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Background: The endocannabinoid system and its extension, the endocannabinoidome (eCBome), are involved in numerous biological processes, notably energy homeostasis, across virtually all tissues. While the circulating eCBome mediator profile is associated with dietary intakes and metabolic status, an important knowledge gap resides in the identification of the precise determinants of these mediators in the gut lumen. We aimed at establishing the profile of eCBome mediators in human feces and investigating their association with circulating eCBome mediators, dietary intakes, metabolic status and gut microbiota composition., Methods: N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2-MAGs) were profiled by LC-MS/MS in plasma and feces of a cross-sectional cohort (n = 195) and a short term dietary intervention trials (n = 21) with comprehensive dietary intakes and gut microbiota measures., Results: Six NAEs and seven 2-MAGs were identified in fecal samples, but some, especially omega-3 derived mediators, were undetectable in the majority of samples. Fecal NAEs, and to a lower extent 2-MAGs, were positively albeit weakly correlated with the circulating levels of eCBome mediators. Fecal 2-AG, PEA and DHEA levels were positively associated with visceral adiposity and with some parameters of the metabolic profile. Dietary intakes of foods rich in fibers were associated with lower fecal levels of several eCBome mediators, while intakes of unsaturated fatty acids were associated with fecal 2-OG and 2-LG. Interestingly, gut microbiota diversity and composition were a strong correlate of the fecal eCBome profile., Conclusion: The fecal eCBome profile is associated with gut microbiota composition and dietary intakes, more than with the circulating profile. These results strengthen the hypothesis of an interrelation between the gut microbiome and eCBome signaling involved in the regulation of numerous host biological processes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB 1 and CB 2 , the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB 2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB 2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB 2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.

Chronic HIV infection is associated with accelerated coronary artery disease (CAD) due to chronic inflammation. The expanded endocannabinoid system (eCBome) and gut microbiota modulate each other and are key regulators of cardiovascular functions and inflammation. We herein investigated the interplay between plasma eCBome mediators and gut microbiota in people with HIV (PWH) and/or subclinical CAD versus HIV-uninfected individuals. CAD was determined by coronary computed tomography (CT) angiography performed on all participants. Plasma eCBome mediator and fecal microbiota composition were assessed by tandem mass spectrometry and 16S rDNA sequencing, respectively. HIV infection was associated with perturbed plasma eCBome mediators characterized by an inverse relationship between anandamide and N -acyl-ethanolamines (NAEs) versus 2-AG and 2-monoacylglycerols (MAGs). Plasma triglyceride levels were positively associated with MAGs. Several fecal bacterial taxa were altered in HIV-CAD+ versus controls and correlated with plasma eCBome mediators. CAD-associated taxonomic alterations in fecal bacterial taxa were not found in PWH., Competing Interests: We have no competing interest to declare., (© 2024 The Author(s).)

Objective: Endocannabinoids and their N -acyl-ethanolamines (NAEs) and 2monoacyl-glycerols (2-MAGs) congeners are involved in the central and peripheral regulation of energy homeostasis, they are present in human milk and are associated with obesity. Infants exposed in utero to gestational diabetes mellitus (GDM) are more likely to develop obesity. The objective of this cross-sectional study is to compare the profile of eCBome mediators in milk of women with gestational diabetes (GDM+) and without (GDM-) and to assess the association with offspring growth. The hypothesis is that the eCBome of GDM+ human milk is altered and associated with a difference in infant growth., Methods: Circulating eCBome mediators were measured by LC-MS/MS in human milk obtained at 2 months postpartum from GDM+ (n=24) and GDM- (n=29) women. Infant weight and height at 2 months were obtained from the child health record. Z-scores were calculated., Results: Circulating Npalmitoylethanolamine (PEA) was higher in human milk of GDM+ women than in GDM- women (4.9 ± 3.2 vs. 3.3 ± 1.7, p=0.04). Higher levels were also found for several 2monoacyl-glycerols (2-MAGs) (p<0.05). The levels of NAEs (β=-4.6, p=0.04) and especially non-omega-3 NAEs (B=-5.6, p=0.004) in human milk were negatively correlated with weight-for-age z-score of GDM+ offspring., Conclusion: The profile of eCBome mediators in human milk at 2 months postpartum was different in GDM+ compared to GDM- women and was associated with GDM+ offspring growth at 2 months., Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT04263675 and NCT02872402)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fradet, Castonguay-Paradis, Dugas, Perron, St-Arnaud, Marc, Doyen, Flamand, Dahhani, Di Marzo, Veilleux and Robitaille.)

Prostaglandin E2 (PGE2) is a recognized inhibitor of granulocyte functions. However, most of the data supporting this was obtained when available pharmacological tools mainly targeted the EP2 receptor. Herein, we revisited the inhibitory effect of PGE2 on reactive oxygen species production, leukotriene biosynthesis, and migration in human neutrophils. Our data confirm the inhibitory effect of PGE2 on these functions and unravel that the effect of PGE2 on human neutrophils is obtained by the combined action of EP2 and EP4 agonism. Accordingly, we also demonstrate that the inhibitory effect of PGE2 is fully prevented only by the combination of EP2 and EP4 receptor antagonists, underscoring the importance of targeting both receptors in the effect of PGE2. Conversely, we also show that the inhibition of ROS production by human eosinophils only involves the EP4 receptor, despite the fact that they also express the EP2 receptor., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Human studies have linked obesity-related diseases, such as type-2 diabetes (T2D), to the modulation of endocannabinoid signaling. Cannabinoid CB 1 and CB 2 receptor activation by the endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and N -arachidonoylethanolamine (AEA), both derived from arachidonic acid, play a role in homeostatic regulation. Other long chain fatty acid-derived endocannabinoid-like molecules have extended the metabolic role of this signaling system through other receptors. In this study, we aimed to assess in depth the interactions between the circulating and intestinal tone of this extended eCB system, or endocannabinoidome (eCBome), and their involvement in the pathogenesis of diabetes., Methods: Plasma and ileum samples were collected from subjects with obesity and harboring diverse degrees of insulin resistance or T2D, who underwent bariatric surgery. The levels of eCBome mediators and their congeners were then assessed by liquid chromatography coupled to tandem mass spectrometry, while gene expression was screened with qPCR arrays., Findings: Intestinal and circulating levels of eCBome mediators were higher in subjects with T2D. We found an inverse correlation between the intestinal and circulating levels of monoacylglycerols (MAGs). Additionally, we identified genes known to be implicated in both lipid metabolism and intestinal function that are altered by the context of obesity and glucose homeostasis., Interpretation: Although the impact of glucose metabolism on the eCBome remains poorly understood in subjects with advanced obesity state, our results suggest a strong causative link between altered glucose homeostasis and eCBome signaling in the intestine and the circulation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Alain Veilleux, Vincenzo Di Marzo reports financial support was provided by 10.13039/501100000024Canadian Institutes of Health Research., (© 2024 The Authors. Published by Elsevier Ltd.)

The scientific and medical community faced an unprecedented global health hazard that led to nearly 7 million deaths attributable to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In spite of the development of efficient vaccines against SARS-CoV-2, many people remain at risk of developing severe symptoms as the virus continues to spread without beneficial patient therapy. The hyper-inflammatory response to SARS-CoV-2 infection progressing to acute respiratory distress syndrome remains an unmet medical need for improving patient care. The viral infection stimulates alveolar macrophages to adopt an inflammatory phenotype regulated, at least in part, by the cluster of differentiation 36 receptor (CD36) to produce unrestrained inflammatory cytokine secretions. We suggest herein that the modulation of the macrophage response using the synthetic CD36 ligand hexarelin offers potential as therapy for halting respiratory failure in SARS-CoV-2-infected patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gauvin, Huynh, Dubuc, Lê, Tugores, Flamand, Flamand, Lubell, Ong and Marleau.)

Dietary omega-3 polyunsaturated fatty acids ( n -3 PUFAs) and the gut microbiome affect each other. We investigated the impact of supplementation with Buglossoides arvensis oil (BO), rich in stearidonic acid (SDA), on the human gut microbiome. Employing the Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME), we simulated the ileal and ascending colon microbiomes of four donors. Our results reveal two distinct microbiota clusters influenced by BO, exhibiting shared and contrasting shifts. Notably, Bacteroides and Clostridia abundance underwent similar changes in both clusters, accompanied by increased propionate production in the colon. However, in the ileum, cluster 2 displayed a higher metabolic activity in terms of BO-induced propionate levels. Accordingly, a triad of bacterial members involved in propionate production through the succinate pathway, namely Bacteroides, Parabacteroides, and Phascolarctobacterium , was identified particularly in this cluster, which also showed a surge of second-generation probiotics, such as Akkermansia , in the colon. Finally, we describe for the first time the capability of gut bacteria to produce N -acyl-ethanolamines, and particularly the SDA-derived N -stearidonoyl-ethanolamine, following BO supplementation, which also stimulated the production of another bioactive endocannabinoid-like molecule, commendamide, in both cases with variations across individuals. Spearman correlations enabled the identification of bacterial genera potentially involved in endocannabinoid-like molecule production, such as, in agreement with previous reports, Bacteroides in the case of commendamide. This study suggests that the potential health benefits on the human microbiome of certain dietary oils may be amenable to stratified nutrition strategies and extend beyond n -3 PUFAs to include microbiota-derived endocannabinoid-like mediators.

Overconsumption of added sugars is now largely recognized as a major culprit in the global situation of obesity and metabolic disorders. Previous animal studies reported that maple syrup (MS) is less deleterious than refined sugars on glucose metabolism and hepatic health, but the mechanisms remain poorly studied. Beyond its content in sucrose, MS is a natural sweetener containing several bioactive compounds, such as polyphenols and inulin, which are potential gut microbiota modifiers. We aimed to investigate the impact of MS on metabolic health and gut microbiota in male C57Bl/6J mice fed a high-fat high-sucrose (HFHS + S) diet or an isocaloric HFHS diet in which a fraction (10% of the total caloric intake) of the sucrose was substituted by MS (HFHS + MS). Insulin and glucose tolerance tests were performed at 5 and 7 wk into the diet, respectively. The fecal microbiota was analyzed by whole-genome shotgun sequencing. Liver lipids and inflammation were determined, and hepatic gene expression was assessed by transcriptomic analysis. Maple syrup was less deleterious on insulin resistance and decreased liver steatosis compared with mice consuming sucrose. This could be explained by the decreased intestinal α-glucosidase activity, which is involved in carbohydrate digestion and absorption. Metagenomic shotgun sequencing analysis revealed that MS intake increased the abundance of Faecalibaculum rodentium , Romboutsia ilealis , and Lactobacillus johnsonii , which all possess gene clusters involved in carbohydrate metabolism, such as sucrose utilization and butyric acid production. Liver transcriptomic analyses revealed that the cytochrome P450 (Cyp450) epoxygenase pathway was differently modulated between HFHS + S- and HFHS + MS-fed mice. These results show that substituting sucrose for MS alleviated dysmetabolism in diet-induced obese mice, which were associated with decreased carbohydrate digestion and shifting gut microbiota. NEW & NOTEWORTHY The natural sweetener maple syrup has sparked much interest as an alternative to refined sugars. This study aimed to investigate whether the metabolic benefits of substituting sucrose with an equivalent dose of maple syrup could be linked to changes in gut microbiota composition and digestion of carbohydrates in obese mice. We demonstrated that maple syrup is less detrimental than sucrose on metabolic health and possesses a prebiotic-like activity through novel gut microbiota and liver mechanisms.

Background: Cystic fibrosis (CF) neutrophils fail to eradicate infection despite their massive recruitment into the lung. While studies mostly focus on pathogen clearance by normal density neutrophils in CF, the contribution of low-density neutrophil (LDNs) subpopulations to disease pathogenesis remains unclear., Methods: LDNs were isolated from whole blood donations of clinically stable adult CF patients and from healthy donors. LDN proportion and immunophenotype was assessed by flow cytometry. Associations of LDNs with clinical parameters were determined., Results: LDN proportion was increased in CF patients' circulation compared with healthy donors. LDNs are a heterogeneous population of both mature and immature cells in CF and in healthy individuals. Moreover, a higher proportion of mature LDN correlates with a gradual decline in lung function and repeated pulmonary exacerbations in CF patients., Conclusions: Collectively, our observations suggest that low-density neutrophils are linked to CF pathogenesis and underscore the potential clinical relevance of neutrophil subpopulations in CF., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The gut microbiota and the endocannabinoidome (eCBome) play important roles in regulating energy homeostasis, and both are closely linked to dietary habits. However, the complex and compositional nature of these variables has limited our understanding of their interrelationship. This study aims to decipher the interrelation between dietary intake and the gut microbiome-eCBome axis using two different approaches for measuring dietary intake: one based on whole food and the other on macronutrient intakes. We reveal that food patterns, rather than macronutrient intakes, were associated with the gut microbiome-eCBome axis in a sample of healthy men and women (n = 195). N-acyl-ethanolamines (NAEs) and gut microbial families were correlated with intakes of vegetables, refined grains, olive oil and meats independently of adiposity and energy intakes. Specifically, higher intakes in vegetables and olive oil were associated with increased relative abundance of Clostridiaceae, Veillonellaceae and Peptostreptococaceae, decreased relative abundance of Acidominococaceae, higher circulating levels of NAEs, and higher HDL and LDL cholesterol levels. Our findings highlight the relative importance of food patterns in determining the gut microbiome-eCBome axis. They emphasize the importance of recognizing the contribution of dietary habits in these systems to develop personalized dietary interventions for preventing and treating metabolic disorders through this axis., (© 2023. Springer Nature Limited.)

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E 2 (PGE 2 ) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E 3 (PGE 3 ), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N -eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

Psoriasis is an inflammatory skin disease that is characterized by keratinocyte hyperproliferation, abnormal epidermal differentiation and dysregulated lipid metabolism. Some lipid mediators of the N-acylethanolamines (NAEs) and monoacylglycerols (MAGs) can bind to cannabinoid (CB) receptors and are referred to as part of the endocannabinoidome. Their implication in psoriasis remains unknown. The aim of the present study was to characterize the endocannabinoid system and evaluate the effects of n-3-derived NAEs, namely N-eicosapentaenoyl-ethanolamine (EPEA), in psoriatic keratinocytes using a psoriatic skin model produced by tissue engineering, following the self-assembly method. Psoriatic skin substitutes had lower FAAH2 expression and higher MAGL, ABHD6 and ABHD12 expression compared with healthy skin substitutes. Treatments with alpha-linolenic acid (ALA) increased the levels of EPEA and 1/2-docosapentaenoyl-glycerol, showing that levels of n-3 polyunsaturated fatty acids modulate related NAE and MAG levels. Treatments of the psoriatic substitutes with 10 μM of EPEA for 7 days resulted in decreased epidermal thickness and number of Ki67 positive keratinocytes, both indicating decreased proliferation of psoriatic keratinocytes. EPEA effects on keratinocyte proliferation were inhibited by the CB 1 receptor antagonist rimonabant. Exogenous EPEA also diminished some inflammatory features of psoriasis. In summary, n-3-derived NAEs can reduce the psoriatic phenotype of a reconstructed psoriatic skin model., (© 2023. The Author(s).)

Objective: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome., Methods: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents., Results: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae&#95;g&#95;2 in the proximal and distal jejunum and in the ileum., Conclusions: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2023. The Author(s).)

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 D 2 (PGD 2 ) and F2α (PGF 2α ); 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., (© 2022 British Pharmacological Society.)

Background: Bioactive lipids produced by human cells or by the gut microbiota might play an important role in health and disease. Dietary intakes are key determinants of the gut microbiota, its production of short-chain (SCFAs) and branched-chain fatty acids (BCFAs), and of the host endocannabinoidome signalling, which are all involved in metabolic diseases. This hypothesis-driven longitudinal fixed sequence nutritional study, realized in healthy participants, was designed to determine if a lead-in diet affects the host response to a short-term dietary intervention. Participants received a Mediterranean diet (MedDiet) for 3 days, a 13-day lead-in controlled diet reflecting the average Canadian dietary intake (CanDiet), and once again a MedDiet for 3 consecutive days. Fecal and blood samples were collected at the end of each dietary phase to evaluate alterations in gut microbiota composition and plasma levels of endocannabinoidome mediators, SCFAs, and BCFAs., Results: We observed an immediate and reversible modulation of plasma endocannabinoidome mediators, BCFAs, and some SCFAs in response to both diets. BCFAs were more strongly reduced by the MedDiet when the latter was preceded by the lead-in CanDiet. The gut microbiota response was also immediate, but not all changes due to the CanDiet were reversible following a short dietary MedDiet intervention. Higher initial microbiome diversity was associated with reduced microbiota modulation after short-term dietary interventions. We also observed that BCFAs and 2-monoacylglycerols had many, but distinct, correlations with gut microbiota composition. Several taxa modulated by dietary intervention were previously associated to metabolic disorders, warranting the need to control for recent diet in observational association studies., Conclusions: Our results indicate that lipid mediators involved in the communication between the gut microbiota and host metabolism exhibit a rapid response to dietary changes, which is also the case for some, but not all, microbiome taxa. The lead-in diet influenced the gut microbiome and BCFA, but not the endocannabinoidome, response to the MedDiet. A higher initial microbiome diversity favored the stability of the gut microbiota in response to dietary changes. This study highlights the importance of considering the previous diet in studies relating the gut microbiome with lipid signals involved in host metabolism. Video Abstract., (© 2023. The Author(s).)

Obesity is associated with a cluster of metabolic disorders, chronic low-grade inflammation, altered gut microbiota, increased intestinal permeability, and alterations of the lipid mediators of the expanded endocannabinoid (eCB) signaling system, or endocannabinoidome (eCBome). In the present study, we characterized the profile of the eCBome and related oxylipins in the small and large intestines of genetically obese ( ob/ob ) and diabetic ( db/db ) mice to decipher possible correlations between these mediators and intestinal inflammation and gut microbiota composition. Basal lipid and gene expression profiles, measured by LC/MS-MS-based targeted lipidomics and qPCR transcriptomics, respectively, highlighted a differentially altered intestinal eCBome and oxylipin tone, possibly linked to increased mRNA levels of inflammatory markers in db/db mice. In particular, the duodenal levels of several 2-monoacylglycerols and N -acylethanolamines were increased and decreased, respectively, in db/db mice, which displayed more pronounced intestinal inflammation. To a little extent, these differences were explained by changes in the expression of the corresponding metabolic enzymes. Correlation analyses suggested possible interactions between eCBome/oxylipin mediators, cytokines, and bacterial components and bacterial taxa closely related to intestinal inflammation. Collectively, this study reveals that db/db mice present a higher inflammatory state in the intestine as compared to ob/ob mice, and that this difference is associated with profound and potentially adaptive or maladaptive, and partly intestinal segment-specific alterations in eCBome and oxylipin signaling. This study opens the way to future investigations on the biological role of several poorly investigated eCBome mediators and oxylipins in the context of obesity and diabetes-induced gut dysbiosis and inflammation.

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Dietary micronutrients act at the intestinal level, thereby influencing microbial communities, the host endocannabinoidome, and immune and anti-oxidative response. Selenium (Se) is a trace element with several health benefits. Indeed, Se plays an important role in the regulation of enzymes with antioxidative and anti-inflammatory activity as well as indicators of the level of oxidative stress, which, together with chronic low-grade inflammation, is associated to obesity. To understand how Se variations affect diet-related metabolic health, we fed female and male mice for 28 days with Se-depleted or Se-enriched diets combined with low- and high-fat/sucrose diets. We quantified the plasma and intestinal endocannabinoidome, profiled the gut microbiota, and measured intestinal gene expression related to the immune and the antioxidant responses in the intestinal microenvironment. Overall, we show that intestinal segment-specific microbiota alterations occur following high-fat or low-fat diets enriched or depleted in Se, concomitantly with modifications of circulating endocannabinoidome mediators and changes in cytokine and antioxidant enzyme expression. Specifically, Se enrichment was associated with increased circulating plasma levels of 2-docosahexaenoyl-glycerol (2-DHG), a mediator with putative beneficial actions on metabolism and inflammation. Others eCBome mediators also responded to the diets. Concomitantly, changes in gut microbiota were observed in Se-enriched diets following a high-fat diet, including an increase in the relative abundance of Peptostreptococcaceae and Lactobacillaceae. With respect to the intestinal immune response and anti-oxidative gene expression, we observed a decrease in the expression of proinflammatory genes Il1β and Tnfα in high-fat Se-enriched diets in caecum, while in ileum an increase in the expression levels of the antioxidant gene Gpx4 was observed following Se depletion. The sex of the animal influenced the response to the diet of both the gut microbiota and endocannabinoid mediators. These results identify Se as a regulator of the gut microbiome and endocannabinoidome in conjunction with high-fat diet, and might be relevant to the development of new nutritional strategies to improve metabolic health and chronic low-grade inflammation associated to metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guevara Agudelo, Leblanc, Bourdeau-Julien, St-Arnaud, Lacroix, Martin, Flamand, Veilleux, Di Marzo and Raymond.)

The endocannabinoids 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA) are eicosanoids implicated in numerous physiological processes like appetite, adipogenesis, inflammatory pain and inflammation. They mediate most of their physiological effects by activating the cannabinoid (CB) receptors 1 and 2. Other than directly binding to the CB receptors, 2-AG and AEA are also metabolized by most eicosanoid biosynthetic enzymes, yielding many metabolites that are part of the oxyendocannabinoidome. Some of these metabolites have been found in vivo, have the ability to modulate specific receptors and thus potentially influence physiological processes. In this review, we discuss the biosynthesis and metabolism of 2-AG and AEA, as well as their congeners from the monoacyl-glycerol and N-acyl-ethanolamine families, with a special focus on the metabolism by oxygenases involved in arachidonic acid metabolism. We highlight the knowledge gaps in our understanding of the regulation and roles the oxyendocannabinoidome mediators., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Omega-3 fatty acids support cardiometabolic health and reduce chronic low-grade inflammation. These fatty acids may impart their health benefits partly by modulating the endocannabinoidome and the gut microbiome, both of which are key regulators of metabolism and the inflammatory response. Whole hemp seeds ( Cannabis sativa ) are of exceptional nutritional value, being rich in omega-3 fatty acids. We assessed the effects of dietary substitution (equivalent to about 2 tablespoons of seeds a day for humans) of whole hemp seeds in comparison with whole linseeds in a diet-induced obesity mouse model and determined their effects on obesity and the gut microbiome-endocannabinoidome axis. We show that whole hemp seed substitution did not affect weigh gain, adiposity, or food intake, whereas linseed substitution did, in association with higher fasting glucose levels, greater insulin release during an oral glucose tolerance test, and higher levels of liver triglycerides than controls. Furthermore, hemp seed substitution mitigated diet-induced obesity-associated increases in intestinal permeability and circulating PAI-1 levels, while having no effects on markers of inflammation in epididymal adipose tissue, which were, however, increased in mice fed linseeds. Both hemp seeds and linseeds were able to modify the expression of several endocannabinoidome genes and markedly increased the levels of several omega-3 fatty acid-derived endocannabinoidome bioactive lipids with previously suggested anti-inflammatory actions in a tissue specific manner, despite the relatively low level of seed substitution. While neither diet markedly modified the gut microbiome, mice on the hemp seed diet had higher abundance of Clostridiaceae 1 and Rikenellaceae than mice fed linseed or control diet, respectively. Thus, hemp seed-containing foods might represent a source of healthy fats that are not likely to exacerbate the metabolic consequences of obesogenic diets while producing intestinal permeability protective effects and some anti-inflammatory actions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ben Necib, Manca, Lacroix, Martin, Flamand, Di Marzo and Silvestri.)

Coronavirus disease 19 (COVID-19) is the clinical manifestation of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. A hallmark of COVID-19 is a lung inflammation characterized by an abundant leukocyte infiltrate, elevated levels of cytokines/chemokines, lipid mediators of inflammation (LMI) and microthrombotic events. Animal models are useful for understanding the pathophysiological events leading to COVID-19. One such animal model is the K18-ACE2 transgenic mice. Despite their importance in inflammation, the study of LMI in lung of SARS-CoV-2 infected K18-ACE2 mice has yet to be studied to our knowledge. Using tandem mass spectrometry, the lung lipidome at different time points of infection was analyzed. Significantly increased LMI included N -oleoyl-serine, N -linoleoyl-glycine, N -oleoyl-alanine, 1/2-linoleoyl-glycerol, 1/2-docosahexaenoyl-glycerol and 12-hydroxy-eicosapenatenoic acid. The levels of prostaglandin (PG) E 1 , PGF 2α , stearoyl-ethanolamide and linoleoyl-ethanolamide were found to be significantly reduced relative to mock-infected mice. Other LMI were present at similar levels (or undetected) in both uninfected and infected mouse lungs. In parallel to LMI measures, transcriptomic and cytokine/chemokine profiling were performed. Viral replication was robust with maximal lung viral loads detected on days 2-3 post-infection. Lung histology revealed leukocyte infiltration starting on day 3 post-infection, which correlated with the presence of high concentrations of several chemokines/cytokines. At early times post-infection, the plasma of infected mice contained highly elevated concentration of D-dimers suggestive of blood clot formation/dissolution. In support, the presence of blood clots in the lung vasculature was observed during infection. RNA-Seq analysis of lung tissues indicate that SARS-CoV-2 infection results in the progressive modulation of several hundred genes, including several inflammatory mediators and genes related to the interferons. Analysis of the lung lipidome indicated modest, yet significant modulation of a minority of lipids. In summary, our study suggests that SARS-CoV-2 infection in humans and mice share common features, such as elevated levels of chemokines in lungs, leukocyte infiltration and increased levels of circulating D-dimers. However, the K18-ACE2 mouse model highlight major differences in terms of LMI being produced in response to SARS-CoV-2 infection. The potential reasons and impact of these differences on the pathology and therapeutic strategies to be employed to treat severe COVID-19 are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dubuc, Prunier, Lacasse, Gravel, Puhm, Allaeys, Archambault, Gudimard, Villano, Droit, Flamand, Boilard and Flamand.)

The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise., (© 2022. The Author(s).)

Psoriasis is an inflammatory skin disease mainly associated with an epidermal disorder. However, the involvement of the dermal extracellular matrix (ECM) composition in psoriasis is still poorly understood. This study aimed to investigate the expression of ECM components in psoriatic skin substitutes (PS - ) compared with healthy skin substitutes (HS - ), as well as the effect of an n-3 polyunsaturated fatty acid, namely α-linolenic acid (ALA), on the psoriatic dermal compartment (PS ALA+ ). Liquid chromatography tandem mass spectrometry analyses revealed that the lipidome of PS - contained higher amounts of n-6 derived prostaglandins (PGE 2 ) and lipoxygenase products (9-HODE and 15-HETE). ALA supplementation increased the levels of PGE 3 , 13-HOTrE, 15-HEPE, and 18-HEPE, and decreased the levels of PGE 2 , 15-HETE, and 9-HOPE compared with PS - , indicating that ALA modulates the dermal lipidome of psoriatic skin substitutes. Gene expression profiling showed that several genes encoding for different ECM proteins were overexpressed in PS - compared with HS - , namely COL1A1 (4.2-fold), COL1A2 (3-fold), COL3A1 (4.4-fold), COL4A1 (2.3-fold), COL4A2 (6.3-fold), COL5A1 (3.3-fold), COL5A2 (5.2-fold), and COL5A3 (4.6-fold). Moreover, the expression of collagen IV (Col IV), collagen VII (Col VII), and laminin was found to be increased in PS - compared with HS - , and to be restored with ALA (PS ALA+ ) according to immunofluorescence staining, while only the collagen I to collagen III ratio was altered according to dot blot analyses. Linear regression analysis revealed several positive correlations, including Col III with 14-HDHA levels, fibronectin with 12-HETE and 15-HETE levels, the dermo-epidermal junction Col IV with PGF 2 α , 9-HODE, and 13-HODE levels, and laminin with levels of PGF 2 α , 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE. These results suggest that the ECM plays an underestimated role in the pathogenesis of psoriasis and that ALA supplementation can regulate the ECM composition.

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schebb, Kühn, Kahnt, Rund, O’Donnell, Flamand, Peters-Golden, Jakobsson, Weylandt, Rohwer, Murphy, Geisslinger, FitzGerald, Hanson, Dahlgren, Alnouri, Offermanns and Steinhilber.)

Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA). The supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (EPA) (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA (>20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. STATEMENT OF SIGNIFICANCE: Supplementation of the culture medium with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro., Competing Interests: Declaration of Competing Interest The authors declare no competing interests, (Copyright © 2021. Published by Elsevier Ltd.)

The cannabinoid CB 2 receptor was cloned from the promyeloid cell line HL-60 and is notably expressed in most, if not all leukocyte types. This relatively restricted localization, combined to the absence of psychotropic effects following its activation, make it an attractive drug target for inflammatory and autoimmune diseases. Therefore, there has been an increasing interest in the past decades to identify precisely which immune cells express the CB 2 receptor and what are the consequences of such activation. Herein, we provide new data on the expression of both CB 1 and CB 2 receptors by human blood leukocytes and discuss the impact of CB 2 receptor activation in human leukocytes. While the expression of the CB 2 mRNA can be detected in eosinophils, neutrophils, monocytes, B and T lymphocytes, this receptor is most abundant in human eosinophils and B lymphocytes. We also review the evidence obtained from primary human leukocytes and immortalized cell lines regarding the regulation of their functions by the CB 2 receptor, which underscore the urgent need to deepen our understanding of the CB 2 receptor as an immunoregulator in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Simard, Rakotoarivelo, Di Marzo and Flamand.)

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C 4 and LTB 4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB 4 . The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB 4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

Background: Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes., Results: The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice., Conclusions: The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2/15 epithelial intestinal cells it is elevated by PPARγ activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet-or genetic leptin signaling deficiency-(i.e., ob / ob and db / db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and/or gut mBIome-mediated effects on food intake and energy metabolism.

N-3 polyunsaturated fatty acids (n-3 PUFAs), and in particular docosahexaenoic acid (DHA), have many beneficial metabolic effects, including reducing epidermal thickness in patients with psoriasis. The positive impacts of DHA in psoriasis could be mediated by its interactions with the PPAR signaling pathway, as well as by its secretion of anti-inflammatory bioactive metabolites, but the detailed metabolism is still not understood. In the present study, we evaluated the influence of DHA on the main features of psoriasis and its effects on the PPAR signaling pathway, in a psoriatic in vitro skin model. Healthy and psoriatic skin substitutes were produced according to the tissue-engineered self-assembly method, using culture media supplemented with 10 μM of DHA. The presence of DHA led to a reduction in the abnormal cell differentiation of psoriatic keratinocytes, seen in the increased expression of filaggrin and keratin 10. DHA was incorporated into the membrane phospholipids of the epidermis and transformed principally into eicosapentaenoic acid (EPA). Furthermore, the addition of DHA into the culture medium led to a decrease in the levels of lipid mediators derived from n-6 PUFAs, mainly prostaglandin E 2 (PGE 2 ) and 12-hydroxyeicosatetraenoic acid (12-HETE). Finally, DHA supplementation rebalanced the expression of PPAR receptors and caused a decrease in the secretion of TNF-α. Altogether, our results show that DHA possesses the ability to attenuate the psoriatic characteristics of psoriatic skin substitutes, mostly by restoring epidermal cell differentiation and proliferation, as well as by reducing inflammation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aggregation of alpha-synuclein protein (αSyn) is a hallmark of Parkinson's disease (PD). Considerable evidence suggests that PD involves an early aggregation of αSyn in the enteric nervous system (ENS), spreading to the brain. While it has previously been reported that omega-3 polyunsaturated fatty acids (ω-3 PUFA) acts as neuroprotective agents in the brain in murine models of PD, their effect in the ENS remains undefined. Here, we studied the effect of dietary supplementation with docosahexaenoic acid (DHA, an ω-3 PUFA), on the ENS, with a particular focus on enteric dopaminergic (DAergic) neurons. Thy1-αSyn mice, which overexpress human αSyn, were fed ad libitum with a control diet, a low ω-3 PUFA diet or a diet supplemented with microencapsulated DHA and then compared with wild-type littermates. Our data indicate that Thy1-αSyn mice showed a lower density of enteric dopaminergic neurons compared with non-transgenic animals. This decrease was prevented by dietary DHA. Although we found that DHA reduced microgliosis in the striatum, we did not observe any evidence of peripheral inflammation. However, we showed that dietary intake of DHA promoted a build-up of ω-3 PUFA-derived endocannabinoid (eCB)-like mediators in plasma and an increase in glucagon-like peptide-1 (GLP-1) and the redox regulator, Nrf2 in the ENS. Taken together, our results suggest that DHA exerts neuroprotection of enteric DAergic neurons in the Thy1-αSyn mice, possibly through alterations in eCB-like mediators, GLP-1 and Nrf2.

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N -acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.

Clinical studies have shown that diets enriched with omega-3 (also know as n-3) polyunsaturated fatty acids could relieve the symptoms of patients with psoriasis. However, the mechanisms involved remain poorly understood. The aim of this study was to investigate the effects of α-linolenic acid (ALA) on the proliferation and differentiation of psoriatic keratinocytes in a three-dimensional skin model. Skin models featuring healthy (healthy substitute) or psoriatic (psoriatic substitute) cells were engineered by the self-assembly method of tissue engineering using a culture medium supplemented with 10 μM ALA in comparison with the regular unsupplemented medium. ALA decreased keratinocyte proliferation and improved psoriatic substitute epidermal differentiation, as measured by decreased Ki67 staining and increased protein expression of FLG and loricrin. The added ALA was notably incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids, mainly eicosapentaenoic acid and n-3 docosapentaenoic acid. ALA supplementation led to increased levels of eicosapentaenoic acid derivatives (15-hydroxyeicosapentaenoic acid and 18-hydroxyeicosapentaenoic acid) as well as a decrease in levels of omega-6 (also know as n-6) polyunsaturated fatty acid lipid mediators (9-hydroxyoctadecadienoic acid, 12-hydroxyeicosatetraenoic acid, and leukotriene B 4 ). Furthermore, the signal transduction mediators extracellular signal‒regulated kinases 1 and 2 were the kinases most activated after ALA supplementation. Taken together, these results show that ALA decreases the pathologic phenotype of psoriatic substitutes by normalizing keratinocyte proliferation and differentiation in vitro., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Capsaicinoids, the pungent principles of chili peppers and prototypical activators of the transient receptor potential of the vanilloid type-1 (TRPV1) channel, which is a member of the expanded endocannabinoid system known as the endocannabinoidome (eCBome), counteract food intake and obesity. In this exploratory study, we examined the blood and stools from a subset of the participants in a cohort of reproductive-aged women with overweight/obesity who underwent a 12-week caloric restriction of 500 kcal/day with the administration of capsaicinoids (two capsules containing 100 mg of a capsicum annuum extract (CAE) each for a daily dose of 4 mg of capsaicinoids) or a placebo. Samples were collected immediately before and after the intervention, and plasma eCBome mediator levels (from 23 participants in total, 13 placebo and 10 CAE) and fecal microbiota taxa (from 15 participants in total, 9 placebo and 6 CAE) were profiled using LC-MS/MS and 16S metagenomic sequencing, respectively. CAE prevented the reduced caloric-intake-induced decrease in beneficial eCBome mediators, i.e., the TRPV1, GPR119 and/or PPARα agonists, N -oleoyl-ethanolamine, N -linoleoyl-ethanolamine and 2-oleoyl-glycerol, as well as the anti-inflammatory N -acyl-ethanolamines N -docosapentaenyl-ethanolamine and N -docosahexaenoyl-ethanolamine. CAE produced few but important alterations in the fecal microbiota, such as an increased relative abundance of the genus Flavonifractor , which is known to be inversely associated with obesity. Correlations between eCBome mediators and other potentially beneficial taxa were also observed, thus reinforcing the hypothesis of the existence of a link between the eCBome and the gut microbiome in obesity.

The endocannabinoids 2-arachidonoyl-glycerol and N -arachidonoyl-ethanolamine are lipids regulating many physiological processes, notably inflammation. Endocannabinoid hydrolysis inhibitors are now being investigated as potential anti-inflammatory agents. In addition to 2-arachidonoyl-glycerol and N -arachidonoyl-ethanolamine, the endocannabinoidome also includes other monoacylglycerols and N -acyl-ethanolamines such as 1-linoleoyl-glycerol (1-LG) and N -linoleoyl-ethanolamine (LEA). By increasing monoacylglycerols and/or N -acyl-ethanolamine levels, endocannabinoid hydrolysis inhibitors will likely increase the levels of their metabolites. Herein, we investigated whether 1-LG and LEA were substrates for the 15-lipoxygenase pathway, given that both possess a 1 Z ,4 Z -pentadiene motif, near their omega end. We thus assessed how human eosinophils and neutrophils biosynthesized the 15-lipoxygenase metabolites of 1-LG and LEA. Linoleic acid (LA), a well-documented substrate of 15-lipoxygenases, was used as positive control. N -13-hydroxy-octodecadienoyl-ethanolamine (13-HODE-EA) and 13-hydroxy-octodecadienoyl-glycerol (13-HODE-G) , the 15-lipoxygenase metabolites of LEA and 1-LG, were synthesized using Novozym 435 and soybean lipoxygenase. Eosinophils, which express the 15-lipoxygenase-1, metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was almost complete after five minutes. Substrate preference of eosinophils was LA > LEA > 1-LG in presence of 13-HODE-G hydrolysis inhibition with methyl-arachidonoyl-fluorophosphonate. Human neutrophils also metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was maximal after 15-30 s. Substrate preference was LA ≫ 1-LG > LEA. Importantly, 13-HODE-G was found in humans and mouse tissue samples. In conclusion, our data show that human eosinophils and neutrophils metabolize 1-LG and LEA into the novel endogenous 15-lipoxygenase metabolites 13-HODE-G and 13-HODE-EA. The full biological importance of 13-HODE-G and 13-HODE-EA remains to be explored.