Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation

Abstract

Background and purpose: Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings.

Materials and methods: Male CBA/CaJ mice fed either a methionine-adequate diet or MSD (6.5 mg methionine/kg diet vs 19.5 mg/kg) received localized abdominal X-irradiation (220 kV, 13 mA) using the Small Animal Radiation Research Platform, and tissues were harvested 4, 7, and 10 days after irradiation.

Results: MSD exacerbated gastrointestinal toxicity after local abdominal irradiation with 12.5 Gy. This was evident as impaired nutrient absorption was paralleled by reduced body weight recovery. Mechanistically, significant shifts in the gut ecology, evident as decreased microbiome diversity, and substantially increased bacterial species that belong to the genus Bacteroides triggered proinflammatory responses. The latter were evident as increases in circulating neutrophils with corresponding decreases in lymphocytes and associated molecular alterations, exhibited as increases in mRNA levels of proinflammatory genes Icam1, Casp1, Cd14, and Myd88. Altered expression of the tight junction-related proteins Cldn2, Cldn5, and Cldn6 indicated a possible increase in intestinal permeability and bacterial translocation to the liver.

Conclusions: We report that dietary supplementation with methionine exacerbates gastrointestinal syndrome in locally irradiated mice. This study demonstrates the important roles registered dieticians should play in clinical oncology and further underlines the necessity of preclinical and clinical investigations in the role of diet in the success of cancer therapy.