Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort

Abstract

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (β = −0.37; 95%CI: −0.71 to −0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (β = −0.13; 95%CI: −0.24 to −0.01; P = 0.03), as was the total effect (β = −0.38; 95%CI: −0.72 to −0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (β = −0.25; 95%CI: −0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain

“…Gut microbiota has been shown to produce eCBs and many bioactive lipids that structurally and functionally resemble eCBs (Cani et al, 2016 ; Sharkey and Wiley, 2016 ). Given that the eCB system plays an important role in energy metabolism and inflammation, it may act as a promising therapeutic target for many neurological diseases (Minichino et al, 2021 ). In this study, we observed that AEA and many expanded eCBs showed significant decreases in the blood when pain and its associated cognitive deficits occurred.…”

Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome through Modulation of Microbiome in the Gut-Lung Axis

“…Recently, we demonstrated that AEA can attenuate SEB-mediated ARDS in a mouse model by targeting miRNA which triggers anti-inflammatory pathways involving immunosuppressive cells, such as the myeloid-derived suppressor cells (MDSCs) and the regulatory T cells (Tregs) [ 9 ]. Recent studies have shown that the diversity of the gut microbiota may be regulated by endocannabinoids [ 19 , 26 ]. This raises an important question of whether endocannabinoids can alter the microbiota in the gut and the lungs during ARDS, thereby providing increased protection from pathogenic bacteria as well as suppressing hyperinflammation.…”

Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint

“…In particular, the authors tested the hypothesis that either reduced serum levels of PEA or increased stool levels of PEA would mediate the association between microbial diversity and anhedonia/amotivation. Indeed, the association was found to be mediated by faecal, but not serum, levels of PEA [179].…”

“…From a large cohort study on nearly 800 volunteer twins it has recently emerged that the eCBome mediates the relationship between gut microbiome and anhedonia/amotivation [179]. In particular, the authors tested the hypothesis that either reduced serum levels of PEA or increased stool levels of PEA would mediate the association between microbial diversity and anhedonia/amotivation.…”