Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism

Claudio Pirozzi; Lorena Coretti; Nicola Opallo; Maria Bove; Chiara Annunziata; Federica Comella; Luigia Turco; Adriano Lama; Luigia Trabace; Rosaria Meli; Francesca Lembo; Giuseppina Mattace Raso

doi:10.3389/fnut.2023.1143004

Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism

Front Nutr. 2023 Aug 1:10:1143004. doi: 10.3389/fnut.2023.1143004. eCollection 2023.

Authors

Claudio Pirozzi¹, Lorena Coretti^{1

2}, Nicola Opallo¹, Maria Bove³, Chiara Annunziata¹, Federica Comella¹, Luigia Turco^{1

4}, Adriano Lama^{1

2

3}, Luigia Trabace³, Rosaria Meli¹, Francesca Lembo^{1

2}, Giuseppina Mattace Raso^{1

2}

Affiliations

¹ Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.
² Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy.
³ Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
⁴ Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

Abstract

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward 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 an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 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 (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.

Keywords: N-acylethanolamines; gut microbiota; gut-brain axis; obesity; serotonin.