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

Jennifer Hampton Hill,Eric A Franzosa,Curtis Huttenhower,Karen Guillemin

doi:10.7554/elife.20145

Abstract

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 β cell population during early larval development requires the intestinal microbiota and that specific bacterial members can restore normal β cell numbers. These bacteria share a gene that encodes a previously undescribed protein, named herein BefA (β Cell Expansion Factor A), which is sufficient to induce β 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 β cell proliferation in larval zebrafish. Our findings highlight a role for the microbiota in early pancreatic β cell development and suggest a possible basis for the association between low diversity childhood fecal microbiota and increased diabetes risk.

Highlights

Host-associated microbes play important roles in the development of animal digestive tracts (Bates et al, 2006; Semova et al, 2012; Sommer and Backhed, 2013)
Using a culture collection of zebrafish intestinal bacteria, we show that certain strains can restore b cell expansion in germ free (GF) fish
The microbiota is required for normal expansion of the larval b cell mass To investigate a possible role for the microbiota in pancreas development and in b cell expansion, we quantified total b cells in GF and conventionally reared (CV) Tg(-1.0insulin:eGFP) fish at 3, 4, 5 and 6 dpf (Figure 1A, Figure 1—source data 1)

Summary

Introduction

Host-associated microbes play important roles in the development of animal digestive tracts (Bates et al, 2006; Semova et al, 2012; Sommer and Backhed, 2013). Using the gnotobiotic zebrafish model, our group has shown previously that resident microbes promote host processes in the developing intestine such as epithelial differentiation (Bates et al, 2006) and proliferation (Cheesman et al, 2011). We use gnotobiotic zebrafish to demonstrate a role for resident microbes in promoting pancreatic b cell development. Initial b cells arise from precursors within the dorsal and ventral pancreatic buds (Biemar et al, 2001; Field et al, 2003; Wang et al, 2011).

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Results

Conclusion