Gut Microbiome study at the Interface of Genetics and Environment
Publish Date: 2016-12-23

December 21, 2016, Shenzhen, China—Researchers from BGI, King’s College London, Macau University of Science and Technology and other institutions reported the first cohort of shot-gun sequenced data for the gut microbiome in twins. In this study, fecal samples from 250 adult twins in the TwinsUK registry were sequenced, leading to an updated gut microbial reference gene catalog. The researchers nailed down the importance of host genetics and environment on the composition, SNPs, and metabolism of the gut microbiome. The latest finding was published in Cell Systems.

Gut microbiota is known to be important in human health and disease. Its composition is shaped by environmental and host factors. Twins, who share nearly 100%(identical twins) or 50%(fraternal twins) of their genes, provide a powerful and broader way to look for an effect of human genetic variation on their microbiomes. Additionally, co-twins are raised together and share a household, so the environmental effects on their microbiome are more facilitative to analyze. 

In this study, researchers performed metagenomic shotgun-sequencing on 250 fecal samples from 35 monozygotic (MZ) and 92 dizygotic (DZ) female twin pairs from the TwinsUK registry. They identified 5,901,478 non-redundant genes and merged this gene set with a high-quality reference catalog of 9,879,896 gut microbial genes, leading to an updated reference catalog contained 11,446,577 genes with a saturated mapping ratio. By using this comprehensive gene catalog, the researchers could compare similarities and differences between MZ and DZ twin pairs to estimate the importance of genetic and environmental influences in a wide range of biological levels such as more accurate gut microbial taxa and more complex metabolism pathway.

Living in geographically and culturally distinct settings would lead to diverse patterns of the gut communities. The twin pairs were clustered to four main regions(geo-clusters) across UK by their longitude and latitude. The researchers conducted comparison of gut microbiome between twin sisters in the same or different geo-clusters. Pairs living in different region are more different than pairs living in the same region.

To investigate a host genetic component’s contribution to composition of gut microbiome, the researchers constructed the ACE model to estimate heritability of 109 genera, 143 mOTUs and 5,118 KOs presented in this cohort. A number of important taxa and functions of the gut microbiome are clearly heritable. Furthermore, the researchers demonstrated the associated with the gut microbiota implicated in complex diseases. The type 2 diabetes(T2D) associated MLGs and butyrate biosynthesis pathways, which have been identified in previous study, have been surveyed and many of them are partly influenced by host genetics.

The nucleotide variation in a set of reference genome can provide a higher resolution and a further information of species variation of gut microbiome.
A non- redundant reference genome set, which include 152 gut microbial species, have been generated. Based on this set, the researchers captured total ~8 million single-nucleotide polymorphisms(SNPs), and defined a SNP similarity score to measure the extent of sequence variation in microbial genomes. They compared twins siblings and found that the similarity score for gut microbial SNPs was significantly higher between twins than between unpaired samples and slightly higher between MZ than DZ pairs. For the normal weight-related bacterium, A. muciniphila showed decreased SNP similarity in the obese group compared to the overweight group.

“This is the first cohort of twins surveyed by metagenomic shotgun sequencing so far”, Ruijin Guo, a Researcher from BGI, one of the co-first authors of this article, said “Previous researches linked both genetic variation and composition of gut microbes to metabolic disease were mainly based on 16S rRNA gene amplicon sequencing in twins. Compared to metagenomic shotgun sequencing, 16S rRNA gene amplicon sequencing lacks taxonomic resolution and functional information, limiting the insight. Our results demonstrated a widespread concordance in the composition, SNPs, and functional capacity of the gut microbiome between twins and specifically an increased concordance among MZ twins over DZ twins, quantified heritability of many microbial taxa and functional modules in the gut microbiome, and identified heritable markers previously associated with type 2 diabetes (T2D), rheumatoid arthritis, and colorectal cancer.”

“This study paves the way for further studies on the host genetic underpinnings of the human gut microbiome and suggests that microbiome-based therapeutics, such as probiotics or fecal transplants, should target non-inherited components of the gut microbiome or be aided by genetic screens of the patients.” Dr. Huijue Jia, the corresponding author of this paper and project leader of BGI said in a statement.


Further Reading:

Shotgun Metagenomics of 250 Adult Twins Reveals Genetic and Environmental Impacts on the Gut Microbiome