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Immunology

Clues about the origin of type 1 diabetes

Changes in intestinal microbiota may be associated with onset of the disease

Intestinal mucosal barrier perforated by bacteria, leading to destruction of insulin-producing pancreas cells

CDC

Researchers from the Federal Universities of Minas Gerais (UFMG) and São Paulo (USP) studying animal models have identified a sequence of organic changes in intestinal bacteria (microbiota) that can trigger type 1 diabetes, characterized by the destruction of insulin-producing cells in the pancreas by other cells in the body.

According to the study, published in the Journal of Leukocyte Biology in July, production of antimicrobial substances and antibodies that protect the intestinal membrane is very low in a special strain of mice that spontaneously develops diabetes and is used to study how the disease progresses in humans. Due to the weakness of these natural barriers, the bacteria living in the intestine and the toxins they produce are able to cross the membrane and enter the lymph nodes, which connect the pancreas and the first section of the intestine. In the lymph nodes, the microorganisms and toxins activate a group of white cells known as T lymphocytes.

“The movement of bacteria from the intestine to the lymph nodes precipitates inflammatory processes that may only occur later,” says immunologist Ana Maria Caetano Faria, from UFMG’s Institute of Biomedical Sciences, who led the study. In the lymph nodes, a white blood cell surface protein known as NOD2 responds to the bacteria and toxins and the body’s inflammatory response by activating T lymphocytes, as described by a team at USP’s Ribeirão Preto Medical School (FMRP-USP) in an article published in the Journal of Experimental Medicine in 2016.

The T lymphocytes then move to the pancreas, where, unable to distinguish between the body’s natural microorganisms and those produced by the disease, they destroy the insulin-producing beta cells.

Most common in the first two decades of life, type 1 diabetes affects some 1.1 million people in Brazil and is treated with insulin replacement therapy. Type 2 diabetes, where insulin is produced by the body but not used, is the most common type of the disease, at about 90% of diagnosed cases, affecting 11 million people in Brazil. Certain people are genetically predisposed to type 1 diabetes, but less than 10% of them go on to actually develop the disease. Environmental factors, such as diet, exposure to infectious agents, and changes in the composition of the intestinal microbiota are also associated with the disease. “Genetic predisposition is not the only contributing factor and does not explain everything. There are cases of twins who develop the disease at different stages in life,” says Faria.

The non-obese diabetic (NOD) mice used in the research began to develop the disease when they were four weeks old, shortly after weaning. “We identified inflammatory processes in the intestine before the first clinical sign of diabetes (elevated blood glucose), which normally occurs at about 20 weeks of age,” reports Faria. According to her, this strain of mice produces few antibodies, especially immunoglobulin type A (IgA), and little intestinal mucus, an antimicrobial gel that forms part of the intestinal mucosal barrier.

At UFMG, the tests conducted by biologist Mariana Miranda found that production of interleukin 10 (IL-10) was reduced in the intestines of mice before and during the development of diabetes. IL-10 is an anti-inflammatory cytokine that helps to regulate the defense system in the intestinal mucosal barrier. Low levels of IL-10 result in increased inflammation and greater migration of cells through the intestinal mucosal barrier.

“One of the first stages of type 1 diabetes is a significant change in the profile of the intestinal microbiota,” says biologist Daniela Carlos Sartori, from FMRP-USP, who participated in the research. “Nonpathogenic bacteria with probiotic potential, such as Lactobacillus and Bifidobacterium, are replaced by pathogenic and proinflammatory microorganisms, such as Escherichia coli,” she says.

At the San Raffaele Scientific Institute in Milan, Italy, immunologist Chiara Sorini also found that colitis, a type of intestinal inflammation, can alter the mucus layer in mice, weakening the intestinal barrier and leading to type 1 diabetes. In an article published in the journal PNAS in July, Sorini and other researchers from Italy and Sweden argued that increased intestinal mucosal permeability is “directly responsible” for the destruction of beta cells, which causes type 1 diabetes. According to the study, despite having beta-cell-specific T cells, NOD mice do not become diabetic unless a certain event, such as reduction of the intestinal barrier, triggers the autoimmune process.

“The microbiota may not be directly responsible for type 1 diabetes, but it is certainly one of the factors that triggers the disease,” stresses endocrinologist Mário Saad, from the University of Campinas (UNICAMP), who did not participate in either of the studies. “Advances in our understanding of the causes of diabetes are very important, but we are still a long way from a cure or any new treatment options.”

The causes may be even  more complex. In an article published in Nature Reviews Endocrinology in March 2016, Mikael Knip and Heli Siljander, from the University of Helsinki in Finland, noted that changes in intestinal bacteria populations occur after production of the antibodies that go on to attack beta cells, meaning that they may simply be involved in the disease’s progression rather than being its cause.

“Based on these results, we recommend avoiding diets rich in the refined carbohydrates and fats that facilitate this process and, on the other hand, adopting diets with nutritional supplements such as fiber and probiotics to promote healthy intestinal microbiota,” says Sartori.

Project
Study of the intestinal microbiome profile and therapeutic potential of intervention strategies in the immunopathogenesis of type 1 and 2 diabetes (nº 18/14815-0); Grant Mechanism Junior Researcher; Principal Investigator Daniela Carlos Sartori (USP); Investment R$2,416,301.71.

Scientific articles
MIRANDA, M. C. G. et al. Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes. Journal of Leukocyte Biology. Vol. 106, no. 3, pp. 513–529. July 16, 2019.
SORINI, C. et al. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. PNAS. Vol. 116, no. 30, pp. 15140–15149. July 23, 2019.

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