246-LB: Neonatal Microbes Stimulate Beta-Cell Development

Newborns are exposed to environmental microbes that colonize the gut and increase in diversity during childhood to establish the resident microbiota. Concurrently, insulin-producing β-cells enter a postnatal window of proliferation and maturation. We found that germ-free animal models exhibit significant reductions in β-cell mass compared to their microbe-carrying counterparts, revealing a role for microbes in the establishment of these cells. By mining this unique source, we uncovered mechanisms of bacterially driven β-cell development.

Neonatal mice given strategically timed doses of broad-spectrum antibiotics incurred lasting reductions in β-cell mass, revealing a critical period of microbial influence on β-cells. Though reconstituted with a normal microbiota after antibiotic treatment, as adults these animals had reduced glucose tolerance and insulin secretion, and were more susceptible to metabolic disease. Treatment of neonatal mice with selective antibiotics resulted in variations in β-cell mass, blood glucose, and insulin levels, suggesting unique bacterial taxa or products influence these traits. Sequencing revealed that distinct microbes were enriched within each antibiotic treatment, allowing us to identify candidate bacterial taxa that we show are sufficient to stimulate β-cell expansion and restore insulin function. Further, we have identified multiple islet associated cell types that respond to these microbial cues. Previously, we identified the bacterial protein, BefA, that directly stimulates β-cell proliferation, and we anticipate finding additional bacterial modulators of this important tissue.

Reduced microbiota diversity can be predictive of diabetes in susceptible children, suggesting that early life microbial exposures are critical to prevent disease. Our results indicate loss of specific bacteria may result in reduced insulin production capacity prior to autoimmunity. If we can reinstate these lost microbes, we may be able to bolster the β-cell population against loss.