• Carmen Arto, Elena Cristina Rusu, Helena Clavero-Mestres, Andrea Barrientos-Riosalido, Laia Bertran, Razieh Mahmoudian, Carmen Aguilar, David Riesco, ChicoteJavier UgarteJUDepartament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain.Servei Anatomia Patològica, Hos, David Parada, Salomé Martínez, Fàtima Sabench, Cristóbal Richart, and Teresa Auguet.
• Servei Medicina Interna, Hospital Sant Pau i Santa Tecla de Tarragona, Tarragona, Spain.
• Eur. J. Clin. Invest. 2024 Nov 1; 54 (11): e14279e14279.

Background And AimsThe rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD.Materials And MethodsWe used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO).ResultsKey findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577-39.823) μM of tryptophan in NL subjects; 41.522 (38.803-45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS.ConclusionsWe identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

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