Obesity, diabetes, and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota.
In a recent study conducted in mice and published in the journal Cell Metabolism, a team of researchers from the Joslin Diabetes Centers have identified a strategy in which the host’s genes interact with microbial genes to create diseases such as obesity and diabetes, according to the study lead author C. Ronald Kahn, M.D., Chief Academic Officer at Joslin Diabetes Center and Mary K. Iacocca Professor of Medicine at Harvard Medical School.
The team discovered that one strain of mice with genetic risk of obesity became resistant to excess weight gain after their populations of gut microbiota were changed by sharing an environment with other mice. They were also able to determine that specific bacterial strains play a positive or negative role in the development of obesity, diabetes, or related metabolic disorders, which is partly dependent on the genetics of the host animal.
“Our hope is that if we can identify causal bacteria in these animal models, then we can look in humans for bacteria that serve the same kinds of function,” said Dr. Kahn in a recent news release. “The goal ultimately would be to get a cocktail of purified microbes that is optimized for treatment of humans with obesity or diabetes–kind of a designer probiotic.”
The researchers were able to characterize interactions between host genetics, diet, and the gut microbiota by conducting longitudinal analyses of the responses of three commonly used inbred strains of mice to long-term environmental conditioning as well as to shorter-term dietary challenges
For the experiments, researchers used one mouse model prone to obesity, one prone to diabetes and one resistant to both diseases, all of which originally held very different populations of microbes in their guts. The mice were then presented with high-fat diet and observed alterations in the microbial populations. During the study period, the researchers noticed that these microbial populations became more similar in all the mice and their descendants.
“However, when you change the microbes it has different effects on different mice, depending on the mouse’s genetic background,” Kahn said. “Some animals, and presumably some people, will have much more metabolic syndrome with certain microbes than other animals.”
The team then bred new generations of models, derived from the three mice models and examined if mice that were germ free who were given microbial populations from these three mice strains were likely to develop obesity and diabetes as their donors. After the microbes transfer, some mice that were resistant to diabetes gained weight and had higher levels of glucose. In other animals, “even metabolically bad bacteria didn’t cause a bad problem,” Dr. Kahn said. “They were only a problem if the animal had the genetic susceptibility to let those bacteria grow and cause their effect.”
According to Dr. Kahn, the DNA sequencing used in this research is able to identify nearly 3,000 bacteria in the mouse gut. Of these, about 300 are fairly abundant. Sequencing is a method that can quantify how populations of specific bacterial strains vary under given experimental conditions, so researchers can search for connections with disorders in the mice. Most of the studies in this field of knowledge examine the roles of groups of bacteria instead of individual bacteria strains. However, the team identified that specific bacteria strains correlate with diseases including obesity and high levels of blood glucose. These results indicate that these strains help to cause those conditions.
The researchers will continue their work and give germ-free mice some of these individual bacterial strains to observe if they change the sensitivity to insulin and other metabolic parameters. They are also aiming to examine the results of changing microbiota populations in different manners, including giving antibiotics to the mice. According to the researchers, these interactions between diet, genetics, and the microbiota present a great challenge in any analysis of both preclinical models and human disease.
Transplanting microbiota from donors with distinct phenotypes and microbial communities into mice representing different genetic backgrounds can be used to help establish a causal relationship between microbes and host biology, and also identify interactions between host genetic background and the microbiota.
The researchers suggested that developing strategies to manipulate the microbiota that drive specific components of the metabolic syndrome, especially those components that interact with a permissive host genetic background, may open the door to new strategies for effective and more durable ways of treating disease and ultimately preventing it.
