Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling

Manca, Claudia; Boubertakh, Besma; Leblanc, Nadine; Deschênes, Thomas; Lacroix, Sébastien; Martin, Cyril; Houde, Alain; Veilleux, Alain; Flamand, Nicolas; Muccioli, Giulio G.; Raymond, Frédéric; Cani, Patrice D.; Marzo, Vincenzo Di; Silvestri, Cristoforo

doi:10.1194/jlr.ra119000424

Cited by 95 publications

(107 citation statements)

References 85 publications

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“…Altogether, the results obtained here justify and may help designing future dietary interventions aimed at manipulating endocannabinoidome signaling to exploit the capability of various endocannabinoid congeners in producing potential beneficial effects on obesity and its comorbidities 43,45,54 . Finally, following our finding that some NAEs and 2-MAGs are also associated with gut microbiota composition, interventions aimed at modulating the levels of these mediators might also find application in counteracting the metabolic disturbances linked to gut dysbiosis 26,27,55,56 .…”

Section: Discussionmentioning

confidence: 77%

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

Castonguay-Paradis

Lacroix

Rochefort

et al. 2020

Sci Rep

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The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2‑MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC–MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2‑MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2‑MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.

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Section: Discussionmentioning

confidence: 77%

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

Castonguay-Paradis

Lacroix

Rochefort

et al. 2020

Sci Rep

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“…Importantly, most of these alterations are reversed after only one week by fecal microbiome transfer from CR mice, strongly suggesting that commensal microorganisms directly control intestinal (and particularly small intestinal) eCBome signaling. This interaction seems to particularly impact CB1, PPARα and GPR55 signaling, CB1 and PPARα signaling is increased in the small intestine, whereas GPR55 signaling is decreased in GF mice [28]. On the other hand, genetic or pharmacological inactivation of eCBome mediator biosynthesis or action influences gut microbial composition and the host's metabolic response to high-fat diets [29,[185][186][187].…”

Section: Microbiota-endocannabinoidome-gut Axismentioning

confidence: 99%

“…Seminal studies demonstrated that: (i) infusion of LPS had effects similar to those of a high-fat diet (HFD) at increasing fasting glycaemia, insulinemia and whole-body, hepatic and adipose tissue weight gain; (ii) LPS and endocannabinoid levels are positive correlated [16,17], also because of the downregulation of gene expression of acid amide hydrolase (FAAH, the enzyme that degrades AEA) and N-acylethanolamines (NAEs, congeners of AEA) [18]; and (iii) gut dysbiosis and the eCB system are both involved in adipogenesis through a LPS-dependent neuroinflammatory mechanism under obesity-related conditions. In the past several years, our group and others have provided evidence that obesity is associated with increased eCB tone in the brain and plasma, altered expression of cannabinoid receptor 1 (CB1 mRNA) and increased eCB levels in the adipose tissue, liver, muscle and pancreas [19][20][21][22][23][24][25][26][27][28]. Although genetic and pharmacological impairments of peripheral CB1 receptor have been shown to protect against the development of obesity, steatosis and related inflammation [29,30], the molecular link between gut dysbiosis, the eCB system and metabolic disorders associated with obesity remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

Forte

Fernández-Rilo

Palomba

et al. 2020

IJMS

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The hypothalamus regulates energy homeostasis by integrating environmental and internal signals to produce behavioral responses to start or stop eating. Many satiation signals are mediated by microbiota-derived metabolites coming from the gastrointestinal tract and acting also in the brain through a complex bidirectional communication system, the microbiota–gut–brain axis. In recent years, the intestinal microbiota has emerged as a critical regulator of hypothalamic appetite-related neuronal networks. Obesogenic high-fat diets (HFDs) enhance endocannabinoid levels, both in the brain and peripheral tissues. HFDs change the gut microbiota composition by altering the Firmicutes:Bacteroidetes ratio and causing endotoxemia mainly by rising the levels of lipopolysaccharide (LPS), the most potent immunogenic component of Gram-negative bacteria. Endotoxemia induces the collapse of the gut and brain barriers, interleukin 1β (IL1β)- and tumor necrosis factor α (TNFα)-mediated neuroinflammatory responses and gliosis, which alter the appetite-regulatory circuits of the brain mediobasal hypothalamic area delimited by the median eminence. This review summarizes the emerging state-of-the-art evidence on the function of the “expanded endocannabinoid (eCB) system” or endocannabinoidome at the crossroads between intestinal microbiota, gut-brain communication and host metabolism; and highlights the critical role of this intersection in the onset of obesity.

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“…90 On the other hand, dramatic alterations in gut microbiota amount and/or composition, such as in antibiotic-treated or germ-free mice, was shown to affect, through as yet unidentified mechanisms, the messenger RNA (mRNA) expression of eCBome receptors and enzymes, and the concentrations of eCBome mediators, in the gut. 91 Also this interaction may influence the host gut-brain axis. For example, antibiotic-treated mice contain less N-oleoyl and N-arachidonoyl-serotonin in the small intestine.…”

Section: Thcvmentioning

confidence: 99%

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

Marzo

2020

Dialogues in Clinical Neuroscience

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The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB1 and CB2 receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome). This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids. These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations.

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Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling

Cited by 95 publications

References 85 publications

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

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