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Fighting Intestinal Infections with Body's Own Endocannabinoids: Native Chemicals Similar to Those Found in Cannabis Can Inhibit Bacterial Virulence, UTSW-Led Study Suggests

Endocannabinoids, signaling molecules produced in the body that share features with chemicals found in marijuana, can shut down genes needed for some pathogenic intestinal bacteria to colonize, multiply, and cause disease, new research led by University of Texas (UT) Southwestern (UTSW) scientists shows. The findings, published online on October 7, 2020 in Cell, could help explain why the cannabis plant--the most potent part of which is marijuana--can lessen the symptoms of various bowel conditions and may eventually lead to new ways to fight gastrointestinal infections. The Cell article is titled” Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens.” Discovered in 1992, endocannabinoids are lipid-based neurotransmitters that play a variety of roles in the body, including regulating immunity, appetite, and mood. Cannabis and its derivatives have long been used to relieve chronic gastrointestinal conditions, including irritable bowel syndrome and inflammatory bowel disease. Studies have shown that dysregulation of the body’s endocannabinoid system can lead to intestinal inflammation and affect the makeup of gut microbiota, the population of different bacterial species that inhabit the digestive tract. However, study leader Vanessa Sperandio (photo), PhD, Professor of Microbiology and Biochemistry at UTSW, says it’s been unknown whether endocannabinoids affect susceptibility to pathogenic gastrointestinal infections.

To help answer this question, Dr. Sperandio and her colleagues worked with mice genetically altered to overproduce the potent mammalian endocannabinoid 2-arachidonoyl glycerol (2-AG) in various organs, including the intestines. When the researchers infected these animals and their unmodified littermates with Citrobacter rodentium, a bacterial pathogen that attacks the colon and causes marked inflammation and diarrhea, the mutant mice developed only mild symptoms compared with the more extreme gastrointestinal distress exhibited by their littermates. Examination of the mutant animals’ colons showed far lower inflammation and signs of infection. These mice also had significantly lower fecal loads of C. rodentium bacteria and cleared their infection days faster than their unmodified littermates. Treating genetically unmodified animals with a drug that raised levels of 2-AG in the intestines produced similar positive effects.

Dr. Sperandio’s team found that increased levels of 2-AG could also attenuate Salmonella typhimurium infections in mice and impede enterohemorrhagic Escherichia coli--a particularly dangerous gastrointestinal bacteria that infects humans—by interfering with the expression of the virulence traits these bacteria need for a successful infection.

The mammalian cannabinoid receptors (CB1 and CB2) sense endogenous cannabinoids and plant and synthetic cannabinoids to engender a response in the host that leads to decreased inflammation, intestinal motility and secretion, and increased appetite (see figure below). Mammalian endocannabinoids are also sensed by a bacterial cannabinoid receptor to decrease virulence of enteric pathogens.

Conversely, when the researchers treated mammalian cells in petri dishes with tetrahydrolipstatin, a Food and Drug Administration-approved compound sold commercially as Alli that inhibits 2-AG production, these cells became more susceptible to the bacterial pathogens.

Further experiments showed that 2-AG exerted these anti-bacterial effects on C. rodentium, S. typhimurium, and E. coli by blocking a bacterial receptor known as QseC. When this receptor senses the host signaling molecules epinephrine and norepinephrine, it triggers a molecular cascade necessary to establish infection. Blocking this receptor with 2-AG prevents this virulence program from activating, Dr. Sperandio explains, helping to protect against infection.

Dr. Sperandio notes that these findings could help explain some of the effects of cannabis use on inflammatory bowel conditions. Although studies have shown that cannabis can lower inflammation, recent research has shown that these conditions also tend to have a bacterial component that might be positively affected by plant cannabinoids.

In addition, cannabis compounds, or synthetic derivatives, could eventually help patients defeat intestinal bacterial infections without antibiotics. This could be particularly useful for infections caused by enterohemorrhagic Escherichia coli, Dr. Sperandio says, which produces a deadly toxin when it’s treated with antibiotics, rendering these drugs not only counterproductive, but extremely dangerous. Because many virulent bacteria that colonize areas elsewhere in the body also have the QseC receptor, she adds, this strategy could be used more broadly to fight a variety of infections.

“By harnessing the power of natural compounds produced in the body and in plants,” Dr. Sperandio says, “we may eventually treat infections in a whole new way.”

Other UTSW researchers who contributed to this study include first author Melissa Ellermann, together with Alline R. Pacheco, Angel G. Jimenez, Regan Russell, Santiago Cuesta, Aman Kumar, Wenhan Zhu, Gonçalo Vale, Sarah A. Martin, Prithvi Raj, Jeffrey McDonald, and Sebastian E. Winter.

[Press release] [Cell abstract

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The mammalian cannabinoid receptors (CB1 and CB2) sense endogenous cannabinoids and plant and synthetic cannabinoids to engender a response in the host that leads to decreased inflammation, intestinal motility and secretion, and increased appetite. Mammalian endocannabinoids are also sensed by a bacterial cannabinoid receptor to decrease virulence of enteric pathogens. (Credit:UTSW).