Diacylglycerol kinase synthesized by commensal Lactobacillus reuteri diminishes protein kinase C phosphorylation and histamine-mediated signaling in the mammalian intestinal epithelium
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Author(s)
Ganesh, B P
Ayyaswamy, S
Fultz, R
Major, A
Haag, A
Venable, S
Hall, Alexandra E.
Nelson, Jordan William
Esparza, Marcos A.
Lugo, Michael T
Date Issued
July 2017
Journal
Mucosal Immunology
Publisher
Springer Nature
Citation
Ganesh, B P, A Hall, S Ayyaswamy, J W Nelson, R Fultz, A Major, A Haag, et al. “Diacylglycerol Kinase Synthesized by Commensal Lactobacillus Reuteri Diminishes Protein Kinase C Phosphorylation and Histamine-Mediated Signaling in the Mammalian Intestinal Epithelium.” Mucosal Immunology 11, no. 2 (July 26, 2017): 380–393.
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Final published version
Abstract
Lactobacillus reuteri 6475 (Lr) of thehuman microbiome synthesizes histamine and can suppress inflammation via type 2 histamine receptor (H2R) activation in the mammalian intestine. Gut microbes such as Lr promote H2R signaling and may suppress H1R proinflammatory signaling pathways in parallel by unknown mechanisms. In this study,we identified a soluble bacterial enzyme known as diacylglycerol kinase (Dgk) from Lr that is secreted into the extracellular milieu and presumably into the intestinal lumen. DgK diminishes diacylglycerol (DAG) quantities in mammalian cells by promoting its metabolic conversion and causing reduced protein kinase C phosphorylation (pPKC) as a net effect in mammalian cells. We demonstrated that histamine synthesized by gut microbes (Lr) activates both mammalian H1R and H2R, but Lr-derived Dgk suppresses the H1R signaling pathway. Phospho-PKC and IKBα were diminished within the intestinal epithelium of mice and humans treated by wild-type (WT) Lr, but pPKC and IKBα were not decreased in treatment with δDdgkA Lr. Mucosal IL-6 and systemic interleukin (IL)-1α, eotaxin, and granulocyte colony-stimulating factor (G-CSF) were suppressed in WT Lr, but not in DdgkA Lr colonized mice. Collectively, the commensal microbe Lr may act as a "microbial antihistamine''by suppressing intestinal H1R-mediated proinflammatory responses via diminished pPKC-mediated mammalian cell signaling.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Mathematics
Massachusetts Institute of Technology. Department of Mechanical Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
Massachusetts Institute of Technology. Institute for Data, Systems, and Society
MIT Energy Initiative
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DOI of Published Version
https://doi.org/10.1038/MI.2017.58
