An FXR-Casp6 Axis Mediated Bile Acid/Gut Microbiota Sensing Modulates Neonatal β-Cell Mass Expansion

Abstract

Weaning diet switch brings gut microbiome maturation along with postnatal formation of sufficient matured β-cell mass. The matured gut microbiota elevated agonistic components of bile acid (BA) pool towards farnesoid X receptor (FXR) that was paralleling with the declined β-cell FXR expression. To investigate whether BA/FXR could link postnatal β-cell development and gut microbiota maturation, we forced persistent FXR expression in β cells (βFxrKI) and found decreased neonatal β-cell mass growth and increased glycemia in weaned βFxrKI mice, which could be partially recovered by ablating gut microbiota before weaning. scRNA and scATAC seq analysis showed different β cell growth trajectories with suppressed intrinsic cell proliferation and elevated cell apoptosis in βFxrKI. Caspase-6 was transcriptionally regulated by FXR as its dominant downstream effector in β-cell. The negative regulation of the FXR-Casp6 axis on postnatal β-cell mass expansion reflected a programmed cellular response to gut microbiota maturation in neonatal mice.

Note:
Funding declaration: This study was funded by grants from the National Nature Science Foundation of China (92157112, 82088102, 82100835) and grants from National Key Research and Development Program of China 2021YFA1301103; Innovative research team of high-level local universities in Shanghai. Shanghai Sailing Program 21YF1426900.

Conflict of Interests: The authors declare no competing financial interests.

Ethical Approval: All animal experiments were performed in accordance with procedures approved by the Animal Care Committee of Shanghai Jiao Tong University School of Medicine.

Keywords: FXR, caspase-6, gut microbiome, bile acid, postnatal β-cell mass, diabetes