The Sterol Transporter Npc2c Controls Intestinal Stem Cell Mitosis and Host-Microbiome Interactions in .

Cholesterol is necessary for all cells to function. The intracellular cholesterol transporters Npc1 and Npc2 control sterol trafficking and their malfunction leads to Neimann-Pick Type C disease, a rare disorder affecting the nervous system and the intestine. Unlike humans that encode single Npc1 and Npc2 transporters, flies encompass two Npc1 (Npc1a-1b) and eight Npc2 (Npc2a-2h) members, and most of the family genes remain unexplored. Here, we focus on the intestinal function of in the adult. We find that is necessary for intestinal stem cell (ISC) mitosis, maintenance of the ISC lineage, survival upon pathogenic infection, as well as tumor growth. Impaired mitosis of -silenced midguts is accompanied by reduced expression of genes, and genes encoding ISC regulators, such as , and . ISC-specific silencing induces - expression, a phenotype reminiscent of Gram-negative bacteria overabundance. Metagenomic analysis of -depleted midguts indicates intestinal dysbiosis, whereby decreased commensal complexity is accompanied by increased gamma-proteobacteria. ISC-specific silencing also results in increased cholesterol aggregation. Interestingly, administration of the non-steroidal ecdysone receptor agonist, RH5849, rescues mitosis of -silenced midguts and increases expression of the ecdysone response gene , underscoring the role of and sterols in ecdysone signaling. Assessment of additional family members indicates potential redundant roles with in ISC control and response to ecdysone signaling. Our results highlight a previously unidentified essential role of in ISC mitosis, as well as an important role in ecdysone signaling and microbiome composition in the midgut.