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Human genetic variation and the gut microbiome in disease

Nature Reviews Genetics volume 18, pages 690699 (2017) | Download Citation


Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

Key points

  • Host genetics shape the composition of the gut microbiome in concert with environmental factors such as diet and lifestyle.

  • Certain host genetic variants predispose an individual towards microbiome dysbiosis, which is an important factor in diseases of metabolism and immunity.

  • A subset of species in the gut microbiome are heritable, especially representatives from the phyla Firmicutes and Verrucomicrobia.

  • Variants in single genes (for example, LCT, NOD2 and FUT2) affect the composition of the gut microbiome.

  • Microbiome genome-wide association studies hold promise for the identification of additional host genetic variants that affect disease progression by perturbing the composition of the microbiome.

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A.B.H. is supported by a Helen Hay Whitney Postdoctoral Fellowship. R.J.X. is supported by the Crohn's and Colitis Foundation and NIH grants U54DE023798, R01DK92405 and P30DK43351.

Author information


  1. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.

    • Andrew Brantley Hall
    • , Andrew C. Tolonen
    •  & Ramnik J. Xavier
  2. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Andrew Brantley Hall
    •  & Ramnik J. Xavier
  3. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Ramnik J. Xavier
  4. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • Ramnik J. Xavier


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All authors contributed equally to all aspects of this article.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Andrew Brantley Hall or Ramnik J. Xavier.



The totality of microorganisms (for example, bacteria, fungi and viruses) in a defined environment, such as the human gut. The term microbiome can refer either to the microbial organisms that reside in an environmental niche or specifically to their collective genomes.

Bacterial species

Bacterial organisms with 16S rDNA genes that share greater than 97% identity. However, due to horizontal transfer and high variability in their genomes, bacterial species often differ dramatically in functional potential.

Classic twin studies

A study design used to estimate the importance of genetic versus environmental influences on complex trait variation. The estimate of heritability is based on a comparison of resemblance in monozygotic twins (who share all segregating genetic material) and dizygotic twins (who share, on average, half of their segregating genetic material).


Individual and context-specific taxonomic and functional changes to the composition of the microbiome that result in a disease state.

Genome-wide association studies

(GWAS). Studies in which statistical associations between genetic variants and a disease or trait of interest are identified by genotyping individuals with disease and healthy controls for a set of SNPs that capture variation across the entire genome.


A term used to describe techniques that characterize the genomes of whole communities of organisms rather than individual species.

Human Microbiome Project

An interdisciplinary project funded by the US National Institutes of Health with the aim of generating resources that enable the comprehensive characterization of the human microbiome and the analysis of its role in human health and disease.

Effect sizes

The contributions of loci or alleles to phenotypic variance in a trait.

β diversity

A reflection of the variability in microbial communities between different environments. By contrast, α diversity represents the number of taxa within one microbial environment.

Genetic variance

The variance of trait values that can be ascribed to genetic differences among individuals. The total genetic variance in a trait can be separated into additive, dominance and other components; in populations, these components depend on the frequencies of the alleles at loci affecting the trait.


A non-viable substrate that is selectively utilized by host microorganisms conferring a health benefit


The proportion of variance of a trait attributed to host genetics rather than environmental effects. In the context of this Review, heritability predominantly refers to the proportion of variance in the abundance of a microbial taxon attributed to host genetic effects rather than environmental effects.

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