Composition and Functions of the Gut Microbiome in Pediatric Obesity: Relationships with Markers of Insulin Resistance.

Camila E Orsso,Ye Peng,Jens Walter,Andrea M Haqq,Hein M Tun,Edward C Deehan,Catherine J Field,Qiming Tan,Karen L Madsen,Carla M Prado

doi:10.3390/microorganisms9071490

Abstract

The gut microbiome is hypothesized to play a crucial role in the development of obesity and insulin resistance (IR); the pathways linking the microbiome to IR in pediatrics have yet to be precisely characterized. We aimed to determine the relationship between the gut microbiome composition and metabolic functions and IR in children with obesity. In a cross-sectional study, fecal samples from children with obesity (10–16 years old) were collected for taxonomical and functional analysis of the fecal microbiome using shotgun metagenomics. The homeostatic model assessment for insulin resistance (HOMA-IR) was determined using fasting glucose and insulin. Associations between HOMA-IR and α-diversity measures as well as metabolic pathways were evaluated using Spearman correlations; relationships between HOMA-IR and β-diversity were assessed by permutational multivariate analysis of variance. Twenty-one children (nine males; median: age = 12.0 years; BMI z-score = 2.9; HOMA-IR = 3.6) completed the study. HOMA-IR was significantly associated with measures of α-diversity but not with β-diversity. Children with higher HOMA-IR exhibited lower overall species richness, Firmicutes species richness, and overall Proteobacteria species Shannon diversity. Furthermore, HOMA-IR was inversely correlated with the abundance of pathways related to the biosynthesis of lipopolysaccharides, amino acids, and short-chain fatty acids, whereas positive correlations between HOMA-IR and the peptidoglycan biosynthesis pathways were observed. In conclusion, insulin resistance was associated with decreased microbial α-diversity measures and abundance of genes related to the metabolic pathways. Our study provides a framework for understanding the microbial alterations in pediatric obesity.

Highlights

Childhood obesity is commonly associated with an impaired metabolic profile characterized by insulin resistance, dyslipidemia, and low-grade inflammation [1,2,3,4,5]
We identified 18 pathways related to either metabolic or biological functions of the gut microbiome to be significantly associated with homeostatic model assessment for insulin resistance (HOMA-insulin resistance (IR)) (Figure 3 and Figure S3)
We report for the first time that children with higher homeostasis model assessment (HOMA)-IR levels had lower species richness and Proteobacteria species Shannon diversity, independent of age

Summary

Introduction

Childhood obesity is commonly associated with an impaired metabolic profile characterized by insulin resistance, dyslipidemia, and low-grade inflammation [1,2,3,4,5]. Insulin resistance is a risk factor for youth-onset type 2 diabetes mellitus (T2DM) and cardiovascular diseases [6]. Several mechanisms have been proposed to explain the pathogenesis of insulin resistance in the pediatric population, including an unfavorable lipid partitioning. Microorganisms 2021, 9, 1490 profile [7], early age of puberty onset [8], a family history of T2DM [9], and less healthy lifestyle choices, including suboptimal dietary intake and low physical activity [10,11]. Several studies have attempted to define cut-off values for insulin resistance (ranged from 2.5 to 4.0), there is a lack of consensus on the optimal value that should be applied across all pediatric populations [14,15,16,17,18,19]

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Discussion

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