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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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Depommier, C., Vitale, R. M., Iannotti, F. A., Silvestri, C., Flamand, N., Druart, C., Everard, A., Pelicaen, R., Maiter, D. M., Thissen, J., et al. (2021) · Cells · doi:10.3390/cells10010185 · Cited by 73
“Since these same metabolic functions are under the influence of the intestinal microbiota, the scientific community has been paying increasing interest in the potential cross-talk between the eCBome, the gut microbiome, particularly during gut dysbiosis in the context of obesity [28,33,40].”
BackgroundInfluentialGhaffari, S., Abbasi, A., Somi, M. H., Moaddab, S. Y., Nikniaz, L., Kafil, H. S., & Leylabadlo, H. E. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2045894 · Cited by 74
“These lipids have anti-inflammatory effects and regulate endogenous production of gut peptides involved in glucose regulation and gut barrier, respectively, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) (Cani et al. 2016) (Figure 2).”
BackgroundWang, B., Chen, X., Chen, Z., Xiao, H., Dong, J., Li, Y., Zeng, X., Liu, J., Wan, G., Fan, S., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00911-z · Cited by 70
Gut microbes in metabolic disturbances. Promising role for therapeutic manipulations?
Portincasa, P., Khalil, M., Graziani, A., Frühbeck, G., Baffy, G., Garruti, G., Ciaula, A. D., & Bonfrate, L. (2023) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2023.10.002 · Cited by 78
De Novo Lipogenesis Products and Endogenous Lipokines
Yilmaz, M., Claiborn, K. C., & Hotamışlıgil, G. S. (2016) · Diabetes · doi:10.2337/db16-0251 · Cited by 72
“These endogenously produced ligands of the cannabinoid receptors (CB1 and CB2) are synthesized from cell membrane phospholipid precursors and have been implicated in controlling gut barrier function as well as communicating the state of the gut microbiota with adipose tissue (72).”
Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?
Hasenoehrl, C., Storr, M., & Schicho, R. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1292851 · Cited by 69
“microbiome with the gut epithelial barrier [71].”
Pei, R., DiMarco, D. M., Putt, K. K., Martin, D., Gu, Q., Chitchumroonchokchai, C., White, H. M., Scarlett, C. O., Bruno, R. S., & Bolling, B. W. (2017) · British Journal Of Nutrition · doi:10.1017/s0007114517003038 · Cited by 71
“Inflammation is exacerbated by chronic endotoxin exposure resulting from compromised intestinal barrier function in obese individuals((3,4)).”
InfluentialNiccolai, E., Boem, F., Russo, E., & Amedei, A. (2019) · Nutrients · doi:10.3390/nu11010156 · Cited by 70
“In addition, some bacteria could stimulate the endocannabinoid system, which affects gut barrier activity, host metabolism [200] and the homoeostatic and hedonic control of appetite and food intake [201].”
BackgroundPaola, M. D., Bonechi, E., Provensi, G., Costa, A., Clarke, G. A., Ballerini, C., Filippo, C. D., & Passani, M. B. (2018) · Scientific Reports · doi:10.1038/s41598-018-32925-x · Cited by 65
Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk
Baritaki, S., de Bree, E., Chatzaki, Ε., & Pothoulakis, C. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8101669 · Cited by 67
“The inflammatory potential of chronic gut dysbiosis is further associated with CRC development by facilitating cell proliferation and providing a microenvironment that supports alterations in stem cell dynamics and biosynthesis of toxic and genotoxic metabolites that eventually affect the host metabolism, including gl…”
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Suriano, F., Bindels, L. B., Verspreet, J., Courtin, C. M., Verbeke, K., Cani, P. D., Neyrinck, A. M., & Delzenne, N. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-05698-y · Cited by 61
“, GLP-2 , tight junction proteins such as zonula occludens-1 (ZO1) and occludin, endo cannabinoid system) also contribute to modulate host metabolic alterations s uch as inflammation and endotoxemia[17, 21].”
BackgroundGarcinol Reduces Obesity in High‐Fat‐Diet‐Fed Mice by Modulating Gut Microbiota Composition
Lee, P., Teng, C., Nagabhushanam, K., Ho, C., & Pan, M. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800390 · Cited by 58
Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens
Ellermann, M., Pacheco, A. R., Jimenez, A. G., Russell, R. M., Cuesta, S., Kumar, A., Zhu, W., do Vale, G. D., Martin, S. A., Raj, P., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.022 · Cited by 62
“The GI microbiota has also been implicated in endocannabinoid modulation of host physiology and disease (Cani et al., 2016).”
BackgroundCross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases
Wu, D., Wang, H., Xie, L., & Hu, F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.908868 · Cited by 62
Bioactive lipids in the skin barrier mediate its functionality in health and disease
Nicolaou, A., & Kendall, A. C. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108681 · Cited by 60
Cannabinoids and Opioids in the Treatment of Inflammatory Bowel Diseases
Kienzl, M., Storr, M., & Schicho, R. (2020) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000120 · Cited by 57
“ECS and microbiota Studies of adipogenesis and obesity have revealed a link between the ECS and the microbiome (41,42).”
BackgroundEndocannabinoids and the Gut-Brain Control of Food Intake and Obesity
DiPatrizio, N. V. (2021) · Nutrients · doi:10.3390/nu13041214 · Cited by 59
Effects of Substance Use and Sex Practices on the Intestinal Microbiome During HIV-1 Infection
Fulcher, J. A., Hussain, S. K., Cook, R., Li, F., Tobin, N. H., Ragsdale, A. M., SHOPTAW, S. J., Gorbach, P. M., & Aldrovandi, G. M. (2018) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiy349 · Cited by 55
Iqbal, M., Qian, Y., Tang, J., & Xiang, J. (2025) · Journal of Bacteriology · doi:10.1128/jb.00479-24 · Cited by 72
“The eCB system (ECS) is integral to various physiological processes, including appetite regulation, glucose and lipid metabolism, immunity, and inflammation, and it plays a key role in mediating interactions between microbiota and host (89).”
Metabolomic response to coffee consumption: application to a three‐stage clinical trial
Cornelis, M. C., Erlund, I., Michelotti, G. A., Herder, C., Westerhuis, J. A., & Tuomilehto, J. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12737 · Cited by 53
Dione, N., Lacroix, S., Taschler, U., Deschênes, T., Abolghasemi, A., Leblanc, N., Marzo, V. D., & Silvestri, C. (2020) · Cells · doi:10.3390/cells9122705 · Cited by 56
“There is thus evidence of bidirectional interactions between the gut microbiome and the eCBome leading to the hypothesis of the existence of a microbiome-eCBome axis that is responsive to external factors and is critical for the regulation of host metabolic health at many levels [4,6,19].”
Minichino, A., Jackson, M. A., Francesconi, M., Steves, C. J., Menni, C., Burnet, P. W. J., & Lennox, B. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01147-5 · Cited by 54
“microbiome composition [23, 27] and this might have downstream effect on the host mental health [28].”
BackgroundGamage, H. K. A. H., Tetu, S. G., Chong, R. W. W., Bucio-Noble, D., Rosewarne, C. P., Kautto, L., Ball, M. S., Molloy, M. P., Packer, N. H., & Paulsen, I. T. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.01618 · Cited by 49
“Trillions of microorganisms reside in the human large intestine, which is collectively referred to as the gut microbiota (Cani et al., 2016).”
BackgroundInteractions between gut microbes and host cells control gut barrier and metabolism
Cani, P. D. (2016) · International Journal of Obesity Supplements · doi:10.1038/ijosup.2016.6 · Cited by 47
Little, T. J., Cvijanovic, N., DiPatrizio, N. V., Argueta, D. A., Rayner, C. K., Feinle‐Bisset, C., & Young, R. L. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00355.2017 · Cited by 49
Cannabinoid pharmacology and therapy in gut disorders
Uranga, J. A., Vera, G., & Abalo, R. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.07.048 · Cited by 46
A human gut Faecalibacterium prausnitzii fatty acid amide hydrolase
Cheng, J., Venkatesh, S., Ke, K., Barratt, M. J., & Gordon, J. I. (2024) · Science · doi:10.1126/science.ado6828 · Cited by 47
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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