P0104Fatty Acid Ethanolamides as a Possible Novel Inflammatory Target in the Gut–Brain Axis

Abstract Background Fatty acid ethanolamides are endogenous lipid mediators known to attenuate inflammatory processes and reduce pain sensitivity. Among the emerging pharmacological targets for inflammatory bowel disease (IBD), palmitoylethanolamide (PEA) has gained particular attention due to its robust anti-inflammatory properties. PEA belongs to the N-acylethanolamine (NAE) lipid family, together with oleoylethanolamide (OEA). Both OEA and PEA are potent endogenous ligands of PPAR-α, a nuclear receptor that regulates the transcription of genes involved in lipid metabolism, neuroplasticity, and inflammation. Importantly, DSS-treated mice receiving OEA or PEA displayed a significant improvement in disease severity. Moreover, both compounds restored the DSS-induced disruption of PPAR-α mRNA expression, tight-junction components, and other protective factors involved in maintaining colonic integrity. Collectively, these findings highlight FAEs as promising therapeutic tools in IBD. Recent studies have also shown that PEA administration ameliorates behavioral deficits in a preclinical model of Parkinson’s disease (PD), an effect partially dependent on PPAR-α activation. Given the dual capacity of ethanolamides to modulate both gut inflammation and brain homeostasis, we investigated their involvement in the gut–brain axis. Here, we present our preliminary findings in the MPTP model, focusing on how brain dysfunction contributes to colonic inflammation. Methods The PD model in mice was induced by four intraperitoneal injections of MPTP (20 mg/kg) in saline at 2 h intervals in 1 day for a total dose/mouse of 80 mg/kg. Animals were killed 8 days after MPTP injection, and the inflammatory pathways in brain and colon were assessed. In particular three different brain areas (cortex, striatum, hippocampus) were collected, processed for PCR-array and for immunofluorescence staining. Whereas samples of brain, colon, blood and bone marrow will be collected for FACS analysis. Results The SNC evaluation showed impaired in MPTP model as aspected by PCR array of Brain areas. In detail, we have investigate the number of CD3+CD4+ and CD3+CD8+ cells with, B cells (CD45+Cd11b-B220+) and natural killer (NK) cells (CD11blowCD27low, CD27high, CD11bhighCD27high, and CD11bhighCD27low subsets) by flow cytometry. Importantly, T and B cells were not altered in the colon of MPTP mice. On the contrary we have seen an important increase of CD45+ CD11b+, suggesting an increase in the myeloid compartment of colon of MPTP mice with an increase of the number of both Ly6C+ and Ly6G+ cells. Conclusion Taken together, these findings indicate that induction of the PD model may shift colonic inflammation toward a myeloid-enriched profile, mirroring the initial inflammatory stages of IBD References: Otagiri S, Ohnishi S, Ohara M, Fu Q, Yamamoto K, Yamamoto K, Katsurada T,Sakamoto N. Oleoylethanolamide Ameliorates Dextran Sulfate Sodium-InducedColitis in Rats. Front Pharmacol. 2020 Aug 14;11:1277. Lama A, Provensi G, Amoriello R, Pirozzi C, Rani B, Mollica MP, Raso GM,Ballerini C, Meli R, Passani MB. The anti-inflammatory and immune-modulatoryeffects of OEA limit DSS-induced colitis in mice. Biomed Pharmacother. 2020Sep;129:110368. Palese F, Pontis S, Realini N, Torrens A, Ahmed F, Assogna F, Pellicano C,Bossù P, Spalletta G, Green K, Piomelli D. Targeting NAAA counters dopamineneuron loss and symptom progression in mouse models of parkinsonism. PharmacolRes. 2022 Aug;182:106338. Conflict of interest: Travelli, Cristina: No conflict of interest Cascetta, Greta: No conflict of interest Ferramosca, Angela: No conflict of interest Eremita, Gianmarco: No conflict of interest Balestrero, Federica Carolina: No conflict of interest Panza, Elisabetta: No conflict of interest Romano, Adele: No conflict of interest Paterniti, Irene: No conflict of interest