The results of in vitro and in vivo studies carried out by researchers at the University of Oregon (UO) and at the University of Utah suggest a potential mechanism by which a microbiome-derived protein, BefA, can reduce the risk of type 1 diabetes (T1D). The scientists claim their findings have “important, profound implications,” that could lead to the development of new approaches to prevent diabetes, by harnessing specific types of bacteria that produce BefA, potentially to bolster the microbiomes of high-risk infants.
First author Jennifer Hampton Hill, PhD, lead author Karen Guillemin, PhD, and colleagues, reported their findings in Cell Metabolism. “If we understand how BefA works, it could give us a way to stimulate beta cell production therapeutically, Guillemin said. The team’s paper is titled, “BefA, a microbiota-secreted membrane disrupter, disseminates to the pancreas and increases ß cell mass.”
Almost a decade ago, Hill, then a University of Oregon graduate student, discovered that a protein called beta cell expansion factor A (BefA), which is made by gut bacteria, triggered insulin-producing cells to replicate in model organisms. The protein was an important clue to the biological basis for type 1 diabetes, which is an autoimmune disease in which the pancreas can’t make insulin.
Hill has continued to work on BefA as a postdoc at the University of Utah. Guillemin’s lab at UO has also continued to study BefA. In collaboration with other colleagues, the researchers have now uncovered new insights into what BefA does and why bacteria make it.
The body needs insulin to regulate blood sugar, but insulin is only made by ß cells in the pancreas. “ß cells are essential pancreatic endocrine cells that produce insulin to control blood glucose, the scientists explained. “Patients with diabetes lack functional ß cells due to autoimmune destruction or long-term insulin resistance.” In people with type 1 diabetes, the immune system attacks ß cells and depletes their population, limiting insulin production.
There is only a narrow window of time during early childhood development when ß cells replicate and expand their population. And while microbiome stimulation of immune development helps to properly educate the immune system and prevent autoimmunity, the work by Guillemin’s team suggests an additional role for the microbiome, in stimulating growth of the ß cell population early in development, buffering against later depletion by autoimmune attack.
ß cell population growth “is happening at the same time that microbial communities are diversifying in the gut,” said Hill. “A hallmark of diabetes is kids who develop it tend to have a less diverse gut microbiome. It’s possible they’re missing some of the bacteria that make BefA.”
In their newly published paper Hill, Guillemin, and their colleagues described studies that further investigated BefA. They captured detailed images of BefA’s structure to identify the parts of the molecule that interact with cell membranes. Then, through a series of experiments in zebrafish, mice, and cultured cells, the researchers sketched a picture of BefA’s function. Summarizing their findings, they wrote, “Collectively, these data show that BefA is able to induce ß cell expansion with a concomitant increase in insulin secretion and decrease in blood glucose.”
The results indicated that BefA can disrupt the membranes of many kinds of cells, both bacterial and animal. And while it makes sense that gut bacteria would attack competing bacteria, the results also unexpectedly showed that BefA’s attacks on the membranes of insulin-producing cells triggered those cells to reproduce. The finding suggests that bacterial warfare in the gut can have collateral beneficial effects on the body, boosting the population of cells that can make insulin throughout the lifespan.
The team tested a mutated version of BefA that was modified so that it couldn’t disrupt cell membranes. That version of the protein didn’t impact ß cell production, further suggesting that membrane damage is driving BefA’s effects. “There are other examples in developmental biology where poking holes in membranes is critical in stimulating development,” Hill said, although the researchers acknowledged that they don’t yet know exactly how the damage is triggering cell replication. While noting limitations of their study, the authors wrote, “Our work demonstrates that membrane permeabilization by microbiome-derived and host defense proteins is necessary and sufficient for ß cell expansion during pancreas development, potentially connecting microbiome composition with diabetes risk.”
The investigators don’t know why BefA—which can alter the membranes of many kinds of cells—targets ß cells so specifically. “We think that there’s something special about ß cells that they may be highly sensitized to respond to cues that cause membrane permeabilization,” Hill said. “They’re the only cell type in the whole body that can secrete insulin—they’re highly important.”
“The microbiome plays a role in educating the immune system. If you don’t have that education, the immune system can be hyper-reactive,” Guillemin added. “We think there’s also this other layer here—if you don’t develop a pool of ß cells against future disruption, you’re more at risk for type 1 diabetes.” And a healthy, diverse microbiome plays a key role in building that cell population.
In the future, Guillemin’s team imagines possible therapeutic applications for the finding. For example, proactively fortifying the microbiomes of high-risk infants with BefA-producing bacteria could prevent them from later developing type 1 diabetes. The authors concluded, “The developmental plasticity of the pancreas in response to microbial membrane permeabilizing activities may confer a selective advantage by allowing developing animals to match their metabolic capacities to their nutritional environment … Understanding how different membrane permeabilizing activities stimulate ß cell expansion will spur new strategies to prevent or reverse the consequence of developing with mismatched microbial and nutritional cues.”
Hill was awarded the NOSTER & Science Microbiome Prize this year for her work on BefA. The annual award is given to an early career scientist who has contributed new understanding to microbiome research that could influence human health.