Understanding the microbiome’s role in diabetes

By Lindzi Wessel

Scientists have long suspected diabetes and the gut microbiome are linked. But the confounding impact of diabetes treatment on the microbiome has posed major challenges to studying the connection in people — until now.

It makes sense that type 2 diabetes might be linked to changes in the gut microbiome, the teeming mess of microscopic lifeforms that inhabit our digestive systems helping to process our meals and modulate our immune systems. The metabolic disorder, which leaves high levels of sugar circulating in the blood, is strongly connected to lifestyle factors, including diet. Though scientists have been amassing evidence supporting the theory of microbiome involvement, capturing this connection in humans has been challenging, in large part because treatments for diabetes, themselves, can alter the microbiome. That means when patients participate in clinical studies, it’s hard to tease out which changes are a result of the disease rather than an effect of intervention.

Recently, though, an international team of researchers, including members of MIT’s Center for Microbiome Informatics and Therapeutics (CMIT), have presented the first study to examine how diabetes affects the microbiome in a large group of high-risk patients who had never before received treatment. The unique study, published in Frontiers in Endocrinology in January,  provides a much clearer picture of how the microbiome might be affected in diabetes and sets the groundwork for future research into new potential interventions.

“Though this wasn’t the first study to be done in this area, it was, in many ways, a definitive study because it got rid of those cofounders,” says Eric Alm, Co-Director of CMIT, Professor of Biological Engineering at MIT, and one of the paper’s senior authors. “Now we have a solid starting point.”

The toll of diabetes

Type 2 diabetes, the failure of the body both to produce enough of the hormone insulin and to use it properly, is a serious disease of increasing prevalence around the world. Insulin allows cells to take up glucose from the bloodstream and employ it as a source of energy. When this process goes awry, the resulting high blood sugar and other complications can lead to a range of health issues, including vision problems, slow wound healing, cardiovascular disease, and stroke. Worldwide, diabetes was the ninth leading cause of death in 2019 and in some countries its impact is even more startling.

“Diabetes always falls somewhere between the first and the third leading cause of death in Mexico,” says Rodolfo Guardado-Mendoza, a physician and researcher specializing in endocrinology and diabetes at the University of Guanajuato and at the Regional High Specialty Hospital of  Bajío in Mexico and another senior author of the recent study. “It’s a very, very important disease here.”

Guardado-Mendoza has long been interested in how to stop progression of diabetes once at-risk patients are identified. In “pre-diabetes,” circulating glucose levels are high, but still lower than the threshold for type 2 diabetes. As the disease progresses, high levels of blood sugar overwhelm beta cells of the pancreas that secrete the insulin needed to process that sugar. With more and more demand for insulin, the beta cells can’t keep up and sometimes become “exhausted” to the point where they stop responding to blood sugar or even die. Most pre-diabetics aren’t aware of their condition, says Guardado-Mendoza, and by the time they come to see a physician like him, they’re probably experiencing full-blown diabetes and have already lost the majority of their pancreatic beta cells.

A special kind of cohort

Determined to learn more about interrupting the advancement of the disease, Guardado-Mendoza went about looking for study participants who had never been diagnosed with diabetes but were at risk or unknowingly had the disease. Not only, he realized, would this help him study the point of disease progression which most interested him, but assembling such a group would also allow him to avoid common pitfalls in other diabetes studies in humans.

To deal with the complications of their disease, diabetics often implement dietary and lifestyle changes, take antibiotics when wounds heal too slowly and use medications that cut down blood sugar levels. All these factors are known to change the gut microbiome, creating a huge challenge for researchers trying to understand how type 2 diabetes affects it — it becomes impossible to say which changes are related to the disease and which are simply linked to the medications or other treatments being used. This knowledge gap limits researchers’ ability to explore how an individual’s microbiome might impact their diabetes risk or likelihood of responding to treatment. To get around such problems, Guardado-Mendoza would need to put together a study group who had never received treatment.

To do this, he offered a gold standard assessment to employees of the University of Guanajuato who were willing to consider being research participants. At first, he said, recruitment went slowly, but once word of the research started getting around, the lab was inundated with interest from people within and outside the university who were concerned about their health and wanting to know their diabetes status.

“As soon as more people started to notice and hear about what we were doing in our lab, they started to arrive by themselves asking for the evaluation,” he says.

The first solid evidence

So far, the effort is paying off. In their publication detailing the study, Guardado-Mendoza, Alm and their colleagues reported four kinds of bacteria that marked the progression of type 2 diabetes and were linked to markers of inflammation often seen alongside the disease.

Two of the bacteria types identified, Blautia and Anaerostipes are involved in the production of butyrate, a short-chain fatty acid that provides an important energy source for some cells of the gut and is thought to reduce inflammation. Looking across study participants, the team found that risk for diabetes and the advancement of the disease steadily increased alongside a decline in levels of these two kinds of bacteria. In contrast, two other bacteria types—Escherichia and Veillonella—increased as those measures got worse, indicating a possible role of the microbes in disease progression.

“You can really see that there’s a gradation in abundance of these bacteria that varies in step with clinical measures like how many risk factors a patient has for type 2 diabetes,” says Alm. “That to me is really convincing. It’s exciting to see.”

Since publishing the January study, the team has continued to work with the Guanajuato cohort, studying how tailored lifestyle and drug-treatment interventions might help patients mitigate their diabetes risk. Already the team has seen positive clinical outcomes in preliminary research and is working to characterize how the microbiome might have changed alongside those effects.

“The dream, ultimately, is to be able to stop the progression from pre-diabetes to diabetic and also to stop the progression from normal to pre-diabetic so we can ultimately prevent type 2 diabetes entirely,” says Guardado-Mendoza. “It seems more and more likely that the microbiome will be an important part of that.”