Small molecule shown to target bacteria in the gut microbiome, affecting disease
CLEMSON, South Carolina – Husband and wife researchers Dan and Kristi Whitehead of Clemson University have long been contemplating how they could combine their areas of expertise – his in organic chemistry, hers in microbiology – to do something innovative in science.
The result of the pairing, along with chemistry graduate student Anthony Santilli and undergraduate genetics major and student-athlete Elizabeth Dawson, is a recent study in the journal ACS Chemical Biology, which details the use of a small molecule to slow the growth of a specific genus of bacteria, called Bacteroides, in the gut microbiome. The technique is a novel diversion from existing treatment strategies that target the gut microbiome, in that it holds the potential to edit specific types of bacteria in the gut without harming other microbes that are present.
The connection between the microbiome – our own personal collection of bacteria, archaea, fungi and viruses – and human health is one that has been gaining steam over the last few decades. Supported by numerous studies that implicate the microbiome in chronic diseases, immunity, digestion and even feelings of depression and anxiety, it appears that our bodies’ microbes serve a variety of important functions that are only just being realized.
The Bacteroides genus is no exception. The researchers’ interest in this specific strain of bacteria developed for two reasons, marked first by Bacteroides’ well-defined job in the gut microbiome. The bacteria have an intricate collection of enzymes that are responsible for the breakdown of complex carbohydrates, specifically that of starches. Knowing precisely how the bacteria function made it easier for the researchers to develop hypotheses on how to manipulate the Bacteroides system.
But the second reason considers a peculiar link between Bacteroides and Type 1 diabetes, a chronic disorder in which the pancreas produces little to no insulin.
“We know there are certain genetic risk factors associated with Type 1, but not everybody with those risk factors develops the disease and not everybody with Type 1 has those risk factors,” Kristi said. “When you combine that with the significant increase in the diagnosis of Type 1 over the past two decades, researchers are starting to look at environmental factors – something in our diet or maybe something like C-sections versus vaginal births or antibiotic use in infants. What has changed to cause an increase in the rate of Type 1?”
One study in particular – the TEDDY study – is tracking babies from birth to age 15 to determine which environmental triggers cause children to develop Type 1 diabetes. Most notably to the researchers, the TEDDY study has shown a marked increase in Bacteroides in the gut microbiome prior to the onset of symptoms of Type 1 diabetes in genetically predisposed children.
“What this could be really profoundly effective for is we could hopefully take kids that are genetically at-risk, so maybe they have a brother, sister or parent with Type 1 diabetes, then we can start them on a drug therapy very early in life and hopefully delay or prevent that shift in the microbiota that initially triggers the onset of autoimmunity,” Dan said.
The drug itself is an alpha amylase inhibitor, acarbose, that is used as a treatment for Type 2 diabetes. It works by inhibiting the body’s ability to metabolize starches, blocking the amylase enzyme in our small intestine from cleaving starches into their glucose components. This prevents the influx of glucose into the gastrointestinal tract after a large meal is consumed, helping diabetic patients regulate their blood sugar.
“We knew that one particular enzyme in the Bacteroides enzyme suite was an alpha amylase, and we knew that the bacteria liked to eat starch,” Dan said. “So we then made the hypothesis that maybe a human alpha amylase inhibitor might also have some efficacy against a bacterial alpha amylase. From there, we went and looked at some clinically available human alpha amylase inhibitors, screened those against the bacteria, and one of them – acarbose – turned out to work against the bacterial alpha amylase.”
When two species of Bacteroides were treated with acarbose and fed a meal of starch, the drug significantly reduced the bacteria’s ability to grow. Importantly, the drug did not kill Bacteroides or otherwise influence the growth of several other microbes present in the gut. This differs from traditional treatments for chronic diseases, such as antibiotics, which treat the problem by wiping out large portions of the gut flora – both the good and the bad microbes.
Although other carbohydrates, besides starches, are present in the gut – namely fibers and sugars – treatment with acarbose would prevent Bacteroides from foraging for one of their main nutrient sources, which would likely curtail their ability to grow. What’s more – the Bacteroides genus hails from a phylum of bacteria known as Bacteroidetes that makes up about 50 percent of the microbes in our gut. Many members of the Bacteroidetes phylum are thought to have similar affinity and machinery for starch utilization, Dan says, lending toward the possibility of targeting other members of the phylum with the team’s newfound strategy.
For the researchers, this study is a proof of concept that it’s possible to target a specific strain of bacteria among the plethora that exist in the human gut. Future studies will have the duo testing acarbose in animal studies to see how efficient the drug is at staving off Type 1 diabetes and affecting pointed shifts in the gut microbiota. They are also working on the chemistry of the drug to make it more potent and more selective.