dc.contributor.author	O'Callaghan, Amy A.	en
dc.contributor.author	Dempsey, Elaine	en
dc.contributor.author	Iyer, Namrata	en
dc.contributor.author	Stiegeler, Sarah	en
dc.contributor.author	Mercurio, Kevin	en
dc.contributor.author	Corr, Sinéad C.	en
dc.contributor.funder	Science Foundation Ireland	en
dc.contributor.funder	Crohns and Colitis Foundation of America	en
dc.contributor.funder	Horizon 2020	en
dc.date.accessioned	2023-06-14T10:25:14Z
dc.date.available	2023-06-14T10:25:14Z
dc.date.issued	2021-07-19	en
dc.description.abstract	The metabolite-rich environment that is the intestinal lumen contains metabolic by-products deriving from microbial fermentation and host cell metabolism, with resident macrophages being constantly exposed to this metabolic flux. Succinate, lactate and itaconate are three metabolites secreted by primed macrophages due to a fragmented tri-carboxylic acid (TCA) cycle. Additionally, succinate and lactate are known by-products of microbial fermentation. How these metabolites impact biological functioning of resident macrophages particularly in response to bacterial infection remains poorly understood. We have investigated the potential influence of these metabolites on macrophage phagocytosis and clearance of () infection. Treatment of murine bone-marrow-derived macrophages (BMDMs) with succinate reduced numbers of intracellular early during infection, while lactate-treated BMDMs displayed no difference throughout the course of infection. Treatment of BMDMs with itaconate lead to higher levels of intracellular early in the infection with bacterial burden subsequently reduced at later time-points compared to untreated macrophages, indicative of enhanced engulfment and killing capabilities of macrophages in response to itaconate. Expression of engulfment mediators MARCKS, RhoB, and CDC42 were reduced or unchanged following succinate or lactate treatment and increased in itaconate-treated macrophages following infection. Nitric oxide (NO) levels varied while pro- and anti-inflammatory cytokines differed in secretory levels in all metabolite-treated macrophages post-infection with or in response to lipopolysaccharide (LPS) stimulation. Finally, the basal phenotypic profile of metabolite-treated macrophages was altered according to marker gene expression, describing how fluid macrophage phenotype can be in response to the microenvironment. Collectively, our data suggests that microbe- and host-derived metabolites can drive distinct macrophage functional phenotypes in response to infection, whereby succinate and itaconate regulate phagocytosis and bactericidal mechanisms, limiting the intracellular bacterial niche and impeding the pathogenesis of infection.	en
dc.description.sponsorship	Crohns and Colitis Foundation of America (Litwin IBD Pioneer award: 47894)	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	622491	en
dc.identifier.citation	O’Callaghan, A. A., Dempsey, E., Iyer, N., Stiegeler, S., Mercurio, K. and Corr, S. C. (2021) 'Intestinal metabolites influence macrophage phagocytosis and clearance of bacterial infection', Frontiers in Cellular and Infection Microbiology, 11, 622491 (13pp). doi: 10.3389/fcimb.2021.622491	en
dc.identifier.doi	10.3389/fcimb.2021.622491	en
dc.identifier.eissn	2235-2988	en
dc.identifier.endpage	13	en
dc.identifier.journaltitle	Frontiers in Cellular and Infection Microbiology	en
dc.identifier.startpage	1	en
dc.identifier.uri	https://hdl.handle.net/10468/14575
dc.identifier.volume	11	en
dc.language.iso	en	en
dc.publisher	Frontiers Media	en
dc.relation.project	info:eu-repo/grantAgreement/SFI/SFI Starting Investigator Research Grant (SIRG)/11/SIRG/B2099/IE/Exploration of the role of microRNA(miR)-21 in gut homeostasis and disease./	en
dc.relation.project	info:eu-repo/grantAgreement/EC/H2020::MSCA-COFUND-FP/754535/EU/APC Postdoctoral EXcellence Programme/APEX	en
dc.rights	© 2021, O’Callaghan, Dempsey, Iyer, Stiegeler, Mercurio and Corr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.	en
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	en
dc.subject	Intestinal infection	en
dc.subject	Itaconate	en
dc.subject	Lactate	en
dc.subject	Macrophage	en
dc.subject	Metabolite	en
dc.subject	Succinate	en
dc.title	Intestinal metabolites influence macrophage phagocytosis and clearance of bacterial infection	en
dc.type	Article (peer-reviewed)	en

Intestinal metabolites influence macrophage phagocytosis and clearance of bacterial infection

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