A microbiota membrane disrupter disseminates to the pancreas and increases β-cell mass

Hill, J. H.; Massaquoi, M. S.; Sweeney, E. G.; Wall, E. S.; Bell, R.; Kallio, K.; Derrick, D.; Murtaugh, L. C.; Parthasarathy, R.; Remington, S. J.; Round, J. L.; Guillemin, K.

doi:10.1101/2022.03.24.485696

bioRxiv · 10.1101/2022.03.24.485696

A microbiota membrane disrupter disseminates to the pancreas and increases β-cell mass

Hill, J. H.·Massaquoi, M. S.·Sweeney, E. G.·Wall, E. S.·Bell, R.·Kallio, K.·Derrick, D.·Murtaugh, L. C.·Parthasarathy, R.·Remington, S. J.·Round, J. L.·Guillemin, K.

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Abstract

Microbiome dysbiosis is a feature of diabetes, but how microbial products influence insulin production is poorly understood. Here we report the mechanism of BefA, a microbiome-derived protein that increases proliferation of insulin-producing {beta}-cells during pancreatic development in gnotobiotic zebrafish and mice. BefA disseminates systemically via multiple anatomic routes to act directly on pancreatic islets. We report the structure of BefA, 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 {beta}-cells whereas the pore-forming host defense protein, Reg3, stimulates {beta}-cell proliferation. Our work demonstrates that membrane permeabilization by microbiome-derived and host defense proteins is necessary and sufficient for {beta}-cell expansion during pancreas development, thereby connecting microbiome composition with diabetes risk.

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Hill, J. H., Massaquoi, M. S., Sweeney, E. G., Wall, E. S., Bell, R., Kallio, K., Derrick, D., Murtaugh, L. C., Parthasarathy, R., Remington, S. J., Round, J. L., Guillemin, K.. 2022-03-24. A microbiota membrane disrupter disseminates to the pancreas and increases β-cell mass. https://doi.org/10.1101/2022.03.24.485696

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