plasma-C-reactive protein (Spearman ? = 0.57, P = 0.0001) and a Rhodospirillales genus-?homeostasis model assessment of insulin resistance (Spearman ? = -0.58, P < 0.001). Conclusions: 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.