Macrophage metabolism in the intestine is compartment-specific and regulated by the microbiota

Abstract

Intestinal macrophages play a vital role in the maintenance of gut homeostasis through signals derived from the microbiota. We previously demonstrated that microbial-derived metabolites can shape the metabolic functions of macrophages. Here, we show that antibiotic-induced disruption of the intestinal microbiota dramatically alters both the local metabolite environment, and the metabolic functions of macrophages in the colon. Broad-spectrum antibiotic administration in mice increased expression of the large neutral amino acid transporter and accordingly, amino acid uptake. Subsequently, antibiotic administration enhanced the metabolic functions of colonic macrophages, increasing phosphorylation of components of mammalian/mechanistic target of rapamycin (mTOR) signalling pathways, increasing expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increasing mitochondrial function and increased levels of ECAR and OCR as a direct measure of glycolysis and OXPHOS. Small bowel macrophages were less metabolically active than in the colon, with macrophage metabolism being independent of the microbiota. Finally, we reveal tissue resident Tim4+ CD4+ macrophages exhibit enhanced fatty acid uptake alongside reduced fatty acid synthesis compared to their recruited counterparts. Thus the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for functions when monocyte recruitment and macrophage differentiation.