Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex.

Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals. [Display omitted] • The transporter Tarag is required for the enteroendocrine cell response to acetate • Acetate increases acetyl-CoA pools in tachykinin-expressing enteroendocrine cells • Acetyl-CoA pools modulate the activity of Tip60 histone acetylase complex • The Tip60 complex augments ecdysone-dependent transcription of PGRP-LC Microbe-derived acetate activates the Drosophila immunodeficiency pathway in a subset of intestinal enteroendocrine cells (EECs), which regulates expression of antimicrobial and enteroendocrine peptides. Jugder et al. reveal that acetate induces chromatin remodeling within EECs by specifically modulating the function of the Tip60 histone acetyltransferase complex via a Tip60-steroid hormone axis that is conserved in mammals. [ABSTRACT FROM AUTHOR]