Investigating The Impact Of Host Genetic Variation On The Human Gut Microbiota Using Twin Pairs

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The composition of the human gut microbiome differs markedly among individuals, and is increasingly viewed as a risk factor in chronic diseases such as obesity, inflammatory bowel disease, and diabetes. The gut microbiome is a target for emerging therapies, but their development requires a deeper understanding of the factors shaping the microbiome, including host lifestyle, physiology, and health.!The influence of host genetics on the gut microbiome, and how host genetics interacts with the microbiome to alter disease risk, remain mostly unknown. To gauge the impact of human genetic variation on the composition of the gut microbiota, we used fecal 16S rRNA gene sequencing to characterize the gut microbiota of 2,731 participants of the United Kingdom Adult Twin Registry (TwinsUK), including 489 dizygotic (DZ) and 637 monozygotic (MZ) twin pairs. Comparisons between MZ and DZ twin pairs allowed us to estimate the effect of genotype and early shared environment on the gut microbiota. We found that components of the gut microbiota, particularly Firmicutes, are clearly heritable. ! Our results revealed that the most heritable taxon, the bacterial family Christensenellaceae, forms a co-occurrence consortium with other heritable taxa including methanogenic Archaea. Interestingly, the Christensenellaceae consortium is significantly enriched in individuals with low body mass index. We ! supplemented a fecal sample from an obese individual with Christensenella minuta, a cultured member of the Christensenellaceae family, and transplanted this sample into germ-free mice. C. minuta supplementation reduced weight gain and altered the microbiota of recipient mice. Together these findings indicate that host genetics modulate components of the gut microbiome that have a direct effect on body weight. Finally, we used available genotype data to test for associations between host genetic variation and gut microbiota composition. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism and olfaction. We also replicated a previously reported association between the abundance of the genus Bifidobacterium and genetic variants within the LCT gene region, which is linked to lactase persistence. Our findings indicate that while an individual's microbiota composition is largely influenced by environmental factors, host genetics plays an appreciable role for specific taxa.

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Ley,Ruth E.

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Mezey,Jason G.

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Ph. D., Genetics

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Doctor of Philosophy

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