Responsiveness of cardiometabolic-related microbiota to diet is influenced by host genetics - PubMed (original) (raw)

Annalouise O'Connor et al. Mamm Genome. 2014 Dec.

Abstract

Intestinal microbial community structure is driven by host genetics in addition to environmental factors such as diet. In comparison with environmental influences, the effect of host genetics on intestinal microbiota, and how host-driven differences alter host metabolism is unclear. Additionally, the interaction between host genetics and diet, and the impact on the intestinal microbiome and possible down-stream effect on host metabolism is not fully understood, but represents another aspects of inter-individual variation in disease risk. The objectives of this study were to investigate how diet and genetic background shape microbial communities, and how these diet- and genetic-driven microbial differences relate to cardiometabolic phenotypes. To determine these effects, we used the 8 progenitor strains of the collaborative cross/diversity outbred mapping panels (C57BL/6J, A/J, NOD/ShiLtJ, NZO/HILtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ, and 129S1/SvImJ). 16s rRNA profiling of enteric microbial communities in addition to the assessment of phenotypes central to cardiometabolic health was conducted under baseline nutritional conditions and in response to diets varying in atherogenic nutrient (fat, cholesterol, cholic acid) composition. These studies revealed strain-driven differences in enteric microbial communities which were retained with dietary intervention. Diet-strain interactions were seen for a core group of cardiometabolic-related microbial taxa. In conclusion, these studies highlight diet and genetically regulated cardiometabolic-related microbial taxa. Furthermore, we demonstrate the progenitor model is useful for nutrigenomic-based studies and screens seeking to investigate the interaction between genetic background and the phenotypic and microbial response to diet.

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Figures

Fig. 1

Fig. 1

Cardiometabolic phenotypes between inbred mouse strains fed a synthetic diet. Inbred mouse strains were purchased from Jackson Laboratories at ~6 weeks, and placed on purified synthetic diet (AIN-93). After 2 weeks, animals were weight, body composition assessed by MRI and fasting plasma samples collected. Differences in bodyweight (a), and body composition by MRI are depicted as percentage fat mass (b), percentage of lean mass (c). Fasting plasma levels of cholesterol (d), triglycerides (e) and TMAO (f) were quantitated. Measures of insulin sensitivity were assessed and included plasma glucose (g), insulin (h) and calculated HOMA-IR (i). _p_-value for ANOVA <0.05 for all phenotypes. Significant between-strain differences identified with Tukey’s HSD post hoc test. Strains not sharing letter are significantly different (p < 0.05)

Fig. 2

Fig. 2

Atherogenic diets induce strain-dependent differences in cardiometabolic phenotypes. Following 16 weeks on either a high-fat cholic acid (HFCA; open bars) diet or low-fat cholesterol-containing diet without cholic acid (LFCC; shaded bars). Differences in Bodyweight (a), and body composition by MRI are depicted as percentage fat mass (b), percentage of lean mass (c). Fasting plasma levels of cholesterol (d), triglycerides (e) and TMAO (f) were quantitated. Measures of insulin sensitivity were assessed and included plasma glucose (g), insulin (h) and calculated HOMA-IR (i). Significant within-strain differences between diet groups assessed by independent t-tests. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Fig. 3

Fig. 3

Global regulation of intestinal microbiome communities by genetic background in mice fed a purified synthetic diet. (a) Principle coordinates analysis (PCoA) of unweighted uniFrac. (b) Principle component 1 of unweighted UniFrac. (c) Phyla level relative abundance data. (d) Linear discriminant analysis with effect size (LEfSe) identified differentially abundant taxa between mouse strains. Taxa enriched in A/J (yellow), C57Bl6/J (gray), 129S1/SvlmJ (pink), NOD/ShiLtJ (dark blue), NZO/HiLtJ (light blue), CAST/EiJ (green), PWK/PhJ (red), and WSB/EiJ (purple) meeting LDA significant threshold >2 are shown

Fig. 4

Fig. 4

Global diet and strain-driven regulation of microbial beta-diversity. PCoA of Unweighted UniFrac of: (a) HFCA samples only; (b) LFCC samples only; (c) HFCA and LFCC samples combined; and, (d) HFCA, LFCC and AIN93M samples faceted by strain; (e) Linear discriminant analysis with Effect Size (LEfSe) identified differentially abundant taxa between HFCA and LFCC diet groups. Taxa enriched in HFCA diet (gray) and those enriched in LFCC diet (red) meeting LDA significant threshold >2 are shown. Taxa enriched in LF versus HFCA diet have a negative LDA score

Fig. 5

Fig. 5

Significant relationships between microbial taxa and cardiometabolic phenotypes exist in mice fed purified synthetic diets (baseline) and atherogenic diets for 16 weeks (post diet). Correlations between taxa and phenotype assessed by Spearman rho. Asterisks denotes significant relationship (p values adjusted FDR 10 %)

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