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-ΔMISI (Spearman ρ = 0.45, P < 0.001); LIR-HMUFA: Sutterella-Δplasma-C-reactive protein (Spearman ρ = 0.57, P = 0.0001) and a Rhodospirillales genus-Δhomeostasis model assessment of insulin resistance (Spearman ρ = ‒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.