• George Wang, MD, PhD

Gut Microbiome and Type 1 Diabetes




Type 1 diabetes results from a deficient production of insulin by the pancreas, in contrast with type 2 diabetes, in which the body still produces insulin in response to an increase in blood sugar level after a meal, at least in the early stages of the disease. While type 1 diabetes is most commonly diagnosed in children, about a quarter of cases are now diagnosed in adults. Because their pancreas is not producing insulin adequately, people with type 1 diabetes benefit from the chronic use of insulin injections in order to control their blood sugar levels. Advances in medical technologies have now made it much easier for patients with type 1 diabetes to monitor their blood glucose levels using a continuous glucose monitoring device that provides real-time data through mobile apps.


The reason that people with type 1 diabetes do not produce insulin, or do not produce enough of it, is that the body’s own immune system is attacking and destroying the pancreatic cells (specifically, the islet beta cells) that are responsible for producing insulin. This phenomenon is known as an autoimmune process, which happens in other types of autoimmune diseases as well, such as rheumatoid arthritis, lupus, and Hashimoto’s thyroiditis. The presence of autoantibodies, which are antibodies directed against the self, usually precedes the development of autoimmune disease, but autoantibodies alone are not adequate for the diagnosis of an autoimmune disease, since people without an autoimmune disease may also be found to have autoantibodies. (There is now an understanding by experts that there is another category of type 1 diabetes that does not seem to involve an autoimmune process, termed “type 1B” diabetes. The traditional autoimmune type 1 diabetes is termed “type 1A.”)


In addition to treatment with insulin, what other aspects of care may be considered in type 1 diabetes, through the lens of the integrative and functional medicine approach? Research has shown that genetic factors, environmental exposures, and the gut microbiome all play a role in contributing to the autoimmune disease process in type 1 diabetes. Here, we will focus our discussion on the gut microbiome.


The gut microbiota refers to the community of the trillions of microbes that live in our digestive tract. Technically speaking, the gut microbiome may refer to the total gene pool of all gut microbes, but colloquially, “gut microbiome” is often used synonymously with “gut microbiota.” A “healthy” gut microbiota can be characterized by the richness of the ecosystem (diversity), its ability to tolerate perturbation, such as a course of antibiotics (stability), and its ability to return to its state prior to the perturbation (resilience) (1). In other words, a healthy gut microbiota is one that contains a rich diversity of microorganisms and can tolerate different sorts of challenges, while being able to return to its original state after the challenges have passed. On the other hand, an imbalanced microbiota, termed dysbiosis, can be associated with immune-mediated diseases, such as type 1 diabetes (2).


Research on the relationship between the human gut microbiome and the development of autoimmune type 1 diabetes is still in its relative infancy, but findings so far have shown that the gut microbiome of people with prediabetes or diabetes is different from those who do not have prediabetes or diabetes. The gut microbiota of children with type 1 diabetes is more likely to have a higher abundance of Bacteroides bacteria and lower levels of Lactobacillus, Bifidobacterium, and Prevotella, among other changes, compared with those who do not have diabetes (2). In children who will eventually develop type 1 diabetes, their gut microbiota has a lower diversity, compared with children who do not develop diabetes, and contains a lower proportion of bacteria that produce butyrate, a short-chain fatty acid, which we will explain next. Studies in mice have shown that the short-chain fatty acids produced by bacteria in the gut have a protective effect against the development of autoimmunity in a mouse model of diabetes (3).


Short-chain fatty acids are important for maintaining gut health because they are the main energy source of the cells that line our large intestine. Our digestive tract does not have a built-in ability to ferment the indigestible plant fibers that we eat, and so we rely on the gut bacteria to “digest” these fibers for us through the process of fermentation, which then produces short-chain fatty acids (such as acetate, propionate, and butyrate) that not only benefit the cells of our large intestine but also feed the bacteria in the gut microbiota. It is believed that the amount of short-chain fatty acids in the large intestine and blood is critically important for the regulation of the immune system (4). The production of short-chain fatty acids can change quickly when people switch to a different diet.


Some clarification of terminology is in order. The term “prebiotics” refers in a general sense to any substance that is utilized by health-conferring microbes, in contrast to “probiotics,” which is a different term that refers to the microbes themselves. “Prebiotic-rich foods” are generally fiber-rich foods that our gut microbes ferment to produce large amounts of short-chain fatty acids.


In experiments involving a mouse model of type 1 diabetes, when mice were fed a diet designed to release large amounts of the short-chain fatty acids, acetate and butyrate, the mice were protected from developing diabetes (3). Interestingly, in these mice, the short-chain fatty acid, acetate, markedly decreased the number of a type of autoimmune cells in lymphoid tissues. The autoimmune cells are responsible for damaging the insulin-producing cells in the pancreas. So, if the short-chain fatty acid, acetate, can decrease the number of these destructive autoimmune cells, the pancreas is more likely to be protected from harm and retain its ability to produce insulin.


In another mouse study, when researchers took the gut microbiota from male mice that did not have diabetes, and transferred it into the gut of premature female mice that were at risk of developing autoimmune diabetes, the recipient mice of this “therapy” were protected from developing autoimmune diabetes (5). This transfer of gut microbiota also resulted in reduced inflammation in the pancreatic cells that produce insulin and reduced production of autoantibodies. These results highlight the potential role that the gut microbiome plays in protection against autoimmune diabetes, at least in the mouse model.


What about research results in humans? In a large prospective study that recruited thousands of newborns in the U.S., Finland, Germany, and Sweden, when the researchers examined the gut microbiomes of children who eventually developed type 1 diabetes or developed diabetes-associated autoantibodies, they found that the microbiomes of healthy children (control group) contained more genes related to fermentation and the production of short-chain fatty acids (6). In other words, what this study suggests is that a healthier gut microbiota can do a better job of fermenting the prebiotic foods we eat and synthesizing the beneficial short-chain fatty acids in our gut, and that this healthier microbiome may protect against the development of type 1 diabetes or prevent an autoimmune process that can destroy the pancreatic cells that produce insulin.


Other researchers investigating the same prospective cohort as above found that, in children at risk of developing type 1 diabetes, children who received early probiotic supplementation at the age of 0-27 days had a lower risk of developing harmful autoantibodies against their pancreatic cells that produce insulin, when compared with children who received probiotic supplementation after 27 days of age or received no probiotic supplementation (7). In a randomized, controlled trial conducted in children with new-onset type 1 diabetes, the children who received a high-dose, multi-strain probiotic supplement for 3 months had a significant decrease in their blood sugar levels (measured by a test known as hemoglobin A1c) and a decreased need for insulin, when compared with children who received a placebo (8).


Type 2 diabetes results from different root causes and mechanisms than autoimmune type 1 diabetes, but research has also shown that the consumption of dietary fibers in people with type 2 diabetes promotes a select group of microbe strains that produce short-chain fatty acids in the gut, and that a greater abundance and diversity of these microbes was associated with better blood sugar control (9).


(A finer point for readers who are scientifically trained or inclined: Whether the changes in the gut microbiota in people with autoimmune type 1 diabetes are responsible for initiating the disease process from the outset, whether they are responsible for the progression from autoimmunity to clinical disease, or whether they are a consequence of the disease state remains to be unraveled with future research [2].)


While more research is needed, these are certainly exciting study results that can have significant implications in the prevention and treatment of an autoimmune disease such as type 1 diabetes. Taken together, they also provide a scientific rationale for considering the importance of food as medicine as part of a functional medicine and integrative medicine approach to health recovery. While there are prebiotic and probiotic dietary supplements that can assist a person in restoring a healthy gut microbiome as they transition to a healthier diet, a prudent food plan that incorporates probiotic- and prebiotic-rich foods is an important component of the sustainable path to lifelong gut health. Whole grains, legumes, nuts, seeds, vegetables, and fruits are all foods that contain prebiotics. On the other hand, sauerkraut, miso, fermented vegetables, and plant-based yogurts are some of my patients’ favorite probiotic-rich foods. (Consult your physician before starting dietary supplements. If you have diabetes or other medical conditions, consult your physician before making dietary changes or any changes to your medical treatment.)


More scientific research is welcome to better our understanding of how the gut microbiome can affect such an autoimmune disease as type 1 diabetes. With this knowledge, we can be better prepared to design more effective therapeutic approaches to prevent and treat autoimmune type 1 diabetes at the root cause.



References

1. Levy, M., et al. “Dysbiosis and the immune system.” Nat Rev Immunol. 2017;17(4):219-32.


2. Knip, M., Siljander, H. “The role of the intestinal microbiota in type 1 diabetes mellitus.” Nat Rev Endocrinol. 2016;12(3):154-67.


3. Marino, E., et al. “Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.” Nat Immunol. 2017;18(5):552-62.


4. Maslowski, K.M., Mackay, C.R. “Diet, gut microbiota and immune responses.” Nat Immunol. 2011;12(1):5-9.


5. Markle, J.G., et al. “Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.” Science. 2013;339(6123):1084-8.


6. Vatanen, T., et al. “The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.” Nature. 2018;562(7728):589-94.


7. Uusitalo, U., et al. “Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study.” JAMA Pediatr. 2016;170(1):20-8.


8. Kumar, S., et al. “A high potency multi-strain probiotic improves glycemic control in children with new-onset type 1 diabetes mellitus: A randomized, double-blind, and placebo-controlled pilot study.” Pediatr Diabetes. 2021;22(7):1014-22.


9. Zhao, L., et al. “Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes.” Science. 2018;359(6380):1151-6.