Genomics: Insight

With evidence between the loss of key bacteria such as H. Pylori in our gut microbiota and the increasing rates for allergic disorders, we only grow more curious about the universe hidden beneath our skin. The exploration of mankind’s next frontier calls us to dive into our own bodies--the human gut microbiome--with ever-growing evidence linking this former black box to our health and well-being.

What is the Gut Microbiome?
Beyond the millions of cells that make up who we are, we are hosts to 100 trillion microbial cells (Whiteman et al., 1998) that are composed of archaea, eukaryotic microbes and bacteria while also playing host to a quadrillion viruses in and on our bodies (Haynes and Rohwer et al., 2011). Collectively, these microorganisms play crucial roles in our health and disease by influencing metabolic functions, protecting against pathogens and developing our immune system. The integral impact these organisms have on our biosystems is why our microbiome is sometimes referred to as our “forgotten organ” (O’Hara and Shananhan).

Much like the pathologies which can cause harm upon other bodily organs, imbalance and harm to our gut microbiota has also been linked to a variety of disorders such as allergies, inflammatory bowel syndrome (IBS), obesity and even autism. There is no single bacteria in our gut that is responsible for each of these diseases as the vast array of microbiota perform a complex balancing act that remains in constant flux. The loss of this balance is directly detrimental to our overall well-being and is another viewing glass through which to learn about disease of the human body.

There have been large initiatives and studies that pushed to characterize the gut microbiota such as the HMP (Human Microbiome Project) and MetaHIT (Metagenomics of the Human Intestinal Tract). Our understanding of a healthy gut microbiome’s composition has become proficient due to the sequencing of a shared universal piece of DNA in bacteria--16S rRNA--which was identified through whole genome shotgun sequencing (wgs). Shotgun sequencing breaks down target pieces of genetic info--in this case, 16S rRNA--into smaller pieces from which information regarding cell function can be excised. Then, these small snippets of genetic info are stitched back together to recreate the original 16S rRNA strand and being fully mapped. However, despite this progress, we have yet to find an answer: do environmental factors or host genetics play a more influential role on the composition of the microbiome?

Why use 16S rRNA sequencing for understanding the microbiome?
Since the microbiome is composed of bacteria, sequencing 16S rRNA genetic information is the golden standard for a genetic marker to study bacterial phylogeny and taxonomy.
This method is the standard for 3 reasons: (i) almost all bacteria have the genetic marker for 16S rRNA; (ii) the function of the 16S rRNA multigene family has not changed over years of evolution; and (iii) the 16S rRNA gene (1,500 bp) is large enough for bioinformatics research.

The Heat of the Debate
Fecal samples from newborns demonstrate that during the early stages of development, their prenatal environment is given priority over host genetics in determining the makeup of the newborn microbiome. When we are born, the initial communities of microbiota can be more skin-like (as seen in cases of birth by caesarean) or vaginal-like (due to vaginal birth) and slowly converge to a more adult-like state with the presence of anaerobic bacteria. As we grow, our microbiota become increasingly diverse and our immune system learns which bacteria are pathogenic and which are important for the host. After two years outside the prenatal environment, unique microbiomes begin to flourish and the prioritization of influence between host genetics or environmental factors becomes unclear.

A paper written by Benson et al., 2010 focused on using a large mouse intercross model in order to create controllable environmental factors and thereby, determine the role of host genetics in the composition of the microbiome. Using quantitative trait loci (QTL) analysis, they were able to ‘test whether specific taxa co-segregate as quantitative traits with linked genomic markers.’ As a result, they found that gut microbiota composition for the mouse can be viewed as a complex polygenic trait and is influenced by both host genetics and environmental factors. In order to break down the genetic information of gut microbiota composition, measurable groups of different genera of bacteria were formed. These measurable groups that were found are shared across if not most animals, all animals and account for most of the genetic information found in the microbiome. As such, this research group deemed these groups as core measurable microbiota (CMM) which is influenced by both environmental factors and host genetics. Using CMM as a tool to understand microbiome composition,they saw consistency of influence from host genetic factors that control microbiome composition. However, they were only able to state that there is an influence without being able to discern whether host genetics was a dominating factor over environmental factors.

Turnbaugh et al., 2009 conducted a study on obese and lean monozygotic (MZ) and dizygotic (DZ) twins to find answers our question as well. Twins are uniquely important because they are raised in a similar environment while being genetically different. With regards to their gut microbiome, MZ twins would have a more similar microbiome than DZ twins due to the preservation of hertible taxa of bacteria. This study of ~50 pairs of twins reported that MZ twin pairs had slightly more similar microbiomes than DZ twins, though this finding was not statistically significant. When Goodrich et al., 2014 completed a similar study but with a larger cohort of 416 for twins, they found the difference between MZ and DZ twins’ microbiome composition to be statistically significant for heritable taxa of bacteria.

Goodrich et al., 2016 followed up on the previous studies and focused on 1,126 twin pairs from the TwinsUK cohort. They found that genetic microbiome heritability was lower than other phenotypes such as systolic blood pressure, but the heritable taxa are temporally stable over long periods, which could be attributed to bacterial evolution towards specific host genotypes, thus giving significance to host genetics in microbiome composition. This hypothesis is supported by the presence of the Heliobacter pylori being associated with certain host genotypes (Suerbaum and Josenhans et al., 2007).
 

Environment Dominates over Host Genetics for the Human Gut Microbiota

As the debate continued, a paper by Rothschild et al., 2018 delivered a confident answer to this ongoing question by using biostatistics and applying a statistical model against multiple large cohorts. To start, they studied a cohort of 1,046 healthy Israeli individuals and found no significant association between ancestry and microbiome composition, while sharing a relatively homogenous environment (thereby ruling out the influence of the environment). Rothschild et al, 2018 then applied this same methodology to the TwinsUK cohort and estimated that genetic microbiome heritability lies between 1.9% and 8.1%. This finding would mean that at most, only 8.1% of the microbiome composition would be determined by host genetic factors. They also demonstrated that in addition to a lack of association to genetic ancestry, there is also a lack of association to any one, unique, genetic makeup or individual Single Nucleotide Polymorphisms (SNPs). All these results allowed the researchers to conclude that environmental factors are dominant in determining the composition of the gut microbiota.

Going further, Rothschild et al., 2018 demonstrated that host genetic information can be used additively with microbiome data to possibly predict host phenotypes such as levels of high-density lipoprotein cholesterol. This key finding gives importance to our individual lifestyle and the need for awareness of antibiotic use and nutrition as our microbiome is connected to our well-being more than we know.