Mediterranean diet consumption affects the endocannabinoid system in overweight and obese subjects: possible links with gut microbiome, insulin resistance and inflammation

Abstract

Purpose To investigate whether a Mediterranean diet (MD) affected the plasma concentrations of endocannabinoids (ECs), N-acylethanolamines (NAEs) and their specific ratios in subjects with lifestyle risk factors for metabolic diseases. To identify the relationship between circulating levels of these compounds and gut microbiome, insulin resistance and systemic inflammation. Methods A parallel 8-week randomised controlled trial was performed involving 82 overweight and obese subjects aged (mean ± SEM) 43 ± 1.4 years with a BMI of 31.1 ± 0.5 kg/m2, habitual Western diet (CT) and sedentary lifestyle. Subjects were randomised to consume an MD tailored to their habitual energy and macronutrient intake (n = 43) or to maintain their habitual diet (n = 39). Endocannabinoids and endocannabinoid-like molecules, metabolic and inflammatory markers and gut microbiome were monitored over the study period. Results The MD intervention lowered plasma arachidonoylethanolamide (AEA, p = 0.02), increased plasma oleoylethanolamide/palmitoylethanolamide (OEA/PEA, p = 0.009) and OEA/AEA (p = 0.006) and increased faecal Akkermansia muciniphila (p = 0.026) independent of body weight changes. OEA/PEA positively correlated with abundance of key microbial players in diet–gut–health interplay and MD adherence. Following an MD, individuals with low-plasma OEA/PEA at baseline decreased homeostatic model assessment of insulin resistance index (p = 0.01), while individuals with high-plasma OEA/PEA decreased serum high-sensitive C-reactive protein (p = 0.02). Conclusions We demonstrated that a switch from a CT to an isocaloric MD affects the endocannabinoid system and increases A. muciniphila abundance in the gut independently of body weight changes. Endocannabinoid tone and microbiome functionality at baseline drives an individualised response to an MD in ameliorating insulin sensitivity and inflammation. Clinical Trial Registry number and website NCT03071718; www.clinicaltrials.gov

Plasma Levels of Endocannabinoids and Their Analogues Are Related to Specific Fecal Bacterial Genera in Young Adults: Role in Gut Barrier Integrity

“…Interestingly, the oral supplementation of OEA for eight weeks caused a significant increase in the relative abundance of Akkermansia muciniphila in the colon of individuals with obesity [ 50 ]. Furthermore, higher plasma levels of the OEA/PEA ratio showed an increase in the relative abundance of Akkermansia muciniphila in the feces of middle-aged adults with obesity, which was associated with a reduction in systemic inflammation [ 18 ]. Interestingly, daily oral gavage administration, for 4 weeks, in the high-fat-diet-fed mice of Akkermansia muciniphila diet-restored the gut mucosal layer and increased gut levels of 2-AG and 2-OG, improving the gut barrier integrity and decreasing metabolic endotoxemia [ 51 ].…”

“…Conditional adipocyte-specific deficiency in mice of N-acyl phosphatidylethanolamine phospholipase D, an enzyme involved in the synthesis of N-acylethanolamines, increased body weight and fat mass, inducing gut microbiota dysbiosis [ 17 ]. Plasma levels of certain N-acylethanolamines were positively correlated with the relative abundance of fecal bacteria in middle adults [ 18 ]. Several studies have shown that the endocannabinoid system plays a role in regulating gastric secretion [ 5 ], motility [ 5 ], and gut permeability [ 19 ] by preserving or damaging the gut barrier integrity [ 20 ], by yet unknown mechanisms.…”

Impact of Mediterranean Diet on Chronic Non-Communicable Diseases and Longevity

“…MedDiet modified the endocannabinoid system and increased A. muciniphila abundance in the gut independently of body weight changes. Endocannabinoid tone and microbiome functionality at baseline were associated with individualized responses to MedDiet in ameliorating insulin sensitivity and inflammation [159].…”

Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism

“…Furthermore, the changes in the levels of 2-AG were associated with changes in Peptostrptococcaceae, Veillonellceae and Akkermansiaceae families [ 133 ]. Finally, a short- or long-term Mediterranean diet was associated with a lower circulating level of AEA and a higher fecal Akkermansia mucuniphilia , and this helped to improve insulin sensitivity and systemic inflammation [ 133 , 134 ].…”