Scientists headed by a team at the University of Utah Health have reported on research in mice suggesting that microbiome composition during infancy can shape development of pancreatic insulin-producing cells, leading to long-term changes in metabolism and impacting on diabetes risk later in life. The study, reported in Science by research co-lead June Round, PhD, professor of pathology at University of Utah Health, and colleagues, identified what the team describes as “a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development.”
Round suggests that understanding how the microbiome impacts metabolism could potentially lead to microbe-based treatments to prevent type 1 diabetes. “What I hope will eventually happen is that we’re going to identify these important microbes, and we’ll be able to give them to infants so that we can perhaps prevent this disease from happening altogether.”
In their published paper, titled “Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development,” the team concluded that their results “… identify fungi as critical early-life commensals that promote long-term metabolic health …”
“Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive,” the scientists explained. The body’s control of blood sugar depends on the hormone insulin, which is produced solely by pancreatic β cells, and diabetes develops when there is insufficient insulin. “Loss of insulin production or responsiveness is the basis of diabetes,” they stated.
The investigators in addition found that fecal samples from human infants, 7 to 12 months of age, stimulated mouse β cell mass, whereas samples from other age groups did not. “Mice that were colonized with samples obtained from children between 7 and 12 months of age had significantly more insulin-expressing tissue and serum insulin than did mice colonized from donors of any other age group.” This finding suggests that humans may also exhibit a window of colonization by β cell–promoting microbes, the authors suggested.
By testing in mice a variety of antibiotics that affect different types of microbes, the researchers pinpointed several specific microorganisms that increased the amount of insulin-producing tissue and the level of insulin in the blood. Intriguingly, they found one of these metabolism-boosting microbes to be a largely unstudied fungus called Candida dubliniensis, which isn’t found in healthy human adults but may be more common in infants.
The experiments showed that C. dubliniensis exposure in early life also dramatically reduced the risk of type 1 diabetes in at-risk male mice. When male mice that were genetically predisposed to develop type 1 diabetes were colonized by a metabolically “neutral” microbe in infancy, they developed the disease 90% of the time. In contrast, mice that were colonized with the C. dubliniensis fungus developed diabetes less than 15% of the time.
Exposure to C. dubliniensis could even help a damaged pancreas recover, the study results suggested. When researchers introduced the fungus to adult mice in which insulin-producing cells had been killed off, the insulin-producing cells regenerated and metabolic function improved. The researchers emphasized that this is highly unusual, as this kind of cell normally doesn’t grow during adulthood.
The C. dubliniensis fungus appears to support insulin-producing cells via its effects on the immune system. Previous research has shown that immune cells in the pancreas can promote the development of their insulin-producing neighbors. The researchers found that mice without a microbiome have fewer immune cells in the pancreas and worse metabolic function in adulthood.
When such mice were given a booster of C. dubliniensis in early life, both their pancreatic immune cells and their metabolic function were restored back to normal. The studies showed that C. dubliniensis could only promote the growth of insulin-producing cells in mice that have macrophages, showing that the fungus promotes metabolic health by affecting the immune system. “Here we identify a previously unknown microbiota-mediated mechanism to influence β cell development through macrophage seeding of the islet,” they stated, noting that the results indicated that it is increased numbers of islet macrophages, rather than their functional state, that drive β cell proliferation.
The scientists emphasized that there are probably other microbes that confer similar benefits as C. dubliniensis. The new insights could help scientists better understand how similar health cues from other microbes might function. “We don’t know a lot about how the microbiome is impacting early-life health,” said Jennifer Hill, PhD, first author on the study, who led the research as a postdoctoral scientist in the Round Lab at the U. Hill is now an assistant professor in molecular, cellular, and developmental biology at University of Colorado Boulder. “But we’re finding that these early-life signals do impact early development, and then, on top of that, have long-term consequences for metabolic health.”
The newly reported findings, the researchers suggest, could ultimately help doctors reduce the risk of type 1 diabetes—or potentially even restore lost metabolic function in adulthood—by providing specific gut microbes that help the pancreas grow and heal.
If the benefits seen in mice hold true in humans, microbe-derived molecules might eventually help restore pancreatic function in people with diabetes. Hill added, “One possibility in the far future is that maybe signals like these could be harnessed not only as a preventative but also as a therapeutic to help later in life.” However, Hill also cautions that treatments that help β cells regenerate in mice historically have not led to improvements in human health.