Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
13
01
2021
accepted:
22
04
2021
revised:
15
04
2021
pubmed:
19
5
2021
medline:
15
3
2022
entrez:
18
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34002020
doi: 10.1038/s41380-021-01147-5
pii: 10.1038/s41380-021-01147-5
pmc: PMC8760063
doi:
Substances chimiques
Endocannabinoids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6269-6276Subventions
Organisme : Medical Research Council
ID : MR/N01183X/1
Pays : United Kingdom
Organisme : British Heart Foundation
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M016560/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V005030/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 212904/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
Références
Werbeloff N, Dohrenwend BP, Yoffe R, van Os J, Davidson M, Weiser M. The association between negative symptoms, psychotic experiences and later schizophrenia: a population-based longitudinal study. PLoS ONE. 2015;10:e0119852.
Dominguez MDG, Saka MC, Lieb R, Wittchen HU, van Os J. Early expression of negative/disorganized symptoms predicting psychotic experiences and subsequent clinical psychosis: a 10-year study. Am J Psychiatry 2010;167:1075–1082.
doi: 10.1176/appi.ajp.2010.09060883
Moritz S, Fritzsche A, Engel M, Meiseberg J, Klingberg S, Hesse K. A plea for a transdiagnostic conceptualization of negative symptoms and for consistent psychiatric vocabulary. Schizophrenia Res 2019;204:427–429.
doi: 10.1016/j.schres.2018.08.027
Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research Domain Criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry 2010;167:748–751.
doi: 10.1176/appi.ajp.2010.09091379
Mallet J, Guessoum SB, Tebeka S, le Strat Y, Dubertret C. Self-evaluation of negative symptoms in adolescent and young adult first psychiatric episodes. Prog Neuropsychopharmacol Biol Psychiatry 2020;103:109988.
doi: 10.1016/j.pnpbp.2020.109988
Winograd-Gurvich C, Fitzgerald PB, Georgiou-Karistianis N, Bradshaw JL, White OB. Negative symptoms: a review of schizophrenia, melancholic depression and Parkinson’s disease. Brain Res Bull 2006;70:312–321.
doi: 10.1016/j.brainresbull.2006.06.007
Minichino A, Francesconi M, Carrión RE, Delle Chiaie R, Bevilacqua A, Parisi M, et al. From neurological soft signs to functional outcome in young individuals in treatment with secondary services for non-psychotic disorders: a path analysis. Psychological Med 2017;47:1192–1203.
doi: 10.1017/S0033291716003056
Minichino A, Ando A, Francesconi M, Salatino A, Delle Chiaie R, Cadenhead K. Investigating the link between drug-naive first episode psychoses (FEPs), weight gain abnormalities and brain structural damages: Relevance and implications for therapy. Prog Neuropsychopharmacol Biol Psychiatry 2017;77:9–22.
doi: 10.1016/j.pnpbp.2017.03.020
Nguyen TT, Kosciolek T, Eyler LT, Knight R, Jeste DV. Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. J Psychiatr Res 2018;99:50–61.
doi: 10.1016/j.jpsychires.2018.01.013
Safadi JM, Quinton AMG, Lennox BR, Burnet PWJ, Minichino A. Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis. Mol Psychiatry 2021. https://doi.org/10.1038/s41380-021-01032-1 .
Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol 2019;4:623–632.
doi: 10.1038/s41564-018-0337-x
Kelly JR, Minuto C, Cryan JF, Clarke G, Dinan TG. The role of the gut microbiome in the development of schizophrenia. Schizophrenia Research. 2020. https://doi.org/10.1016/j.schres.2020.02.010 .
Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016;4:30.
Zheng P, Zeng B, Liu M, Chen J, Pan J, Han Y, et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5:eaau8317.
Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 2016;21:786–796.
doi: 10.1038/mp.2016.44
Sarkar A, Harty S, Johnson KVA, Moeller AH, Carmody RN, Lehto SM, et al. The role of the microbiome in the neurobiology of social behaviour. Biol Rev 2020;95:1131–1166.
doi: 10.1111/brv.12603
Cadenhead KS, Minichino A, Kelsven S, Addington J, Bearden C, Cannon TD, et al. Metabolic abnormalities and low dietary Omega 3 are associated with symptom severity and worse functioning prior to the onset of psychosis: findings from the North American Prodrome Longitudinal Studies Consortium. Schizophrenia Res 2019;204:96–103.
doi: 10.1016/j.schres.2018.09.022
Minichino A, Brondino N, Solmi M, del Giovane C, Fusar-Poli P, Burnet P, et al. The gut-microbiome as a target for the treatment of schizophrenia: a systematic review and meta-analysis of randomised controlled trials of add-on strategies. Schizophrenia Res 2020. https://doi.org/10.1016/j.schres.2020.02.012 .
Chevalier G, Siopi E, Guenin-Macé L, Pascal M, Laval T, Rifflet A, et al. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. Nat Commun 2020;11:1–15.
doi: 10.1038/s41467-020-19931-2
Lawn W, Freeman TP, Pope RA, Joye A, Harvey L, Hindocha C, et al. Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses. Psychopharmacology 2016;233:3537–3552.
doi: 10.1007/s00213-016-4383-x
Minichino A, Senior M, Brondino N, Zhang SH, Godwlewska BR, Burnet PWJ, et al. Measuring disturbance of the endocannabinoid system in psychosis: a systematic review and meta-analysis. JAMA Psychiatry 2019;76:914–923.
doi: 10.1001/jamapsychiatry.2019.0970
Alhouayek M, Muccioli GG. Harnessing the anti-inflammatory potential of palmitoylethanolamide. Drug Discov Today 2014;19:1632–1639.
doi: 10.1016/j.drudis.2014.06.007
Couch DG, Cook H, Ortori C, Barrett D, Lund JN, O’Sullivan SE. Palmitoylethanolamide and cannabidiol prevent inflammation-induced hyperpermeability of the human gut in vitro and in vivo-a randomized, placebo-controlled, double-blind controlled trial. Inflamm Bowel Dis 2019;25:1006–1018.
doi: 10.1093/ibd/izz017
Ghazizadeh-Hashemi M, Ghajar A, Shalbafan MR, Ghazizadeh-Hashemi F, Afarideh M, Malekpour F, et al. Palmitoylethanolamide as adjunctive therapy in major depressive disorder: a double-blind, randomized and placebo-controlled trial. J Affect Disord 2018;232:127–133.
doi: 10.1016/j.jad.2018.02.057
Coppola M, Mondola R. Is there a role for palmitoylethanolamide in the treatment of depression? Med Hypotheses 2014;82:507–511.
doi: 10.1016/j.mehy.2013.12.016
Zimmermann T, Bartsch JC, Beer A, Lomazzo E, Guggenhuber S, Lange MD, et al. Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses. Neuropsychopharmacology 2019;44:1377–1388.
doi: 10.1038/s41386-018-0274-7
Cani PD, Plovier H, van Hul M, Geurts L, Delzenne NM, Druart C, et al. Endocannabinoids-at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol 2016;12:133–143.
doi: 10.1038/nrendo.2015.211
Guida F, Boccella S, Belardo C, Iannotta M, Piscitelli F, de Filippis F, et al. Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain. Brain Behav Immun 2020;85:128–141.
doi: 10.1016/j.bbi.2019.04.006
Verdi S, Abbasian G, Bowyer RCE, Lachance G, Yarand D, Christofidou P, et al. TwinsUK: the UK adult twin registry update. Twin Res Hum Genet 2019;22:523–529.
doi: 10.1017/thg.2019.65
Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell 2014;159:789–799.
doi: 10.1016/j.cell.2014.09.053
Jackson MA, Verdi S, Maxan ME, Shin CM, Zierer J, Bowyer RCE, et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun 2018;9:1–8.
doi: 10.1038/s41467-018-05184-7
Zierer J, Jackson MA, Kastenmüller G, Mangino M, Long T, Telenti A, et al. The fecal metabolome as a functional readout of the gut microbiome. Nat Genet 2018;50:790–795.
doi: 10.1038/s41588-018-0135-7
Norton S, Cosco T, Doyle F, Done J, Sacker A. The Hospital Anxiety and Depression Scale: a meta confirmatory factor analysis. J Psychosom Res 2013;74:74–81.
doi: 10.1016/j.jpsychores.2012.10.010
Bowyer RCE, Jackson MA, Pallister T, Skinner J, Spector TD, Welch AA, et al. Use of dietary indices to control for diet in human gut microbiota studies. Microbiome 2018;6:77.
doi: 10.1186/s40168-018-0455-y
Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Personal Soc Psychol 1986;51:1173–1182.
doi: 10.1037/0022-3514.51.6.1173
Mosca A, Leclerc M, Hugot JP. Gut microbiota diversity and human diseases: should we reintroduce key predators in our ecosystem? Front Microbiol 2016;7:455.
doi: 10.3389/fmicb.2016.00455
Schwarz E, Maukonen J, Hyytiäinen T, Kieseppä T, Orešič M, Sabunciyan S, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophrenia Res 2018;192:398–403.
doi: 10.1016/j.schres.2017.04.017
Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 2013;11:200.
doi: 10.1186/1741-7015-11-200
Karhson DS, Hardan AY, Parker KJ. Endocannabinoid signaling in social functioning: an RDoC perspective. Transl Psychiatry 2016;6:e905–e905.
doi: 10.1038/tp.2016.169
Craft RM, Marusich JA, Wiley JL. Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system? Life Sci. 2013;92:476–481.
doi: 10.1016/j.lfs.2012.06.009
Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng S. Application of metagenomics in the human gut microbiome. World J Gastroenterol 2015;21:803–814.
doi: 10.3748/wjg.v21.i3.803
Almeida A, Mitchell AL, Boland M, Forster SC, Gloor GB, Tarkowska A, et al. A new genomic blueprint of the human gut microbiota. Nature 2019;568:499–504.
doi: 10.1038/s41586-019-0965-1
Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 2015;48:186–194.
doi: 10.1016/j.bbi.2015.03.016