Altered endocannabinoidome bioactive lipid levels accompany reduced DNBS-induced colonic inflammation in germ-free mice.

BACKGROUND: Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis. METHODS: Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS. RESULTS: GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation. CONCLUSIONS: These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.

PEA-OXA restores cognitive impairments associated with vitamin D deficiency-dependent alterations of the gut microbiota.

There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In this study we evaluated the possible involvement of gut microbiota in the cognitive impairments mediated by VDD and investigated the effects of pharmacological treatment with the oxazoline derivative of the aliamide palmitoylethanolamide, 2-Pentadecyl-2-oxazoline (PEA-OXA). Mice were submitted to behavioural, biochemical and electrophysiological analysis to assess whether their vitamin D status affected cognitive performance together with gut microbiota composition. In VDD mice we found cognitive malfunctioning associated with reduced neuroplasticity, indicated by impaired long term potentiation, and neuroinflammation at the hippocampal level. Importantly, PEA-OXA counteracted the cognitive impairments and modified the biochemical and functional changes induced by VDD. Additionally, PEA-OXA treatment enhanced gut microbiota diversity, which tended to be decreased by VDD only in female mice, elevated the relative abundance of lactic and butyric acid-producing families, i.e. Aerococcaceae and Butyricicoccaceae, and reversed the VDD-induced decrease of butyrate-producing beneficial genera, such as Blautia in female mice, and Roseburia in male mice. These data provide novel insights for a better understanding of the cognitive decline induced by VDD and related gut dysbiosis and its potential therapeutic treatment.

The emerging role of the endocannabinoidome-gut microbiome axis in eating disorders.

Among the sources of chemical signals regulating food intake, energy metabolism and body weight, few have attracted recently as much attention as the expanded endocannabinoid system, or endocannabinoidome (eCBome), and the gut microbiome, the two systems on which this review article is focussed. Therefore, it is legitimate to expect that these two systems also play a major role in the etiopathology of eating disorders (EDs), in particular of anorexia nervosa, bulimia nervosa and binge-eating disorder. The major mechanisms through which, also via interactions with other endogenous signaling systems, the eCBome, with its several lipid mediators and receptors, and the gut microbiome, via its variety of microbial kingdoms, phyla and species, and armamentarium of metabolites, intervene in these disorders, are described here, based on several published studies in either experimental models or patients. Additionally, in view of the emerging multi-faceted cross-talk mechanisms between these two complex systems, we discuss the possibility that the eCBome-gut microbiome axis is also involved in EDs.

Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome.

BACKGROUND AND PURPOSE: Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. EXPERIMENTAL APPROACH: Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing. KEY RESULTS: LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D2 (PGD2 ) and F2α (PGF2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9. CONCLUSIONS AND IMPLICATIONS: The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome.

Olive oil-derived endocannabinoid-like mediators inhibit palatable food-induced reward and obesity.

N-oleoylglycine (OlGly), a lipid derived from the basic component of olive oil, oleic acid, and N-oleoylalanine (OlAla) are endocannabinoid-like mediators. We report that OlGly and OlAla, by activating the peroxisome proliferator-activated receptor alpha (PPARα), reduce the rewarding properties of a highly palatable food, dopamine neuron firing in the ventral tegmental area, and the obesogenic effect of a high-fat diet rich in lard (HFD-L). An isocaloric olive oil HFD (HFD-O) reduced body weight gain compared to the HFD-L, in a manner reversed by PPARα antagonism, and enhanced brain and intestinal OlGly levels and gut microbial diversity. OlGly or OlAla treatment of HFD-L mice resulted in gut microbiota taxonomic changes partly similar to those induced by HFD-O. We suggest that OlGly and OlAla control body weight by counteracting highly palatable food overconsumption, and possibly rebalancing the gut microbiota, and provide a potential new mechanism of action for the obeso-preventive effects of olive oil-rich diets.

Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome.

Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders.