Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction‐associated steatotic liver disease

• Published in: European journal of clinical investigation Vol. 54; no. 11; pp. e14279 - n/a
• Main Authors: Arto, Carmen, Rusu, Elena Cristina, Clavero‐Mestres, Helena, Barrientos‐Riosalido, Andrea, Bertran, Laia, Mahmoudian, Razieh, Aguilar, Carmen, Riesco, David, Chicote, Javier Ugarte, Parada, David, Martínez, Salomé, Sabench, Fàtima, Richart, Cristóbal, Auguet, Teresa
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2024
• Subjects: Acetic acid; Catabolism; Fatty liver; Fluxes; Gene expression; High performance liquid chromatography; Indoleacetic acid; kynurenine; Liquid chromatography; Liver; Liver diseases; metabolic dysfunction‐associated steatotic liver disease; Metabolic pathways; Metabolism; Metabolites; Obesity; Pathogenesis; Propionic acid; Serotonin; Steatosis; Therapeutic applications; Tryptophan; serotonin; kynurenine; metabolic dysfunction‐associated steatotic liver disease; tryptophan
• ISSN: 0014-2972; 1365-2362; 1365-2362
• DOI: 10.1111/eci.14279

Background and Aims The 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 Methods We 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). Results Key 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. Conclusions We 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. The study delves into tryptophan pathways in obesity and metabolic dysfunction‐associated steatotic liver disease. Fifteen tryptophan‐related metabolites were determined in 76 subjects, spanning normal weight and morbid obesity cohorts categorized by liver condition. Gene expression of hepatic IDO‐1 and kynyrenine‐3‐monooxygenase (KMO) was analysed. We found distinct signatures in obesity: increased kynurenine cascade, decreased indole route and altered serotonin pathway. Reduced hepatic expression of IDO‐1 and KMO is noted in normal liver versus simple steatosis. Tryptophan catabolism shifts across histological stages