Evolution of the human gut microbiome and interplay with host genetics

Our group was the first to identify specific members of the human gut microbiome whose relative abundance in the gut microbiome is explained in part by the genotype of the host (so-called ‘heritable’ microbiota). Using gut microbiome data that we generated for >3000 fecal samples obtained from genotyped twins in the UK, we generated a list of gut microbes under host genetic influence (Goodrich, 2014). This list is not unique to UK twins: it has since been validated in similar studies of populations from various parts of the world (Goodrich, 2017). We now use this list to guide our studies: what is special about the heritable microbes? What is it about human genetic variation that they respond to? Are they more likely than non-heritable microbes to be passed between close relatives? Does their strain diversity map on patterns of human migration?

  • Suzuki TA, L Fitzstevens, VT Schmidt, H Enav, K Huus, M Mbong, BR Adegbite, JF Zinsou, M Esen, TP Velavan, AA Adegnika, L Huu Song, TD Spector, AL Muehlbauer, N Marchi, R Blekhman, L Segurel, ND Youngblut, P Kremsner, RE Ley. Codiversification of gut microbiota with humans. bioRxiv 2021.10.12.462973. (2021)
  • Suzuki T and Ley RE. The role of the microbiota in human genetic adaptation. Science 370 eaaz6827 (2020)Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT, Spector TD, Clark AG and Ley RE. Human genetics shape the gut microbiome. Cell 159: 789-799 (2014)
  • Goodrich JK, Davenport ER, Clark AG and Ley RE. The relationship between the human genome and microbiome comes into view. Annual Review of Genetics 51: 413-433 (2017)

 

We have identified aspects of human genetic variation that are associated with specific aspects of the microbiome (Goodrich, 2016). We have investigated further two that have functional consequences: (1) variation in the lactase LCT gene, which dictates lactose tolerance, and (2) salivary amylase AMY1 gene copy number, which dictates how readily starch is degraded in the mouth. How these are linked to the microbiome is described in Schmidt et al. (2020) and Poole et al. (2019). A conceptual view of how the microbiome interacts with the process of host genetic adaptation to new environments is provided in Suzuki and Ley (2020).

  • Goodrich JK, Davenport ER, Jackson MA, Beaumont M, Knight R, Spector TD, Bell JT, Clark AG and Ley RE. Genetic determinants of the gut microbiome assessed in UK Twins. Cell Host & Microbe 19: 731-43 (2016)
  • Schmidt V, Enav H, Spector T, Youngblut ND, and Ley RE. Strain-level analysis of Bifidobacterium spp. from gut microbiomes of adults of differing lactase persistence genotypes. mSystems 00911-20 (2020)
  • Poole AC, Goodrich JK, Youngblut ND, Luque GG, Ruaud A, Sutter JL, Waters JL, Shi Q, ElHadidi M, Johnson LM, Bar HY, Huson DH, Booth JG and Ley RE. Human salivary amylase gene copy number impacts oral and gut microbiomes. Cell Host & Microbe 25: 553-564 (2019)
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We take a broad view of the evolution of the human gut microbiome by placing it in the context of the vertebrate microbiome (Goodrich 2016). In a series of studies that survey the microbiome of wild animals, we have identified mammalian clades where bacteria and archaea show signs of having tracked with the diversification of their hosts (Youngblut 2019, 2020).

  • Goodrich JK, Davenport ER, Waters JL, Clark AG and Ley RE. Cross-species comparisons of host genetic associations with the microbiome. Science 352: 532-535 (2016)
  • Youngblut ND, Reischer GH, Walters W, Schuster N, Walzer C, Stalder G, Ley RE, Farnleitner AH. Host diet and evolutionary history explain different aspects of gut microbiome diversity among vertebrate clades. Nature Communications 10: 2200 (2019) 
  • Youngblut ND, de la Cuesta-Zuluaga J, Reischer GH, Dauser S, Schuster N, Walzer C, Stalder G, Farnleitner A, and RE Ley. Large scale metagenome assembly reveals novel animal-associated microbial genomes, biosynthetic gene clusters, and other genetic diversity. mSystems DOI: 10.1128/mSystems.01045-20 (2020)

 

Within the human gut microbiome, bacteria of the little-studied family Christensenellaceae are highly heritable. We showed that they are also, along with a suite of other microbiota, enriched in lean versus obese individuals, and could show causality in germfree mice (Goodrich, 2014). We are currently delving into the multi-part symbiosis of these bacteria and archaea (Ruaud 2020). Our aim is to elucidate how they interact with each other and with the host to impact phenotype.

  • Waters JL and Ley RE. The human gut bacteria Christensenellaceae are widespread, heritable, and associated with health. BMC Biology 17: 83 (2019)
  • Ruaud A, Esquivel-Elizondo S, de la Cuesta-Zuluaga J, Waters JL, Angenent LT, Youngblut ND and Ley RE. Syntrophy via interspecies H2 transfer between Christensenella and Methanobrevibacter underlies their global co-occurrence in the human gut. mBio 11 (1) e03235-19 (2020)