Fighting intestinal infections with the body's own endocannabinoids


Date:
October 7, 2020
Source:
UT Southwestern Medical Center
Summary:
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 shows.



FULL STORY ========================================================================== 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 UT Southwestern scientists shows.


==========================================================================
The findings, published online today 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.

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, Ph.D., 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, 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.

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 -- in order to express the virulence traits needed
for a successful infection.

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, they
became more susceptible to the bacterial pathogens.

Further experiments showed that 2-AG exerted these 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. Plugging this receptor with 2-AG prevents this
virulence program from activating, Sperandio explains, helping to protect against infection.

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 kick intestinal bacterial infections without antibiotics. This could be particularly useful for infections caused
by enterohemorrhagic Escherichia coli, 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," she says, "we may eventually treat infections in a whole
new way."

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


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

Endocannabinoids Inhibit the Induction of Virulence in Enteric
Pathogens.

Cell, 2020; DOI: 10.1016/j.cell.2020.09.022 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201007123119.htm

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