BefA, a microbiota-secreted membrane disrupter, disseminates to the pancreas and increases ß cell mass.

Microbiome dysbiosis is a feature of diabetes, but how microbial products influence insulin production is poorly understood. We report the mechanism of BefA, a microbiome-derived protein that increases proliferation of insulin-producing ß cells during development in gnotobiotic zebrafish and mice. BefA disseminates systemically by multiple anatomic routes to act directly on pancreatic islets. We detail BefA's atomic structure, containing a lipid-binding SYLF domain, and demonstrate that it permeabilizes synthetic liposomes and bacterial membranes. A BefA mutant impaired in membrane disruption fails to expand ß cells, whereas the pore-forming host defense protein, Reg3, stimulates ß cell proliferation. 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.

From bugs to ß cells.

Do ancient microbial irritants offer early life protection against diabetes?

A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development.

Resident microbes play important roles in the development of the gastrointestinal tract, but their influence on other digestive organs is less well explored. Using the gnotobiotic zebrafish, we discovered that the normal expansion of the pancreatic ß cell population during early larval development requires the intestinal microbiota and that specific bacterial members can restore normal ß cell numbers. These bacteria share a gene that encodes a previously undescribed protein, named herein BefA (ß Cell Expansion Factor A), which is sufficient to induce ß cell proliferation in developing zebrafish larvae. Homologs of BefA are present in several human-associated bacterial species, and we show that they have conserved capacity to stimulate ß cell proliferation in larval zebrafish. Our findings highlight a role for the microbiota in early pancreatic ß cell development and suggest a possible basis for the association between low diversity childhood fecal microbiota and increased diabetes risk.