Further evidence of a role for the gut microbiome in autoimmunity
by Adam Burrack, PhD
I’ve written a couple articles about the interplay between the bacteria living in our gut and our immune system, and how this interaction can influence the subsequent development of autoimmunity. The first time I touched upon this subject, it was to describe work from Mark Atkinson’s laboratory at the University of Florida. In this work, the authors described a relative lack of diversity in gut-resident bacteria in infants and toddlers who went on to develop type 1 diabetes compared to control subjects who did not develop diabetes. This outcome suggests that gut bacteria diversity may somehow protect against autoimmunity. In another highlighted paper later in our series, I described a study from Yale in which researchers demonstrated that a beta cell toxin used to induce diabetes for mouse experiments promotes movement of gut bacteria into the pancreas-draining lymph node following treatment with a beta cell toxin. This result suggested that beta cell death and inflammation induced by this chemical promoted movement of bacteria as well, supporting a role for bacterial products in activation of the immune system following treatment with this beta cell toxin. Thirdly, an article I described earlier this year demonstrated that a diverse diet promotes a diverse range of gut-resident bacteria, and the reverse: an “American” high fat-high protein diet promotes both a narrow range of gut-resident bacteria along with high levels of systemic inflammation. This suggests that our diet has a clear ability to affect our gut-resident bacteria; the bacteria that thrive in our intestine will be those that are best-adapted to utilize the fuel available. The fuel available in our gut is determined by the foods we eat.
Enter into this conversation three recent papers studying the relationship between our gut bacteria and the timing of type 1 diabetes (T1D) onset in at-risk individuals.
First, a study from Finland and published in the journal Pediatric Diabetes in November 2016 characterized both the bacteria and the viruses in the gut of individuals at-risk of developing T1D. In particular, the authors were interested in the prevalence of a type of gut-resident bacteria called Bacteroides, which is a common component of the gut microbiome but could be considered an opportunistic pathogen. An opportunistic pathogen means Bacteroides might mediate harmful effects if its population were out of proportion to other gut microbes. No previous study had established a pathogenic role for any specific gut bacteria in subsequent autoimmunity. Results from this study suggest that a particular bacteriophage (bacteriophages are viruses which attack bacteria), which targets Bacteroides may be more prevalent in the gut of toddlers who go on to develop T1D. These results should be interpreted with caution; this study demonstrates a correlation between changes in the prevalence of these gut microbes and later development of T1D. This study does not establish any of these changes as causative of beta cell destruction.
Second, in a publication in the March 2017 issue of Diabetologia a partially overlapping set of authors from Finland examined the presence of enterovirus and whether the presence of this category of gut microbe at higher-than-normal levels might predict later beta cell destruction. Enteroviruses are named for their life-style; they live within the intestine. These authors examined stool samples from 129 ‘case children’ (who went on to develop islet autoantibodies) and 282 control children who did not develop islet autoantibodies. This was a prospective study, the authors’ aim was to determine if infection with any particular enterovirus serotypes correlated with later development of islet-specific autoantibodies. These authors found that children who developed autoantibodies experienced more frequent enterovirus infections than control subjects. Coxsackie virus is a sub-type of enterovirus which has been hypothesized to play a role in beta cell destruction. The presence of several types of coxsackie virus were associated with later development of islet autoantibodies: A4, A2, and A16. Importantly, these infections occurred more than 1 year prior to development of autoantibodies, suggesting a slowly-evolving autoimmune process. These results suggest these types of coxsackie virus may help to precipitate later development of islet autoantibodies. Caution assigning causation to these serotypes, however; this was an observational study and this work does not describe how these viruses promote autoreactivity against insulin-producing beta cells. Future studies are required to determine how these viruses might promote autoimmunity specifically against beta cells in the pancreas and not against other hormone-producing cell types within pancreatic islets.
Third and most recently, scientists at Washington University in St Louis and collaborators characterized the stool microbiome, beginning at birth, of 11 at-risk children. Five of these 11 children have subsequently developed clinical T1D, compared to none of the control subjects in this study. In general, these authors observed less diverse ‘gut viromes’ in subjects who subsequently developed T1D than in controls. In other words, the smaller the range of gut microbes, the more likely the subject was to develop T1D. In addition, the authors demonstrate that bacteriophage diversity was significantly lower in T1D at-risk subjects than controls – in agreement with the study cited above. Here’s why this paper was published in Proceedings of the National Academy: moving toward causation, since the authors collected stool samples over the lifespan of these subjects they could test how gut microbe diversity related to T1D development. The authors found that decreases in gut virome diversity in at-risk subjects who developed T1D were different from control subjects who did not develop T1D. In other words, these changes in gut microbe diversity may be causative of beta cell-specific autoimmunity rather than a consequence of the disease process.
This is exciting news. Next steps include determining which bacteria and bacteriophage might be protective versus which might be pathogenic, or whether it’s ‘just maintain microbe diversity’ to stave off T1D. Then, how and why do some microbes promote beta cell-specific autoimmunity? It’s not clear to me whether coxsackie virus infection of beta cells matters, or whether its beta cell-specific inflammation in general that promotes autoimmunity in at-risk individuals. Whatever the answer to these questions, clinical translation of these results – harnessing the diversity of the gut microbiome to prevent or reverse beta cell-specific autoimmunity – is a long way off. But these initial observations establishing that there might be a causative relationship between decreased gut microbe diversity and subsequent beta cell-specific autoimmunity is a very interesting start.
In other words, these results might represent the “end of the beginning” of this sub-field. It looks, to me, like the gut microbiome ‘matters’ for developing autoimmune diabetes. The question of mechanism (eg, decreased diversity of gut microbes precedes T1D development) and what we do about this change to prevent diabetes (eg, maintain gut microbe diversity, somehow) are more challenging to address, but represent the next key steps in leveraging this knowledge to prevent T1D in some at-risk individuals.