October 11, 2022 | Microbiome

Shaping your metabolism – gut microbiota and the endocannabinoidome

In the early 2010s, the research community got excited about the idea that the gut microbiota might be a “master orchestrator” of metabolism and obesity. Studies showed that mice either remained slim or gained weight, depending on whether they received a human gut microbiota transplant from a slim person or someone obese. But since that time, scientists have continued trying to uncover the complex processes that control human metabolism – and while gut microbiota indeed may be part of the picture, a more complete understanding of these mechanisms will be needed to make a clinically relevant difference for weight loss in humans.

Dr. Cristoforo Silvestri of Université Laval, Canada, says one additional complex system must be understood to discern the relationship between the gut microbiota and obesity: the endocannabinoid system. This consists of endocannabinoid molecules (naturally produced cannabinoids), receptors and enzymes.

“This system is defined by the principal active component of cannabis, which is THC,” he says. Thus, the endocannabinoid system encompasses receptors activated by THC (tetrahydrocannabinol), plus all of the other compounds made in the body that happen to activate these receptors. These are generally a variety of lipids that look nothing like THC structurally. So if the endocannabinoid receptors in the body are “locks” and THC is the “key,” it’s as if an unpredictable assortment of key-like objects also fit into the lock.

In the context of metabolic health, Dr. Silvestri prefers to expand this complex system to include structurally and functionally similar compounds that are not a perfect fit for the receptors – sometimes referred to as “the endocannabinoid system and related bioactive lipids”. He calls this broader system the “endocannabinoidome”.

Using mouse models, Dr. Silvestri’s work investigates how the endocannabinoidome, gut microbes and metabolism are closely intertwined.

He says, “We really think the interaction between the gut microbiome and the endocannabinoidome, [both of which] can respond to multiple external and lifestyle factors, is important for regulating metabolism, as well as mental health through the gut–brain axis.”

Dr. Silvestri and colleagues have developed three lines of evidence showing the bidirectional interaction between gut microbiome and endocannabinoidome.

First, they found germ-free mice – lacking gut microbiota – have disordered endocannabinoidomes. The altered gene expression in this system was partially restored when the mice were given a fecal transplant from normal mice, showing the normalizing effect of gut microbes on the whole system.

Next, they looked at mouse genetic models that were known to have an altered endocannabinoidome and whose metabolism had gone awry so that they did not gain weight on a high-fat diet. These mice, they found, had a different gut microbiota from normal mice – and the microbiota differences (i.e., certain bacteria responding very differently to the high-fat diet in the two types of mice) helped explain the origin of the metabolic/weight differences.

Finally, Silvestri and colleagues picked the endocannabinoid 2-AG and tested whether it had the potential to change bacterial communities in vitro. When they combined 2-AG with fecal communities from normal mice, they found that various bacterial families, which were identified as changing in the genetic model mentioned above, were similarly altered. This backed the idea that the endocannabinoidome exerts pressure on the gut microbiota.

Dr. Silvestri’s group continues to expand knowledge on the endocannabinoidome and how it works in concert with gut microbes to shape host metabolism. The ultimate goal is to find new strategies to address weight loss in humans. Silvestri says he is collaborating with others to test a number of compounds that have shown promise preclinically and appear to work through the gut microbiota–endocannabinoidome axis: oleoylethanolamide provided systemically, low-dose capsaicinoids, and a THC analog in prescription drug form.

“We’re investigating more and more how these interactions are modifying the metabolism of the host organism, as well as the compounds produced by the gut microbiome,” says Silvestri. “I think the gut microbiome could be a major way in which cannabinoids that are ingested are able to modify metabolism.”

For most experiments, Dr. Silvestri’s team relies upon the DNeasy PowerSoil Pro Kit, the DNeasy 96 PowerSoil Pro Kit and the DNeasy 96 PowerSoil Pro QIAcube HT Kit on the QIAcube HT for high-throughput extractions for most applications. Additionally, the team uses the QIAseq 16S/ITS panels (V3V4) for some of their sequencing work. The group also recently purchased a QIAxcel Advanced instrument for automated electrophoresis analysis.

“We find the new Pro technology in the DNeasy PowerSoil Pro Kit excellent at isolating high yields of microbial DNA from stool and gut samples,” he says.

To find out more about Dr. Silvestri’s research on the endocannabinoidome and obesity, you can view his presentation here.

Dr. Cristoforo Silvestri
About Dr. Cristoforo Silvestri

Dr. Silvestri is an Assistant Professor at the Faculty of Medicine at Université Laval, Quebec, Canada. His laboratory (in the Quebec Heart and Lung Institute) focuses on the molecular and cellular actions of the endocannabinoid system on metabolism. He also holds the Sentinel North partnership research chair on the gut microbiome-endocannabinoid system as an integrator of extreme environmental influences on bioenergetics.

Dr. Silvestri was a guest presenter at QIAGEN Human Microbiome Days, 2021.