Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice is known to induce dysbiosis, causing a shift towards bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA), is endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders, however, the mechanisms underlining its enteroprotective and neuroprotective effects are not fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations as result of lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan-kynurenine metabolism were evaluated. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and the levels of corticotropin releasing hormone. In particular, PEA modulated HFD-altered tryptophan (TRP) metabolism in colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through the increase in the levels of butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate the restructuring of gut microbiota following PEA supplementation contribute to promote host 5-HT biosynthesis, crucial in regulating intestinal function, and that PEA regulates the crosstalk between host immune system and gut microbiota, via rebalancing colonic TRP metabolites.