It is now clear that over recent generations there has been a distinct rise in Type 1 diabetes. You may never have considered that scientists on the vanguard of this mystery are looking in a surprising place for answers: our poop.
The increase of T1D conflicts with the general understanding of the disease as essentially a matter of genetics. Researchers believe that there must also be environmental influences, as yet undiscovered, that make T1D more likely to develop. There are many theories on potential the identity of these environmental factors. One particularly intense area of study is the microbiome: the microscopic world of bacteria, fungi, viruses and protozoa that live on and inside our body. The invisible community in our gut is believed to be of particular importance, and to study it, we turn to our fecal matter, each gram of which has billions of living microbes.
Much study has shown one deceptively simple fact: the gut microbiome of people with Type 1 diabetes is different from that of people without. But it’s not easy to tease out cause from effect, or conclude to what extent these differences drive or are driven by the various phenomena of T1D, including autoimmunity and Beta cell loss. The microbiome is astonishingly complex – just one month ago Science Daily called it a “somewhat of a mystery” – and the science is still young.
Ultimately, we’re most interested in the real-life applications of the science. If the microbiome is important in the development of Type 1 diabetes, could treating one’s population of gut microbes change the odds of developing the disease? Or, for those with well-established Type 1 diabetes, could the microbiome offer a novel avenue for treatment? Can poop solve these problems?
A recent panel of experts at the American Diabetes Association’s Scientific Sessions pondered these questions.
Dr. Emma Hamilton-Williams, an immunologist from Australia’s University of Queensland, explained that the fundamental and consistent change in the gut microbiome of people with Type 1 diabetes is a “decrease in the bacteria able to ferment fiber into short-chain fatty acids.” These particular fatty acids “have a wide-ranging effect on the body,” promoting glucose uptake, strengthening a healthy gut barrier, decreasing insulin resistance and, perhaps critically, improving immune regulation.
If changing gut flora were to cause dysfunction in the immune system that contributes to the progression of T1D, it seems logical that adjusting the composition of the gut flora by supplementing with bacteria better able to ferment fiber could possibly prevent, slow, or remedy the disease. In fact, Dr. Hamilton-Williams’ lab was able to prevent mice from developing diabetes by feeding them a special probiotic diet formulated to address those gaps in the typical diabetic gut microbiome. But the cure of rodent diabetes has been achieved many times before, and only rarely has it led to meaningful improvements in the treatment of human diabetes. In a study that has not yet been published or peer-reviewed, Dr. Hamilton-Williams fed adults with established T1D the same probiotics. Initially, it seemed as if there were no result – glycemic control did not improve in any way.
Peering into the data more carefully, Dr. Hamilton-Williams realized that study participants could be divided into two rough groups: those who responded to the probiotic diet, and those who did not. The “responders” evinced significant changes in gut flora composition and function. And the responders also showed significantly improved blood sugar control, and reduced A1c, a very positive result that should inspire more detailed study.
This result, revealed for the first time at the conference, confirmed the general feeling of the other experts: that given how unique every individual gut microbiome is, future therapies focusing on the microbiome are likely to be highly personalized. As Dr. Max Nieuwdorp of the University of Amsterdam stated, we should expect “no blockbusters,” no miracle treatments that work for everybody equally well.
Dr. Nieuwdorp first tried to tackle the same issue – the relative decrease in bacteria able to ferment fiber into short-chain fatty acids – in a more direct manner. He simply introduced the missing short-chain fatty acids into patients’ diets. This, unfortunately, yielded no results. Dr. Nieuwdorp concluded that this was just “too easy,” and that the complex interactions of the bacteria with the immune system couldn’t be mimicked with an inert supplement.
The experiments Dr. Nieuwdorp really specializes in are anything but inert. He is a pioneer in studying the fecal microbiata transplant (FMT), in which fecal matter chosen for its microbial content is inserted into the digestive system (via pill, tube or enema), with the hope of adjusting or rebalancing a patient’s gut microbiome community.
For years Dr. Nieuwdorp has been overseeing a trial in which adults newly diagnosed with T1D were given fecal transplants. Patients only recently diagnosed, often enjoying a “honeymoon” phase, are more likely to have residual beta cell activity and insulin production, and therefore seem more likely to respond to interventions that aim to stem the autoimmune attacks that provoke the disease. This was a difficult trial to recruit for, as you might imagine: I myself would not have been eager to accept experimental fecal transplants while still in a daze from learning that I had developed a lifelong disability. It took him five years to find twenty willing patients.
The experiment pitted two groups of ten against each other: the first group was given FMTs from healthy donors, and the second was given FMTs of their own feces. Surprisingly, those that received their own fecal matter had significantly better beta cell preservation (as measured by C-peptide level), although it did not result in an improvement in A1c. Dr. Nieuwdorp theorized that the fecal transplants “might ignite a protective innate immune response that redresses and regroups T-cell function,” thereby extending or strengthening the honeymoon response. He declined to speculate on the mechanism at work, but he did caution us against doing our own DIY fecal transplants, apparently a Youtube trend. (This writer needed no warning.)
Several studies have analyzed the gut flora of children that are known to be of a high genetic risk of Type 1 diabetes, to see if there are differences in those that do eventually develop the condition. The largest study of this type, the TEDDY Study, spanned continents to look for environmental determinants of T1D, and found no evidence that the microbiome mattered. Smaller and more geographically constrained studies, however, do tend to find associations, particularly in the 6 months prior to diagnosis, when the gut flora appears to undergo significant changes. We can only guess to what extend those changes are causing, or are caused by, the onset of illness, but the observation is promising.
If there’s hope for a microbiome adjustment that can really reduce the incidence of T1D, it may require action very early, even in the first year of the patient’s life. As explained by Dr. Christopher Stewart of Newcastle University, in the first year after birth an infant’s microbiome is determined by several factors, the most significant of which is the composition of the mother’s breast milk (when present). After that year the microbiome begins to shift, and at around the 30-month mark the microbiome has largely completed a transition to an “adult type.” This adult mix is highly individual – it is no longer easy to identify environmental, genetic, or dietary factors influencing its composition. It is also both very stable and very resilient, meaning that probiotics and other interventions tend not to cause lasting changes. It is thought that if a treatment can take permanent effect, it may need to be administered within the first year, before a patient’s individual microbial mix begins to stabilize.
Consider the plight of the University of Florida’s Dr. Eric Triplett, who, in order to conduct his own studies on the topic, ordered stool samples that had been sitting in a deep-freezer in Sweden for some twenty years. His research suggests that genetic risk of T1D is associated with significant differences in gut microbiome communities, and that “this happens very early in life,” supporting the idea that successful interventions might have to take place as early as infancy.
If there are possibilities for a probiotic therapy, they will likely need to be highly personalized. In the future, as Dr. Triplett concluded, “we may know enough so that if we know the genotype of a person, and model their microbiome, we may be able to intervene with probiotic strains.”
“We’re a long way from that.”
