Guardian genes may protect against diabetes by shaping gut flora

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Gut microbiome

Around 300 to 500 species of microbial flora inhabit the gut of humans, mice and even insects, and are comprehensively known as the intestinal microbiome. These denizens of the gut are vital for numerous physiological processes such as digestion and interestingly, regulation of their host’s immune response.

Not only does this complex symbiotic community in the intestinal microbiome compete against invading germs, it also modulates autoimmune disorders such as type I diabetes and multiple sclerosis. An autoimmune disease develops when our immune system, which defends our body against disease, decides that our healthy cells are foreign and mounts a misdirected attack on one’s own healthy cells.

Past studies on mice have shown that for some autoimmune disorders, supplementing the gut biota with a particular species of bacteria significantly ameliorates the autoimmune response. Similar research on intestinal flora has dissected individual bacterial species, and their effect on the immune cells or intestinal gene expression of the host system.

However, the question regarding the mechanism by which these bacteria exert their effects on the host’s autoimmune responses remained unanswered.

Gut bacteria can alter the protective effects of a gene that wards off type 1 diabetes

Scientists at the Harvard Medical School have studied a promising link between the gut microbiome and type I diabetes, via a complex of proteins that is displayed on the surface of host cells. These proteins are the human leukocyte antigen or HLA (in humans) and major histocompatibility complex or MHC (in mice).

Gene variants of the HLA/MHC complexes are known guardians of the body’s organ systems against certain autoimmune diseases like type I diabetes. The current research, published in the Proceedings of the National Academy of Sciences, showed how the immune modulating effects of the HLA/MHC complexes in diabetes are shaped by the gut microbiome.

The experiments were performed on diabetes-prone mice, which also carried the protective variants of the MHC protein complex. The results of these experiments showed that in the absence of the gut microbiota, the MHC genes could not guard against type I diabetes-related autoimmune response.

The scientists also studied the importance of proper development of the gut flora in the intestines of mice progeny which possessed the guardian genes. Young mice raised in sterile cages, or treated with antibiotics during the first six weeks of development, developed symptoms of type I diabetes despite carrying the protective genes. Later treatments with antibiotics did not have the same drastic effect on diabetes onset.

The scientists pointed out that a sterile environment during early stages of growth prevents exposure to foreign microbes, and therefore interfered with both establishment of a balanced gut microbiome, and proper development of the acquired immune system in young mice.

“We believe that our results not only offer a clue into a longstanding mystery but also raise the possibility that substances or environmental influences that alter the intestinal balance can modulate the effects of a powerfully protective gene and shape disease risk,” said Diane Mathis, who led the study together with Christophe Benoist, both professors in the Department of Microbiology and Immunobiology at Harvard Medical School.

Interestingly, mice that got their protective genes from the father eventually developed diabetes. On the other hand, genes inherited from the mother exerted a synergistic effect along with maternal gut microbiota to protect against diabetes. If the mothers were treated with antibiotics in the week before birth, their progeny developed diabetes despite inheriting the guardian genes.

In another set of experiments, the researchers worked on diabetes-prone mice without the protective genes, and transplanted fecal matter from mice that carried the guardian gene. The diabetes-prone mice exhibited reduced autoimmune responses and were guarded against diabetes.

These results highlight the role of the gut microbial community in shaping a balanced immune response in the host. It also shows that there might be an interplay between host proteins and gut flora, and that this cross-talk shapes the composition of intestinal microbes in the individual.

Further research is required, to extend the results of these experiments to human systems and autoimmune disorders. Mapping the bacterial species that specifically cross-talk with the host system via precise protein interactions could further explain the complex mechanism by which the gut microbiome balances our immune response.

“Our findings need to be borne out in further experiments,” Mathis said. “However, our results powerfully illustrate the notion that early antibiotic exposure can modulate disease risk and that avoiding or at least minimizing antibiotic treatment in infants and pregnant women during critical periods of development may be a good idea.”

Source: Harvard Medical School