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Endocannabinoids–at the crossroads between the gut microbiota and host metabolism
Abstract
Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota-endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation.
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“The ECS and GM interact to regulate intestinal homeostasis resulting in relevant functional effects in the gut and CNS (238, 246, 248, 250).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [238]
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“Reduced microbial diversity was associated with increased fecal excretion of the endocannabinoid (palmitoylethanolamide), which is considered a sign of an “unhealthy” microbiome and has been related to a variety of negative health outcomes, including psychosis and depression.(36) As a result, it would be intriguing to…”
BackgroundNecib, R. B., Manca, C., Lacroix, S., Martin, C., Flamand, N., Marzo, V. D., & Silvestri, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.882455 · Cited by 24
“In the same way, the gut microbiome changes induced by an obesogenic diet increase gut barrier permeability, thereby causing increased circulating levels of LPS, which, in turn, modulate the eCBome (40).”
BackgroundCannabis and Cannabis Derivatives for Abdominal Pain Management in Inflammatory Bowel Disease
Bogale, K., Raup‐Konsavage, W. M., Dalessio, S., Vrana, K. E., & Coates, M. D. (2021) · Medical Cannabis and Cannabinoids · doi:10.1159/000517425 · Cited by 24
Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome
Forteza, F., Giorgini, G., & Raymond, F. (2021) · Cells · doi:10.3390/cells10040938 · Cited by 23
“Some eCB congeners and non-eCB long chain fatty acid derivatives have been found to regulate functions that are controlled by eCBs, such as gut-barrier permeability [31], antinociception, appetite, the immune system, and cell biology in general [32], but do so via non-CB1 and nonCB2 receptors.”
BackgroundPendharkar, S. A., Walia, M., Drury, M., & Petrov, M. S. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.08.27 · Cited by 22
At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk
Khan, R. N., Maner-Smith, K. M., Owens, J. A., Barbian, M. E., Jones, R. M., & Naudin, C. R. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1911572 · Cited by 24
“CB1 agonists like AEA have been referred to as ‘gate openers,’ as they induce gut permeability (Figure 2).(59) The deletion of NAPE-PLD led to a decrease in N-acylethanolamines, like oleoylethanolamide (OEA), palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) and was linked to increased inflammation in adipose…”
BackgroundGut-liver axis in diabetes: Mechanisms and therapeutic opportunities
Abdalla, M. M. I. (2025) · World Journal of Gastroenterology · doi:10.3748/wjg.v31.i29.109090 · Cited by 23
“Collectively, these findings position the gut microbial-AhR axis as a critical modulator of hepatic inflammation and glucose metabolic in T2D[121].”
InfluentialPorphyran‐derived oligosaccharides alleviate NAFLD and related cecal microbiota dysbiosis in mice
Wang, X., Liu, D., Wang, Z., Cai, C., Jiang, H., & Yu, G. (2021) · The FASEB Journal · doi:10.1096/fj.202000763rrr · Cited by 21
Cuddihey, H., Cavin, J., Keenan, C. M., Wallace, L. E., Vemuri, K. V., Makriyannis, A., MacNaughton, W. K., & Sharkey, K. A. (2022) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00341.2021 · Cited by 24
Pancreatic Macrophages: Critical Players in Obesity-Promoted Pancreatic Cancer
Teper, Y., & Eibl, G. (2020) · Cancers · doi:10.3390/cancers12071946 · Cited by 21
“Animal studies have shown that metabolic endotoxemia is associated with an altered composition of the gut microbiota and an increased intestinal permeability [79,83,84].”
BackgroundRodriguez, J., Olivares, M., & Delzenne, N. M. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900481 · Cited by 20
Structural and quantitative alterations of gut microbiota in experimental small bowel obstruction
Mo, J., Gao, L., Zhang, N., Xie, J.-L., Li, D., Shan, T., & Fan, L. (2021) · PLoS ONE · doi:10.1371/journal.pone.0255651 · Cited by 20
“It has been estimated that the microbes in our gastrointestinal tract harbor over 10(14) bacterial cells, tenfold higher numbers of human cells, which encode 150-fold more unique genes than the human genome [7].”
BackgroundOrtiz-Alvarez, L., Xu, H., Di, X., Köhler, I., Osuna‐Prieto, F. J., Acosta, F. M., Vilchez‐Vargas, R., Link, A., Plaza‐Díaz, J., van der Stelt, M., et al. (2022) · Nutrients · doi:10.3390/nu14102143 · Cited by 22
Metabolomics: The Key to Unraveling the Role of the Microbiome in Visceral Pain Neurotransmission
Shute, A., Bihan, D. G., Lewis, I. A., & Nasser, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.917197 · Cited by 21
Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation
Varsha, K. K., Nagarkatti, M., & Nagarkatti, P. S. (2022) · Advances in Drug and Alcohol Research · doi:10.3389/adar.2022.10550 · Cited by 24
“Elevated eCBs level impedes excitatory and inhibitory neurotransmitters release which affects immune homeostasis and energy balance while increasing gut permeability (59, 60).”
Tong, Y., Wang, Q., Zhang, J., & Yang, R. (2022) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202200171 · Cited by 21
Liu, S., Fu, J., Liao, Z.-Y., Liu, Y., He, J., He, L., Bai, J., Yang, J., Niu, S., & Guo, J. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156117 · Cited by 20
Seguella, L., Corpetti, C., Lu, J., Pesce, M., Franzin, S. B., Palenca, I., Zilli, A., Vincenzi, M., Caprioli, D., Paytuví-Gallart, A., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.02.014 · Cited by 21
“Apart from its role in regulating the energy homeostasis, OEA also acts as a “ gate-keepers ” in the intestine by locking the epithelial barrier and reducing the inflammatory response (Cani, 2016).”
Prevalence of Cannabidiol Use in Patients With Spine Complaints: Results of an Anonymous Survey
Lovecchio, F. C., Langhans, M. T., Bennett, T., Steinhaus, M. E., Premkumar, A., Cunningham, M. E., Farmer, J., Albert, T. J., Huang, R. C., Katsuura, Y., et al. (2021) · The International Journal of Spine Surgery · doi:10.14444/8087 · Cited by 19
Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer
Cherkasova, V., Kovalchuk, O., & Kovalchuk, I. (2021) · Cancers · doi:10.3390/cancers13174353 · Cited by 20
“On the other hand, AEA can work as a “gate opener” [85] that increases intestinal permeability.”
BackgroundInfluentialMoriello, A. S., Marzo, V. D., & Petrosino, S. (2022) · Animals · doi:10.3390/ani12030348 · Cited by 24
“Currently, it is becoming clear that the eCBome and gut microbiota mutually affect each other [1,117,140].”
BackgroundJi, S., You, Y., Peng, B., Zhong, T., Kuang, Y., Li, S., Du, L., Chen, L., Sun, X., Dai, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.944591 · Cited by 19
“The potential damage-associated molecular patterns (DAMPs), but not the pathogens themself, can enter though impaired intestinal barrier, resulting in the host innate immune responses and a low-grade inflammatory condition (5).”
BackgroundDu, Y., Zhang, R., Zheng, X., Zhao, Y., Chen, Y., Ji, S., Guo, M., & Tang, D. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117681 · Cited by 19
Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance
Taschler, U., Hasenoehrl, C., Storr, M., & Schicho, R. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_105 · Cited by 20
Iannotti, F. A., & Marzo, V. D. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100070 · Cited by 23
The Gut Microbiome in Anxiety Disorders
Butler, M., Kittel‐Schneider, S., Wagner‐Skacel, J., Mörkl, S., & Clarke, G. A. (2025) · Current Psychiatry Reports · doi:10.1007/s11920-025-01604-w · Cited by 21
“The endocannabinoid system, which is thought to buffer against many of the effects of stress [26], is also influenced by gut microbiota composition [27].”
Kurlyandchik, I., Lauche, R., Tiralongo, E., Warne, L. N., & Schloss, J. M. (2022) · PAIN Reports · doi:10.1097/pr9.0000000000001045 · Cited by 19
Koto, A., Nobu, M. K., & Miyazaki, R. (2020) · mBio · doi:10.1128/mbio.00408-20 · Cited by 17
“The importance of symbiont diversity is becoming increasingly recognized as a key component of the host’s physiology and behavior (1, 2).”
BackgroundGadgil, M. D., Kanaya, A. M., Sands, C., Chekmeneva, E., Lewis, M. R., Kandula, N. R., & Herrington, D. M. (2022) · The Journal of Nutrition · doi:10.1093/jn/nxac191 · Cited by 16
“and have been implicated in metabolic disorders such as obesity and type 2 diabetes (40).”
Basnet, T. B., Srijana, G. C., Basnet, R., Fatima, S., Safdar, M., Sehar, B., Alsubaie, A. S. R., & Zeb, F. (2023) · Access Microbiology · doi:10.1099/acmi.0.000403 · Cited by 16
“This modification has been associated with the gut microbiota [49, 51].”
BackgroundPsychiatric Disorders and Cannabinoid Receptors
Joshi, N., & Onaivi, E. S. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-57369-0_9 · Cited by 19
Metadata
- Authors
- Cani, P. D., Plovier, H., Van Hul, M., Geurts, L., Delzenne, N. M., Druart, C., & Everard, A.
- Affiliations
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- UCLouvain (BE)
- Corresponding author
- Cani, Patrice D.
- ORCID
- Venue
- Nature Reviews Endocrinology
- Published
- 2015-12-18
- Volume
- 12
- Issue
- 3
- Pages
- 133-143
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- OpenAlex
- W2206708469
- Cited by
- 367
- References
- 156
- Citations by year
- 2026: 23 · 2025: 30 · 2024: 27 · 2023: 37 · 2022: 51 · 2021: 55 · 2020: 45 · 2019: 25 · 2018: 30 · 2017: 24 · 2016: 20
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- endocannabinoid system, gut microbiota, host metabolism, intestinal permeability, intestinal barrier, bioactive lipids, obesity, adipose tissue, type 2 diabetes, cardiometabolic disease, intestinal inflammation, fat mass
- MeSH terms
- Gastrointestinal Microbiome, Animals, Humans, Gastrointestinal Tract, Receptors, Cannabinoid, Endocannabinoids
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