Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint

Abstract

There is growing evidence that perturbation of the gut microbiome, known as “dysbiosis”, is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond.

Palmitoylethanolamide and Related ALIAmides for Small Animal Health: State of the Art

“…Although studies in small animals are still scarce, there is growing evidence that endocannabinoid-like ALIAmides play key roles in the health of different body organs, such as the gastrointestinal tract [ 113 , 114 ] and the nervous system [ 32 , 34 , 37 ], as well as the upper and lower urinary tract [ 115 , 116 , 117 , 118 ] and the musculoskeletal system [ 97 , 119 , 120 ]. In addition, the deep involvement of ALIAmides in obesity-induced metainflammation is becoming increasingly evident [ 69 , 113 , 121 , 122 , 123 ].…”

Gut microbiota and oleoylethanolamide in the regulation of intestinal homeostasis

“…Many bioactive lipids regulate several physiological processes that maintain the gut-barrier integrity, control inflammation, pain and energy metabolism (see ( 49 ) for a comprehensive review). OEA in particular exerts prominent roles in intestinal physiology; it reduces intestinal motility together with other lipid mediators such as PEA and oleamide, suggesting a potential target for the development of efficient drugs to reduce intestinal motility ( 50 ); OEA presumably partakes in the maintenance of normal glucose homeostasis as it increases the secretion of Glucagon-like Peptide-1 (GLP-1, an intestinal hormone with potent insulinotropic effects) by binding to GPR119 expressed on enteroendocrine L-cells ( 51 ).…”

“…There is no doubt that the microbiota affects gut physiology and its role in the gut brain-axis has been convincingly established ( 75 ). Many physiological roles of intestinal microorganisms are associated to the regulation of the intestinal endocannabinoid tone [the so called endocannabinoidome ( 49 ) as extensively described in recent exhaustive reviews ( 76 – 78 ). There is increasing evidence that both selected intestinal microorganisms and bioactive lipids covary in pathological conditions such as obesity, type 2 diabetes and inflammation ( 76 ).…”

Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases

“…The eCB system is comprised of endogenous lipids that trigger specific G protein-coupled receptors termed cannabinoid receptors 1 and 2 (CB1 and CB2). It has been demonstrated that the eCB system consists of more than 100 lipid mediators and 50 proteins, such as CB1, CB2, N-arachidonoylethanolamine (AEA), 2-arachidonoyi-glycerol (2-AG), and the anabolic and catabolic enzymes for the endocannabinoids (146,147). The eCB system has the ability to regulate gut-barrier function, gut permeability, and metabolic endotoxemia in obesity, and control energy balance by manipulating the metabolic process, energy intake and fat accumulation in adipocytes (148)(149)(150).…”

“…found chronic N -oleoyl-ethanolamine (OEA) administration to mice in normal diet could shift Firmicutes/Bacteroides ratio, decrease Lactobacillus , and reduce intestinal cytokines expression ( 153 ). In obese humans, supplementation of OEA decreased BMI and waist circumference, which might due to the activation of PPARα ( 147 ). And the administration of palmitoyl ethanolmaide (PEA), which is a member of N -acyl ethanolamide (NAE) similar to AEA, could decrease body weight, food intake, and fat mass in HFD rats ( 154 ).…”