Diacylglycerol kinase synthesized by commensal Lactobacillus reuteri diminishes protein kinase C phosphorylation and histamine-mediated signaling in the mammalian intestinal epithelium

B. P. Ganesh, A. Hall, S. Ayyaswamy, J. W. Nelson, R. Fultz, A. Major, A. Haag, M. Esparza, M. Lugo, S. Venable, M. Whary, J. G. Fox, James Versalovic

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Lactobacillus reuteri 6475 (Lr) of the human 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 IκBα were diminished within the intestinal epithelium of mice and humans treated by wild-type (WT) Lr, but pPKC and IκBα were not decreased in treatment with ΔdgkA 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 ΔdgkA 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.

Original languageEnglish (US)
Pages (from-to)380-393
Number of pages14
JournalMucosal Immunology
Volume11
Issue number2
DOIs
StatePublished - Mar 1 2018

Keywords

  • Animals
  • Bacterial Proteins/genetics
  • Cytokines/metabolism
  • Diacylglycerol Kinase/genetics
  • Histamine/immunology
  • Humans
  • Inflammation Mediators/metabolism
  • Intestinal Mucosa/immunology
  • Lactobacillus reuteri/metabolism
  • Mice
  • Mice, Inbred BALB C
  • Microbiota
  • Mutation/genetics
  • Phosphorylation
  • Protein Kinase C/metabolism
  • Receptors, Histamine H1/metabolism
  • Receptors, Histamine H2/metabolism
  • Signal Transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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