The endocannabinoid system (ECS) regulates metabolism and plays an important role in sugar metabolism and gut flora. Italian and French researchers found in a study of overweight people that diet influences the endocannabinoid system and gut microbiome.
The study shows that after changing their diet to a Mediterranean diet – consisting of fruit, vegetables, fish and nuts, for example – the study participants had more good intestinal bacteria and their waist and hip circumferences decreased. In addition, the levels of the endocannabinoid anandamide, which binds to the same receptors as tetrahydrocannabinol (THC), decreased.
What is a Mediterranean diet?
The Mediterranean diet is a complex concept. Simplified, we can compare it to the western dietary style like this:
Compared to the Western diet, the Mediterranean diet is characterised by a higher consumption of unsaturated fatty acids (e.g. nuts, fish), long-chain carbohydrates (e.g. whole grain products), vegetable proteins (e.g. legumes) and micronutrients. The diet in western countries, on the other hand, is characterised by meat, saturated fatty acids and quickly digestible carbohydrates (e.g. soft drinks).
Epidemiological studies showed that Mediterranean diets are associated with a reduced incidence of metabolic diseases and obesity. How a person responds to a change in diet depends on the function of the endocannabinoid system and the composition of the intestinal flora. The microbiome regulates the permeability of the intestinal epithelium and thereby influences metabolic inflammatory processes.
Controlled study with 82 overweight people
To find out more about the relationship between the endocannabinoid system, gut microbiome, insulin resistance and inflammation, a team of researchers from the University of Naples, Italy, conducted a randomised trial to investigate the effects of dietary changes in healthy individuals. In order to be able to evaluate the effects independently of body type and weight, a total of 82 participants with risk factors for metabolic diseases and similar lifestyles were selected from an original 334 people.
Selection criteria for the study were:
- Healthy men and women between 20 and 65 years of age
- Body mass index (BMI) of 24 or higher, corresponding to overweight
- No intake of probiotics, functional foods and food supplements
- Eating less than three portions of fruit and vegetables a day
- Low-fibre diet with a maximum of two portions of whole grain products daily
- Sedentary lifestyle
With an average body mass index (BMI) of 31.1, the 82 participants were overweight, which can lead to many diseases such as type 2 diabetes (insulin resistance, altered glucose tolerance) and fatty liver. The participants, who were on average 43 years old, ate a western diet and did little exercise.
The participants were randomly divided into two groups: One half (39 people) continued the Western diet style as usual. The other 43 people switched to an isocaloric (i.e. according to need), Mediterranean diet. The participants kept a food diary. Waist circumference and hip circumference as well as weight, body fat, body water and fat-free mass were recorded regularly. In the course of the eight-week study phase, endocannabinoids as well as metabolic and inflammatory parameters were determined in blood samples. The scientists determined the composition of the intestinal microbiome through stool samples.
Endocannabinoids and N-acylethanolamines investigated were:
- Arachidonylethanolamide (AEA, anandamide)
- Oleoylethanolamide (OEA)
- Palmitoylethanolamide (PEA)
In addition, the relationship between the endocannabinoids OEA and AEA and between OEA and PEA were investigated. In particular, changes resulting from the dietary change were investigated in order to better understand the relationship between the gut microbiome, diet, insulin resistance (HOMA-IR = Homeostasis Model Assessment for Insulin Resistance) and inflammation (hs-CRP = high-sensitivity C-reactive protein). For this purpose, blood sugar and insulin as well as the inflammation value high-sensitivity C-reactive protein were determined from fasting blood samples.
Mediterranean diet lowers anandamide levels
At the beginning of the study, the 82 participants had a similar dietary pattern with low-fibre white flour products, snacks, oils and fats, and meat. The 43 participants in the Mediterranean diet ate less of these foods over the course of the study and met their energy needs with fruits, vegetables, legumes, whole grains, fish and nuts.
After eight weeks on the Mediterranean diet, reduced anandamide levels were found in the blood. In contrast, the concentrations of 2-arachidonylglycerol (2-AG), linoleoylethanolamide (LEA), OEA and PEA did not change significantly. After 4 and 8 weeks, the ratio between OEA and PEA and between OEA and AEA increased. The research team observed a negative relationship between the level of the OEA/AEA ratio and hip and waist circumference. These results show: Mediterranean diet and high OEA/AEA levels are related to a slimmer figure.
How do endocannabinoids, gut microbiome and metabolism interact?
The endocannabinoid system regulates the balance, the so-called homeostasis of many body processes such as energy metabolism, appetite, pain, inflammation and immune system. Endocannabinoids and related substances (N-acylethanolamines) influence metabolism and interact with the gut microbiome. They are involved in the development of metabolic disorders and obesity.
Blood levels of endocannabinoids and N-acylethanolamines are a marker of white adipose tissue distribution and reflect cholesterol levels and insulin resistance in obesity.
They influence the pleasure of eating and have an appetite-regulating effect. The psychotropic cannabinoid tetrahydrocannabinol (THC), for example, increases appetite.
Studies in patients with an ileostomy have previously shown links between endocannabinoids, nutrition and systemic inflammatory responses.
Mediterranean diet increases beneficial gut bacterium Akkermansia muciniphila
Particularly important for intestinal health and maintenance of metabolic homeostasis is the bacterium Akkermansia muciniphila, which feeds on mucins (mucins) of the intestinal mucosa and thus contributes to the maintenance of the intestinal barrier. Stool tests showed that the intestinal flora responded to the Mediterranean diet: the reduced anandamide level was associated with an increased presence of this beneficial intestinal bacterium.
High concentrations of the endocannabinoids OEA, PEA, LEA and anandamide as well as a low OEA/PEA ratio correlated with reduced occurrence of Akkermansia muciniphila. In contrast, a high OEA/AEA ratio was associated with increased occurrence of this intestinal inhabitant.
The bacterium is reduced in diseases associated with dysbiosis, disturbed intestinal barrier and endotoxemia, such as type 2 diabetes, inflammatory bowel disease (IBD) and hypertension. According to the research team, the high concentration of Akkermansia muciniphila is an indicator of a better intestinal barrier and less obesity. In addition, other microorganisms important for intestinal health were influenced by the endocannabinoid system.
Improvement of insulin resistance, cholesterol levels and systemic inflammation
The randomised study showed that diet influences endocannabinoids. Switching from a Western to a Mediterranean diet influenced the occurrence of Akkermansia muciniphila in the gut microbiome. The effects of the Mediterranean diet were individual and dependent on the state of the endocannabinoid system and the microbiome before the dietary change.
The Mediterranean diet is therefore a healthy eating style and can improve insulin sensitivity and systemic inflammation. Anandamide concentration in the blood may indicate changes in intestinal permeability and dysbiosis of intestinal bacteria.
The OEA/PEA ratio could reflect barrier function: Participants with the highest OEA/PEA levels had higher concentrations of good gut bacteria (e.g. Bacteroides, Bifidobacteria, Clostridia, Roseburia) that break down fibre and protein and produce short-chain fatty acids essential for gut health. Participants with low OEA/PEA ratios, on the other hand, showed an increased presence of bacteria associated with inflammation, obesity and diets with animal foods. Participants with higher OEA/PEA ratios have healthier gut flora, as evidenced by lower anandamide and higher 2-AG concentrations. High OEA/PEA and OEA/AEA levels were associated with reduced cholesterol levels.
Studies in obese people and patients with inflammatory bowel disease thus show increasing evidence that anandamide mediates the effects of obesity on the intestinal barrier, permeability and inflammation. Mediterranean diets can lower anandamide and thereby have metabolic and anti-inflammatory effects.
Tagliamonte S, Laiola M, Ferracane R, et al. Mediterranean diet consumption affects the endocannabinoid system in overweight and obese subjects: possible links with gut microbiome, insulin resistance and inflammation. Eur J Nutr. 2021;60(7):3703-3716. doi:10.1007/s00394-021-02538-8