Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens

Melissa Ellermann, Alline R. Pacheco, Angel G. Jimenez, Regan M. Russell, Santiago Cuesta, Aman Kumar, Wenhan Zhu, Gonçalo Vale, Sarah A. Martin, Prithvi Raj, Jeffrey G. McDonald, Sebastian E. Winter, Vanessa Sperandio

Research output: Contribution to journalArticlepeer-review

Abstract

Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.

Original languageEnglish (US)
Pages (from-to)650-665.e15
JournalCell
Volume183
Issue number3
DOIs
StatePublished - Oct 29 2020

Keywords

  • 2-AG
  • 2-arachidonoyl glycerol
  • Citrobacter rodentium
  • EHEC
  • QseC
  • Salmonella enterica
  • endocannabinoids
  • enterohemorrhagic E. coli
  • gut-brain axis
  • locus of enterocyte effacement
  • type three secretion system

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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