Epigenetics: The Microbiome and Diabetes
By Joseph C. Kovatch, BA
The advent of the field of epigenetics has challenged the old conventional wisdom that “you cannot deny the genes.” We now appreciate that environmental variables such as what we eat, our pets, and where we live can play a major role in the expression of the DNA sequencing (inherited at our conception) over the course of the lifetime. In this regard, epigenetics functions as the captain of our fate, much like a director controls and influences the script of a movie.
Recent research suggests that the immunologic “cascade” that destroys the insulin-producing beta cells of the pancreas and produces the symptoms of type 1 diabetes mellitus (formerly known as juvenile-onset diabetes mellitus) occurs over months to years and may be reversible (if detected early enough) or, at least, delayed by medical interventions, such as anti-autoantibody medications (for example, cyclosporin). The PediaBlog (“Turning On Celiac Disease” — August 18, 2017) recently highlighted a study in the prestigious journal Science where researchers hypothesized that infection with an intestinal pathogen, T1L reovirus, triggers the damaging auto-immunologic process of celiac disease.
The microbiome is the collection of all the microorganisms in and on an individual. These microbiota play a vital role in human health, as they break down food in the digestive system into important metabolites that could not be created otherwise. In addition, they also prevent opportunistic pathogens from causing infection throughout the body. In return, these microbiota receive a suitable location to colonize, as well as nutrients from host food consumption. In this light, we are all more bacterial than human!
Multiple studies have shown that the gut microbiome of children with type 1 diabetes (T1D) lacks the diversity and balance that non-diabetic controls possess, and that this disparity persists throughout life. Second, characteristic differences in specific gut composition have been seen between normal and diabetic individuals, most notably in the presence of more Bacteroides — the unhealthy anaerobic bacteria which overgrow during periods of illness and constipation and produce the foul, musty odor we all have recognized. Inversely, children with diabetes showed a reduction in the more benevolent Firmicutes species compared to healthy controls.
The mechanism by which these host bacteria may exert their influence is through their own specific inherent genes. Individuals with T1D have a higher abundance of microbial genes associated with carbohydrate metabolism, motility, and stress response, while healthy individuals have more microbial genes associated with protein metabolism and amino acid synthesis.
Geographic location has also been linked to microbial diversity of the microbiome and a preponderance of the Bacteroides genus. States (notably Colorado) and countries (Finland tops the list) with low microbial diversities statistically have the highest rates of T1D.
Location! Location! Location!
Since the innate system is known to play a key role in the development of T1D, modifications in the microbiome can influence the function of so-called “toll-like receptors” which are important pattern recognition agents in the host defense. Studies in mice suggest that Bacteroides and Firmicutes may in some way interact with these Toll-like receptors in order to trigger the immune response that ignites the onset of T1D (much like reovirus infection ignites that of celiac disease).
This research begs the question as to how the microbiome can be regulated — and, consequently, the immune system reprogramed — to prevent the development of T1D or to facilitate its control. Although creation and sustainability of a healthy microbiome by use of oral probiotics is a widespread practice, research in mice has focused on the possibilities of fecal transplant. A study conducted in 2014 showed that the fecal material of diabetes-resistant mice could be transferred to wild type mice at a young age, resulting in diabetes protection to the recipients.
The groundbreaking field of fecal transplantation has been studied in humans with inflammatory bowel disease (see The PediaBlog, “Promising Data On Crohn’s” –May 19, 2015) and with bacterial overgrowth (see The PediaBlog, “A Bitter Pill To Swallow” –October 23. 2015). This novel approach should gather more momentum in research attempting to arrest the development of T1D in humans in the pre-clinical, “evolving” window of time. The above research has set the stage for more radical interventions.
In a nutshell — regarding the health of humans — we may be becoming more and more dependent “on the kindness of strangers.” And these strangers may be of a species other than our own.
***Joseph Kovatch is a graduate of the University of Pittsburgh (BA — Biology). After taking a gap year, he will be applying to medical school. This essay is condensed from his senior year thesis, “The Role of Microbiota in the Development and Treatment of Type 1 Diabetes.” Tomorrow, Joey’s father, Dr. Tony Kovatch, shows us what he has learned from his son’s thesis as he answers a reader’s question regarding the role of the microbiome in the development of celiac disease.
(Back pat: Mind On The Run)