The microbes that inhabit the human body are viewed as an integral component of our biology, and microbiome variability has been found to result in differences in disease predisposition. The proposed research will develop and apply methods to infer how variation in the human genome mediates composition and function of the gut microbiome. To achieve this objective, we will pursue four specific aims in an analysis of genome-wide SNP genotype data already available from the TwinsUK project to identify genetic determinants of microbiome composition.
For Specific Aim 1, we will use whole- genome sequence data of the twins along with deep metagenomic sequencing of their gut microbiomes to infer heritability and gene-specific associations with a) greater resolution taxonomic data, and b) metabolic attributes of the bacterial community. These data are already in hand, and provide unique opportunities to dissect the means by which variation in the human genome mediates gut microbiome properties.
For Specific Aim 2, we will infer individual strains in the gut microbiomes from the metagenomics data, making use of the fact that our sequencing depth is sufficient to identify clonal haplotypes of the most common ~50 bacterial species. The biological impacts of specific strains can vary widely, and this strain-specific analysis is likely to be highly informative by improving specificity and accuracy of associations between host genes and microbiome composition.
For Specific Aim 3, we will resample 1000 individuals from the original TwinsUK microbiome survey, and use this information to identify attributes of the gut microbiome that are stable over time, and to test the relationship between heritability and stability of microbes in the microbiome.
For Specific Aim 4, we will use the gnotobiotic mouse experimental system to dissect the effects of the heritable bacterium Christensenella minuta on gut function as well has whole-organism physiology. The results of this research will be used to establish links between regions of the human genome and composition of the microbiome. The results of this study have the potential to reveal fundamental human host-microbe interactions that may be applicable to the prevention and treatment of chronic inflammatory diseases.

Public Health Relevance

Analysis of bacterial 16S sequences and human SNP genotypes provides clear evidence that components of the human gut microbiome are heritable and are impacted by variation in the human genome. Many compelling and biologically richer questions can be answered with whole genome data and metagenomics sequences, including heritability of bacterial consortia, metabolic pathways, relative growth rates, and transmission of bacterial strains within and among twins. Results obtained from the proposed research will bridge this knowledge gap, and will ultimately be used to improve the lifestyles of individuals suffering from common diseases such as obesity and diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Karp, Robert W
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Cornell University
Schools of Arts and Sciences
United States
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Menni, Cristina; Lin, Chihung; Cecelja, Marina et al. (2018) Gut microbial diversity is associated with lower arterial stiffness in women. Eur Heart J 39:2390-2397
Verdi, Serena; Jackson, Matthew A; Beaumont, Michelle et al. (2018) An Investigation Into Physical Frailty as a Link Between the Gut Microbiome and Cognitive Health. Front Aging Neurosci 10:398
Jackson, Matthew A; Verdi, Serena; Maxan, Maria-Emanuela et al. (2018) Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun 9:2655
Goodrich, Julia K; Davenport, Emily R; Clark, Andrew G et al. (2017) The Relationship Between the Human Genome and Microbiome Comes into View. Annu Rev Genet 51:413-433
Menni, Cristina; Zierer, Jonas; Pallister, Tess et al. (2017) Omega-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Sci Rep 7:11079
Menni, C; Jackson, M A; Pallister, T et al. (2017) Gut microbiome diversity and high-fibre intake are related to lower long-term weight gain. Int J Obes (Lond) 41:1099-1105
Pallister, Tess; Jackson, Matthew A; Martin, Tiphaine C et al. (2017) Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome. Sci Rep 7:13670
Davenport, Emily R; Goodrich, Julia K; Bell, Jordana T et al. (2016) ABO antigen and secretor statuses are not associated with gut microbiota composition in 1,500 twins. BMC Genomics 17:941
Jackson, Matthew A; Jackson, Matt; Jeffery, Ian B et al. (2016) Signatures of early frailty in the gut microbiota. Genome Med 8:8
Jackson, Matthew A; Goodrich, Julia K; Maxan, Maria-Emanuela et al. (2016) Proton pump inhibitors alter the composition of the gut microbiota. Gut 65:749-56

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