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

Scott, Nicholas A., Lawson, Melissa A. E., Hodgetts, Ryan James, Le Gall, Gwénaëlle ORCID:, Hall, Lindsay J. ORCID: and Mann, Elizabeth R. (2022) Macrophage metabolism in the intestine is compartment specific and regulated by the microbiota. Immunology, 166 (1). pp. 138-152. ISSN 0019-2805

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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 the expression of the large neutral amino acid transporter LAT1 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 signalling pathways, with increased expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increased mitochondrial function, increased rate of extracellular acidification (ECAR; measure of glycolysis) and increased rate of oxygen consumption (OCR; measure of OXPHOS). Small bowel macrophages were less metabolically active than their colonic counterparts, with macrophage metabolism in the small intestine 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 recruited macrophages. Thus, the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for monocyte recruitment and macrophage differentiation.

Item Type: Article
Additional Information: Research Funding: Wellcome Trust. Grant Numbers: 206206/Z/17/, 100974/C/13/Z, 220876/Z/20/Z; Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme Gut Microbes and Health. Grant Numbers: BB/R012490/1, BBS/E/F/000PR10353, BBS/E/F/000PR10356
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health
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Depositing User: LivePure Connector
Date Deposited: 11 Mar 2022 16:30
Last Modified: 19 Oct 2023 03:17
DOI: 10.1111/imm.13461


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