PMID- 34350128
OWN - NLM
STAT- MEDLINE
DCOM- 20210817
LR  - 20210817
IS  - 2235-2988 (Electronic)
IS  - 2235-2988 (Linking)
VI  - 11
DP  - 2021
TI  - Intestinal Metabolites Influence Macrophage Phagocytosis and Clearance of 
      Bacterial Infection.
PG  - 622491
LID - 10.3389/fcimb.2021.622491 [doi]
LID - 622491
AB  - 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 
      Escherichia coli (E. coli) infection. Treatment of murine bone-marrow-derived 
      macrophages (BMDMs) with succinate reduced numbers of intracellular E. coli 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 E. coli 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 E. coli infection. Nitric oxide (NO) 
      levels varied while pro- and anti-inflammatory cytokines differed in secretory 
      levels in all metabolite-treated macrophages post-infection with E. coli 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.
CI  - Copyright (c) 2021 O'Callaghan, Dempsey, Iyer, Stiegeler, Mercurio and Corr.
FAU - O'Callaghan, Amy A
AU  - O'Callaghan AA
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
FAU - Dempsey, Elaine
AU  - Dempsey E
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
FAU - Iyer, Namrata
AU  - Iyer N
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
AD  - APC Microbiome Ireland, University College Cork, Cork, Ireland.
FAU - Stiegeler, Sarah
AU  - Stiegeler S
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
FAU - Mercurio, Kevin
AU  - Mercurio K
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
FAU - Corr, Sinead C
AU  - Corr SC
AD  - Department of Microbiology, Moyne Institute of Preventative Medicine, School of 
      Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
AD  - APC Microbiome Ireland, University College Cork, Cork, Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210719
PL  - Switzerland
TA  - Front Cell Infect Microbiol
JT  - Frontiers in cellular and infection microbiology
JID - 101585359
RN  - 0 (Lipopolysaccharides)
SB  - IM
MH  - Animals
MH  - *Bacterial Infections
MH  - *Escherichia coli
MH  - Lipopolysaccharides
MH  - Macrophages
MH  - Mice
MH  - Phagocytosis
PMC - PMC8327167
OTO - NOTNLM
OT  - intestinal infection
OT  - itaconate
OT  - lactate
OT  - macrophage
OT  - metabolite
OT  - succinate
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/08/06 06:00
MHDA- 2021/08/18 06:00
PMCR- 2021/01/01
CRDT- 2021/08/05 06:29
PHST- 2020/10/28 00:00 [received]
PHST- 2021/06/30 00:00 [accepted]
PHST- 2021/08/05 06:29 [entrez]
PHST- 2021/08/06 06:00 [pubmed]
PHST- 2021/08/18 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcimb.2021.622491 [doi]
PST - epublish
SO  - Front Cell Infect Microbiol. 2021 Jul 19;11:622491. doi: 
      10.3389/fcimb.2021.622491. eCollection 2021.