One of the structural variations detected in Anaerostipes hadrus, which is deleted in ~40% of the population (top), and associated with higher disease risk. Genes in this region (bottom) code a composite inositol catabolism - butyrate production pathway, potentially supplying the microbe with additional energy while supplying the host with butyrate, previously shown to have positive metabolic and anti-inflammatory effects. (Credit: Korem lab)

Our gut microbiome has been linked to everything from obesity and diabetes to heart disease and even neurological disorders and cancer. In recent years, researchers have been sorting through the multiple bacterial species that populate the microbiome, asking which of them can be implicated in specific disorders. But a paper recently published in Nature addressed a new question: "What if the same microbe is different in different people?" The study was co-led by Dr. Tal Korem , assistant professor of systems biology and core faculty member in the Program for Mathematical Genomics at Columbia University Irving Medical Center . 

It has been long known that the genomes of microbes are not fixed from birth, as ours are. They are able to lose some of their genes, exchange genes with other microorganisms, or gain new ones from their environment. Thus, a detailed comparison of the genomes of seemingly identical bacteria will reveal sequences of DNA that occur in one genome and not others, or possibly sequences that appear just once in one and several times over in others. These differences are called structural variants. Structural variants - even tiny ones - can translate into huge differences in the ways that microbes interact with their human hosts. A variant might be the difference between a benign presence and a pathogenic one, or it could give bacteria resistance to antibiotics.

Drs. Korem and David Zeevi, initially in the lab of Dr. Eran Segal in the Weizmann Institute of Science and then in their present positions at Columbia University's Department of Systems Biology and Rockefeller University, developed algorithms that systematically identify structural variants across human gut microbiomes. The researchers began with microbiomes from nearly 900 Israeli subjects, in which they succeeded in identifying over 7,000 variants. Next, they formed a collaboration with Dutch researchers from the University of Groningen, in the Netherlands, and they looked for these variants in the microbiomes of a large group of Dutch subjects. Most of the structural variants they had identified in the Israeli subjects could also be found among the Dutch ones, despite the differences in genetics and lifestyle between the groups.

The scientists next asked whether any of the structural variants they had identified are associated with health or disease. The group turned up more than 100 that were associated with risk factors for disease. Many of these associations were again replicated in the Dutch cohort.

In one case, individuals who had a certain variant present in the genome of a particular microbial species in their microbiome were 13 lbs. thinner and had a 1.5-in. narrower waist, on average, than individuals who had the same microbe - but one that did not harbor that particular variant. The scientists then analyzed the genes encoded on this variant and found that it gives the bacterium the potential ability to turn certain sugars into a substance called butyrate. Butyrate is a small, odorous fatty acid; despite its odor, butyrate has been shown to have anti-inflammatory effects and a positive influence on metabolism. This ability, say the scientists, could help explain the weight difference between those carrying bacteria with and those without the structural variant.

The finding suggests the method the group developed could help researchers pinpoint the connections between our microbiome, health and disease in significant ways that might be missed with other means. "The real potential of this approach," says Dr. Zeevi, "is that it allows us to look for the actual mechanisms behind the associations we find."

Segal estimates there may be tens of thousands of structural variants within the human gut microbiome and thousands of these could be associated with disease and disease risk. Since the makeup of the microbiome has been implicated in so many different syndromes and disorders, this research could have a lasting impact on the search for better, more targeted probiotics for treating disease.

“An exciting next step would be to study the consequences of these variations in the context of the metabolic potential and activity of the entire microbial ecosystem," says Dr. Korem.

Dr. Korem joined Columbia's Department of Systems Biology in the fall of 2019. Working at the intersection between computational biology and medicine, the Korem lab both develops algorithms and computational methods that aim to understand microbial growth, activity and metabolic production, as well as apply these methodologies as the basis for clinical inquiries in diverse settings, with a special focus on reproductive sciences. Dr. Korem also is a faculty member of Columbia's Department of Obstetrics and Gynecology.

"Structural variation in the gut microbiome associates with host help" was published March 27, 2019, in Nature. 

Press release: Weizmann Institute of Science