Social living allows genetic effects to spread through the gut microbiome

Your "roommate's" genes could be influencing the bacteria living in your gut, and vice versa, according to a study of rats published today in Nature Communications. 

The research, carried out by studying more than four thousand animals, reveals that the composition of the rat gut microbiome is shaped not only by an individual's own genes but also by the genes of the individuals they share a living space with. 

The discovery reveals a new way genes and social life intertwine: through the exchange of commensal gut microbes that move between individuals. Though genes don't jump between individuals, microbes can. The study found some genes favour certain gut bacteria and these can spread through close social contact. 

"This is not magic, but rather the result of genetic influences spilling over to others through social contact. Genes shape the gut microbiome and we found that it is not just our own genes that matter," explains Dr. Amelie Baud, researcher at the Centre for Genomic Regulation in Barcelona and senior author of the study. 

Three new gene-microbe links in rats 

The gut microbiome is the collection of trillions of microorganisms which live in the digestive tract, where they play key roles in digestion and overall health. While diet and medication are known to be among the main factors influencing these microbial ecosystems, the contribution of genetics has been more difficult to ascertain. 

In humans, only two genes have been reliably linked to gut bacteria. The lactase gene determines whether adults can digest milk and influences milk-digesting microbes. The ABO blood group gene also has an effect through yet-to-be discovered mechanisms. 

More gene microbe links could exist but are yet to be confirmed because nature and nurture are tricky to separate in the real world. For example, genes can influence diet and lifestyle choices, which in turn affect the gut microbiome. But families and friends share food, homes and microbes, blurring the line between nature vs. nurture's contribution to the gut microbiome. 

Instead, researchers at the Centre for Genomic Regulation and the University of California San Diego turned to rats. The animals share many features of mammalian biology, but can be raised in controlled conditions, such as giving everyone the same diet. 

All animals were genetically unique and coming from one of four different cohorts, each housed in a different facility in the United States and with different care routines, allowing the researchers to test which genetic effects held up across different environments. 

By combining genetic and microbiome data from all 4,000 rats, the team identified three genetic regions that consistently influenced gut bacteria despite differences in rearing conditions across the four cohorts. 

The strongest link was between the gene St6galnac1, which adds sugar molecules to the gut's mucus, and the abundance of Paraprevotella, a bacterium the researchers believe feeds off these sugars. It was found in all four cohorts. 

A second region contained several mucin genes, which make up the gut's protective mucous layer and were linked to bacteria from the Firmicutes group. The third region included the Pip gene encoding an anti-bacterial molecule, and was linked to bacteria in the Muribaculaceae family, common in rodents and also found in humans. 

Genes have social lives 

The large size of the cohort allowed researchers, for the first time, to estimate how much of each rat's microbiome was explained by its own genes and how much by the genes of the other rats it lives with. 

Classic examples of this phenomenon, also known as indirect genetic effects, are when a mother's genes shape her offspring's growth or immune system through the environment she provides. 

The controlled conditions of the rat study allowed researchers to study these effects in a completely new way. The authors of the study built a computational model to separate genetic effects on a rat's own microbes from the effects of its social partners. 

They found that the abundance of some Muribaculaceae were shaped by both direct and indirect genetic influence, meaning that some genetic effects spread socially through microbial exchange. 

Once these social, or indirect, effects were included in a statistical model, the total genetic influence increased by four to eight times for the three new gene-microbe links discovered. The researchers say this may represent only a fraction of the true picture. 

"We've probably only uncovered the tip of the iceberg," says Dr. Baud. "These are the bacteria where the signal is strongest, but many more microbes could be affected once we have better microbiome profiling methods." 

By demonstrating that genetic influences can be coupled with gut microbe transmission, the authors of the study paint a new mechanism of action whereby the genetic effects of one individual can ripple through entire social groups, altering the biology of others without changing their DNA. 

If similar effects occur in humans, and given increasing evidence that the gut microbiome plays an important role in health, it could mean that genetic influences on human health have been underestimated in large studies. Genes may shape not only an individual's disease risk, but also the disease risk of others. 

What the study means for human health 

According to Dr. Baud, the microbiome has been linked to everything from immunity and metabolism to behaviour, but not all the reported correlations reflect causal effects and the exact mechanisms of action remain elusive. Genetic studies like hers, which use animal models in controlled environments, can help move from correlations to testable causal hypotheses, helping explain how genes and the gut microbiome interact in human health. 

For example, the researchers note that the gene they discovered in rats, St6galnac1, is functionally related to the human gene ST6GAL1 which, in other studies, has also been linked to Paraprevotella. It suggests the way animals coat their gut mucous with sugars can determine which microbes are able to thrive in the digestive system, and that this could be a shared biological mechanism across species. 

The authors of the study also hypothesise how this possible mechanism could, in turn, influence infectious diseases like COVID-19. 

ST6GAL1 has been previously linked in other studies to breakthrough SARS-CoV-2 infections, cases where people catch COVID despite vaccination. It has also been demonstrated that Paraprevotella induces the degradation of the digestive enzymes that are used by the virus to enter the host's cells, so the researchers hypothesise that genetic variants in ST6GAL1 could influence Paraprevotella abundance and, in turn, viral infection. 

They also hypothesise why some people develop an autoimmune kidney disease called IgA nephropathy. Paraprevotella could alter IgA, an antibody that protects the gut but that, when altered, can leak into the bloodstream and form clumps that damage the kidneys, the hallmark of IgA nephropathy. 

The researchers now plan to investigate in detail how St6galnac1 influences Paraprevotella in rats, and what biological chain reactions this triggers in the gut and the whole body. 

"I am obsessed with this bacterium now. Our results are supported by data from four independent facilities, which means we can do follow up studies in any new setting. They're also remarkably strong compared with most host–microbiome links. It's a unique opportunity," concludes Dr. Baud.