| Abstract | By systematically ablating and restoring the microbiota during defined windows of pre- and postnatal life in mice, we identified a 10-day period before weaning when resident microbes are required to establish normal β cell mass. These observations were replicated using antibiotic and antifungal drugs, indicating that both bacteria and fungi promote host β cells. We also found that fecal samples from human infants, 7 to 12 months of age, robustly stimulated mouse β cell mass, whereas samples from other age groups did not, suggesting that humans also exhibit a window of colonization by β cell–promoting microbes. By comparing microbial communities that could and could not elicit β cell development, we identified specific bacterial and fungal taxa (Escherichia coli, Enterococcus gallinarum, and Candida dubliniensis) that were sufficient to promote murine postnatal β cell expansion. RNA sequencing of islets from germ-free and conventional pups across the critical window revealed a necessary role for microbes in stimulating macrophage infiltration of islets. Among our microbial candidates, we found that C. dubliniensis colonization promoted islet macrophages most significantly. Further, ablation of macrophages reversed the pro–β cell effects of C. dubliniensis, indicating that macrophages are required to mediate β cell promotion by C. dubliniensis in the developing islet. C. dubliniensis cell wall modifications were critical components of this islet-fungal signaling axis. We also tested the capacity of C. dubliniensis to mitigate diabetes in mouse models and found that not only could it reduce disease prevalence and severity, but it could also promote β cell restoration in adult animals after ablation. Our study identifies a critical window in early life when transient enrichments of specific microbes are necessary to promote pancreatic β cell development. Bacteria and fungi provide important cues that are sufficient to promote this process. However, host sensing of these cues differs according to their microbial origins, highlighting the diverse host-microbe signaling mechanisms that have evolved to support insulin production. We describe a microbiota-mediated macrophage-dependent mechanism that supports recognition of distinct cell wall stimuli from commensal yeast, which may be used as a tool to prevent or reverse β cell loss. |
