Influence of Tryptophan Metabolism on the Protective Effect of Weissella paramesenteroides WpK4 in a Murine Model of Chemotherapy-Induced Intestinal Mucositis.

Abstract

Dysbiosis is a notable marker of intestinal mucositis, an inflammatory condition induced by antineoplastic chemotherapy. Scientific evidence supports the effectiveness of probiotics in managing dysbiosis associated with intestinal mucositis. It is known that tryptophan metabolism is a regulatory component in the multifactorial phenomenon of mucosal homeostasis. In the face of that, we aimed to investigate if oral administration of Weissella paramesenteroides WpK4, a probiotic candidate strain, has a protective effect in a murine model of intestinal mucositis induced by 5-fluorouracil (5-FU) and if tryptophan metabolism plays any role in this effect. Gavage with viable cells of W. paramesenteroides WpK4 increased intestinal mucus production, regeneration of villi, as well as control of dysbiosis in mice submitted to 5-FU chemotherapy, and resulted in 100% survival, unlike the control saline-treated group, which resulted in 60% survival of mice after mucositis induction. Weissella paramesenteroides WpK4 genome harbors sequences encoding enzymes for tryptophan production and catabolism and can synthesize tryptophan, tryptamine, and indole acetic acid in vitro. Besides, oral administration of WpK4 induced increased expression of molecules involved in tryptophan metabolism in mouse ileum and serum. Notably, simultaneous treatment with alfa-naphthoflavone, an aryl hydrocarbon receptor (AhR) inhibitor, abolished the protective effects exerted by W. paramesenteroides Wpk4, as manifested by a significant decline in body weight, suggesting that treatment with the probiotic strain modulates AhR activation. Our results suggest that tryptophan metabolism is potentially involved in the protective effects caused by oral administration of W. paramesenteroides WpK4 to mice during gut inflammatory conditions induced by 5-FU.