Cannabinoids may combat intestinal infections

Endocannabinoids, the signaling molecules that operate the body's natural endocannabinoid system, can effectively switch off the genes needed for the development of pathogenic intestinal bacteria, according to new research.

Led by scientists from the University of Texas Southwestern and published in Cell, the new study details how an increase in the production of these endocannabinoid molecules in mice effectively protected the animals from the most extreme symptoms of gastrointestinal infection.

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Researchers claim that their findings may help explain why the use of cannabis is often reported as helpful for various intestinal diseases and may eventually lead to new methods of combating gastrointestinal infection in humans.

Discovered in the early 1990s by scientists researching THC, the endocannabinoid system (ECS) plays a major role in the action of the central nervous system and the body's response to various endogenous and environmental factors.

The ECS is composed of different endocannabinoid receptors, endocannabinoid molecules, and enzymes responsible for the generation and degradation of these endocannabinoids. The most abundant and perhaps best-known parts of the ECS are the cannabinoid receptors CB1 and CB2. These are the receptors affected by THC when a person uses cannabis.

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However, outside of cannabis use, the ECS is modulated by endocannabinoids naturally produced by the body. The two main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), are generated by the body when needed and act on cannabinoid receptors to ensure that the ECS is functioning properly.

In recent years, more in-depth research conducted on these compounds and the broader endocannabinoid system has highlighted the area as a potential therapeutic pathway for pain, inflammation, and immune response, and even pathological conditions such as multiple sclerosis and Alzheimer's disease.

2-AG is effective against three different bacterial infections in mice

In the new study, researchers from UT Southwestern analyzed mice that were genetically altered to overproduce the endocannabinoid 2-AG in various organs, including the intestines. To study the effects of this endocannabinoid on host susceptibility to infection, the researchers then exposed the genetically altered mice, along with a group of unaltered littermates, to three different bacterial pathogens.

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The first pathogen of interest studied was Citrobacter rodentium, a pathogen that attacks the colon in rodents and causes extensive inflammation and diarrhea. Although there have been no reported cases of C. rodentium in humans, this pathogen is the only known fixture to naturally infect mice and is therefore a very useful model for understanding the pathogenesis of other human pathogens, such as Escherichia coli (E. Coli).

The researchers observed that the mutant mice developed only mild symptoms associated with C. rodentium infection, compared to the extreme gastrointestinal discomfort experienced by the unaltered animals. A closer examination of the mice's colons also revealed that the mutant mice had significantly lower levels of inflammation and signs of infection. These mutants also had significantly lower loads of C. rodentium in their fecal matter and recovered from the infection a few days faster than the control group of mice from the same litter.

Taking it a step further, the researchers repeated the experiment using unaltered mice that this time received a drug that increased 2-AG levels in the body. These mice also showed similar positive health benefits with the increased 2-AG.

In addition to being effective against C. rodentium, the research team also found that increased levels of 2-AG were able to limit infection by Salmonella typhimurium, a bacterial pathogen that causes gastroenteritis in humans, and in mice can cause symptoms similar to typhoid fever.

Likewise, increased levels of 2-AG were able to effectively prevent the spread of enterohemorrhagic E. coli (EHEC). This particular form of E. coli is most commonly seen in humans and causes severe intestinal infection. Unlike other E. coli pathogens, EHEC can also produce an extremely potent toxin, known as Shiga toxin, which attacks the lining of the intestinal wall.

In addition to studies with mouse models, researchers also treated mammalian cells in Petri dishes with the bacterial pathogens. They noted that when they applied a drug that inhibited the production of 2-AG in the cells, the cells became more susceptible to bacterial infection - an observation that further reinforced the importance of endocannabinoid signaling for infection.

More than just treating inflammation

Seeing the effects of 2-AG in mice and cell cultures, the UT Southwestern team began to examine exactly how the endocannabinoid was influencing the body. They found that the molecule was able to block a specific bacterial receptor, known as QseC.

When the QseC receptor detects host signaling molecules, epinephrine and norepinephrine, it triggers the molecular cascade necessary to establish infection. 2-AG is able to "turn on" this receptor, preventing this cascade and helping the body avoid infections, explained lead researcher and UTSW professor Vanessa Sperandio, PhD.

Sperandio believes that these findings may extend to explain some of the positive effects observed in inflammatory intestinal conditions after cannabis use. While other research has linked these effects to the anti-inflammatory properties of some plant cannabinoids, Sperandio notes that other recent research has also indicated that these conditions tend to have a bacterial component as well, and that this too may be affected by the presence of cannabinoids.

"Harnessing the power of naturally produced compounds in the body and plants, we may eventually treat infections in an entirely new way," Sperandio said in a statement.

A crucial pathway where this could be useful would be in the treatment of enterohemorrhagic E. coli in humans. When exposed to antibiotics, this pathogen begins to excrete deadly toxins, rendering conventional treatments obsolete and even harmful. Developing a treatment based on blocking the QseC receptor could provide an alternative pathway for care that would mitigate this risk.

Source: Alexander Beadle/Analytical Cannabis