The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitaryadrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer's Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. Their effective role has been studied in inflammation, acute and chronic pain, obesity and central nervous system diseases. A possible correlation has been shown between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in the rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in the central nervous system diseases.

Alzheimer disease (AD) is the most common form of neurodegenerative dementia. Amyloid-β deposition, neurofibrillary tangle formation, and neuro-inflammation are the major pathogenic mechanisms that in concert lead to memory dysfunction and decline of cognition. Palmitoylethanolamide (PEA) is the naturally occurring lipid amide between palmitic acid and ethanolamine. Despite its clear role in inflammation and pain control, only limited in vitro evidence exist about a role for PEA in neurodegenerative diseases. Here we describe the neuroprotective activities of PEA in mice injected intracerebroventricularly with amyloid-β 25-35 (Ab25-35) peptide (9 nmol). We used spatial and non-spatial memory tasks to evaluate learning and memory dysfunctions. Ab25-35 injection significantly impaired spontaneous alternation performances, water maze spatial reference and working-like memory, and novel object recognition test. PEA was administered once a day (3-30 mg/kg, subcutaneously), starting 3 h after Ab25-35, for 1 or 2 weeks. PEA reduced (10 mg/kg) or prevented (30 mg/kg) behavioral impairments induced by Ab25-35 injection. PEA failed to rescue memory deficits induced by Ab25-35 injection in peroxisome proliferator-activated receptor-α (PPAR-α) null mice. GW7647 (2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid; 5 mg/kg per day), a synthetic PPAR-α agonist, mimicked the effect of PEA. Acute treatment with PEA was ineffective. According with the neuroprotective profile of PEA observed during behavioral studies, experimental molecular and biochemical markers induced by Ab25-35 injection, such as lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, and caspase3 activation, were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, unrevealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.

Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.

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AimsButyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function.In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H 2 O 2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO.