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

Amedeo Minichino; Matthew A. Jackson; Marta Francesconi; Claire J. Steves; Cristina Menni; Philip W.J. Burnet; Belinda R. Lennox

doi:10.1038/s41380-021-01147-5

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

Amedeo Minichino^*, Matthew A. Jackson, Marta Francesconi, Claire J. Steves, Cristina Menni, Philip W.J. Burnet, Belinda R. Lennox

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

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.

Original language	English
Pages (from-to)	6269-6276
Number of pages	8
Journal	Molecular Psychiatry
Volume	26
Issue number	11
DOIs	https://doi.org/10.1038/s41380-021-01147-5
Publication status	Published - Nov 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41380-021-01147-5

Cite this

@article{680376cafec14f9eac6e95bb54079538,

title = "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.",

author = "Amedeo Minichino and Jackson, {Matthew A.} and Marta Francesconi and Steves, {Claire J.} and Cristina Menni and Burnet, {Philip W.J.} and Lennox, {Belinda R.}",

note = "Funding Information: Acknowledgements The Department of Twin Research receives support from grants from the Wellcome Trust (212904/Z/18/Z) and the Medical Research Council (MRC)/British Heart Foundation (BHF) Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY; MR/M016560/1), European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd., the NIHR Clinical Research Facility and Biomedical Research Centre (based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London). C.M. is funded by the Chronic Disease Research Foundation and by the MRC AIM-HY project grant. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

doi = "10.1038/s41380-021-01147-5",

language = "English",

volume = "26",

pages = "6269--6276",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature [academic journals on nature.com]",

number = "11",

}

TY - JOUR

T1 - Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort

AU - Minichino, Amedeo

AU - Jackson, Matthew A.

AU - Francesconi, Marta

AU - Steves, Claire J.

AU - Menni, Cristina

AU - Burnet, Philip W.J.

AU - Lennox, Belinda R.

N1 - Funding Information: Acknowledgements The Department of Twin Research receives support from grants from the Wellcome Trust (212904/Z/18/Z) and the Medical Research Council (MRC)/British Heart Foundation (BHF) Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY; MR/M016560/1), European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd., the NIHR Clinical Research Facility and Biomedical Research Centre (based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London). C.M. is funded by the Chronic Disease Research Foundation and by the MRC AIM-HY project grant. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85105950361&partnerID=8YFLogxK

U2 - 10.1038/s41380-021-01147-5

DO - 10.1038/s41380-021-01147-5

M3 - Article

AN - SCOPUS:85105950361

SN - 1359-4184

VL - 26

SP - 6269

EP - 6276

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 11

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this