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

Silvia Tagliamonte, Manolo Laiola, Rosalia Ferracane, Marilena Vitale, Maria A Gallo, Victoria Meslier, Nicolas Pons, Danilo Ercolini, Paola Vitaglione, Silvia Tagliamonte, Manolo Laiola, Rosalia Ferracane, Marilena Vitale, Maria A Gallo, Victoria Meslier, Nicolas Pons, Danilo Ercolini, Paola Vitaglione

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.

Keywords: Akkermansia muciniphila; Cardiovascular disease risk; Gut barrier; Gut microbiome; Obesity.

Conflict of interest statement

On behalf of all authors, the corresponding author states that there is no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Violin plots showing the distribution of plasma endocannabinoids (a), concentrations of N-acylethanolamines (b), and box plots showing the plasma OEA/PEA ratio (c) and the OEA/AEA ratio (d) in participants from the control group (CT) and the Mediterranean diet group (MD) at baseline (0 wk), 4 weeks (4 wk) and 8 weeks (8 wk). # p < 0.05 within group by Wilcoxon test. In C and D, two outliers were removed for simpler visualisation. 2-AG, 2-Arachidonoylglicerol; AEA, Arachidonoylethanolamide; LEA, Linoylethanolamide; OEA, Oleoylethanolamide; PEA, Palmitoylethanolamide
Fig. 2
Fig. 2
Faecal Akkermansia muciniphila relative abundance calculated from shotgun metagenomics in participants from the control group (CT) and Mediterranean diet group (MD) at baseline (0 wk), 4 weeks (4 wk) and 8 weeks (8 wk). § p < 0.05 pairwise time points (Δ) between CT and MD by the Mann–Whitney test
Fig. 3
Fig. 3
Heatmap showing hierarchical ward-linkage clustering of AEA and the OEA/PEA ratio based on Spearman’s correlation with gut microbiome species. The colour scale represents the magnitude of Spearman’s rho coefficient, with red indicating negative correlations and blue indicating positive correlations. Adjustments were performed using the Benjamini–Hochberg procedure, and Spearman’s rho values were filtered by maintaining correlations with at least one false discovery rate (FDR) of 

Fig. 4

Heatmap correlation matrix between plasma…

Fig. 4

Heatmap correlation matrix between plasma ECs, NAEs, OEA/PEA ratio, OEA/AEA ratio and food…

Fig. 4
Heatmap correlation matrix between plasma ECs, NAEs, OEA/PEA ratio, OEA/AEA ratio and food categories and IMI. The colour scale represents the magnitude of Spearman’s rho coefficient, with blue indicating a positive correlation and red indicating a negative correlation. * p < 0.05; ** p < 0.01; *** p < 0.001 significant Spearman’s correlations and Holm correction adjusted for Energy intake. IMI, Italian Mediterranean Index; 2-AG, 2-Arachidonoylglicerol; AEA, Arachidonoylethanolamide; LEA, Linoylethanolamide; OEA, Oleoylethanolamide; PEA, Palmitoylethanolamide

Fig. 5

Plasma OEA/PEA ratio ( a…

Fig. 5

Plasma OEA/PEA ratio ( a ), HOMA index ( b ), plasma AEA…

Fig. 5
Plasma OEA/PEA ratio (a), HOMA index (b), plasma AEA concentration (c), plasma 2-AG concentration (d), serum hs-CRP concentration (e) and faecal Akkermansia muciniphila relative abundance (f) in participants from the control group (CT) and Mediterranean diet group (MD) in the lowest (Q1) and highest quartile (Q4) for OEA/PEA ratio at baseline (0 wk), 4 weeks (4 wk) and 8 weeks (8 wk). Q1 = minimum to 25th percentile of OEA/PEA ratio at baseline (CT, n = 9; MD, n = 11), Q4 = 75th percentile to maximum of OEA/PEA ratio at baseline (CT, n = 10; MD, n = 10). Different letters on the box plots indicate p < 0.05 between quartiles (MD + CT) at 0 wk by independent samples T test. *p < 0.05 within-group comparison by 2-way ANOVA with repeated measures; #p < 0.05 within-group comparison by Wilcoxon test. Two outliers have been removed from panel E and 1 outlier from panel F for simpler visualisation. 2-AG, 2-Arachidonoylglicerol; AEA, Arachidonoylethanolamide; OEA, Oleoylethanolamide; PEA, Palmitoylethanolamide; hs-CRP, high-sensitivity C-reactive protein; HOMA index, Homeostatic model assessment of insulin resistance index

Fig. 6

Linear discriminant analysis effect size…

Fig. 6

Linear discriminant analysis effect size (LEfSe) showing species that were differentially abundant between…

Fig. 6
Linear discriminant analysis effect size (LEfSe) showing species that were differentially abundant between Q1 (grey) and Q4 (black). Logarithmic linear discriminant analysis (LDA) score > 2, p < 0.05. Q1 = minimum to 25th percentile of OEA/PEA ratio at baseline (CT, n = 9; MD, n = 11), Q4 = 75th percentile to maximum of OEA/PEA ratio at baseline (CT, n = 10; MD, n = 10)
Fig. 4
Fig. 4
Heatmap correlation matrix between plasma ECs, NAEs, OEA/PEA ratio, OEA/AEA ratio and food categories and IMI. The colour scale represents the magnitude of Spearman’s rho coefficient, with blue indicating a positive correlation and red indicating a negative correlation. * p < 0.05; ** p < 0.01; *** p < 0.001 significant Spearman’s correlations and Holm correction adjusted for Energy intake. IMI, Italian Mediterranean Index; 2-AG, 2-Arachidonoylglicerol; AEA, Arachidonoylethanolamide; LEA, Linoylethanolamide; OEA, Oleoylethanolamide; PEA, Palmitoylethanolamide
Fig. 5
Fig. 5
Plasma OEA/PEA ratio (a), HOMA index (b), plasma AEA concentration (c), plasma 2-AG concentration (d), serum hs-CRP concentration (e) and faecal Akkermansia muciniphila relative abundance (f) in participants from the control group (CT) and Mediterranean diet group (MD) in the lowest (Q1) and highest quartile (Q4) for OEA/PEA ratio at baseline (0 wk), 4 weeks (4 wk) and 8 weeks (8 wk). Q1 = minimum to 25th percentile of OEA/PEA ratio at baseline (CT, n = 9; MD, n = 11), Q4 = 75th percentile to maximum of OEA/PEA ratio at baseline (CT, n = 10; MD, n = 10). Different letters on the box plots indicate p < 0.05 between quartiles (MD + CT) at 0 wk by independent samples T test. *p < 0.05 within-group comparison by 2-way ANOVA with repeated measures; #p < 0.05 within-group comparison by Wilcoxon test. Two outliers have been removed from panel E and 1 outlier from panel F for simpler visualisation. 2-AG, 2-Arachidonoylglicerol; AEA, Arachidonoylethanolamide; OEA, Oleoylethanolamide; PEA, Palmitoylethanolamide; hs-CRP, high-sensitivity C-reactive protein; HOMA index, Homeostatic model assessment of insulin resistance index
Fig. 6
Fig. 6
Linear discriminant analysis effect size (LEfSe) showing species that were differentially abundant between Q1 (grey) and Q4 (black). Logarithmic linear discriminant analysis (LDA) score > 2, p < 0.05. Q1 = minimum to 25th percentile of OEA/PEA ratio at baseline (CT, n = 9; MD, n = 11), Q4 = 75th percentile to maximum of OEA/PEA ratio at baseline (CT, n = 10; MD, n = 10)

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