M1956 Bimodal Effects of Dietary Macronutrient Manipulation On Carcinogenesis in Barrett's Mucosa

Abstract

INTRODUCTION: Reflux& being overweight are strong risk factors for esophageal adenocarcinoma (EAC). There is a trend toward Low-Carb (LC) diet use among both obese & healthy individuals. The LC diet reduces weight, improves insulin resistance, may decrease reflux & potentially decrease risk of EAC. However, we previously found that LC diet increased levels of procarcinogenic bile salt deoxycholic acid (DCA) in rats. Our AIM was to examine the effect of LC diet on procarcinogenic signaling in Barrett's mucosa & EAC development in rats with reflux. METHODS: Sprague-Dawley rats (n=65) were operated to induce gastroduodenal reflux & randomized at 22 weeks post-op (time to develop Barrett's). The effect of LC diet on procarcinogenic signaling in Barrett's was tested in a short term investigation involving 20 rats randomized (1:1) to LC or balanced (ADA) diet for 4 weeks. The effect of LC diet on development of EAC was examined in a long-term study involving 45 rats randomized (1:2) to LC or ADA diet for 20 weeks. Rats were sacrificed & esophageal tissue tested for PGE2 levels & key enzymes (cPLA2, COX-2) involved in PGE2 synthesis. Presence of Barrett's mucosa & EAC was noted. Serum IGF1 levels & animal weight was examined. RESULTS: The 4 week short-term LC diet significantly increased PGE2 levels (245±41 vs 95±22pg/mg, p=0.002), cPLA2 & COX-2, compared to ADA diet. As seen previously, LC diet increased levels of DCA. In-vitro assays showed that increasing DCA levels up-regulated cPLA2, increased COX-2 & induced PGE2 synthesis. LC diet was associated with weight loss but serum IGF1 levels were not different. Based on these results, we anticipated that up-regulation of carcinogenic signaling with LC diet would increase the rate of EAC. However, the rate of EAC was not different in long-term LC vs ADA rats (9/15, 60% vs 19/30, 63% p=1.0). The long-term LC diet did result in significant weight reduction (321±28gms vs 396±11gms, p=0.03) & lower IGF-1 levels(10±3 vs 1.2±1 ng/ml, p=0.02) compared to ADA diet. CONCLUSIONS: Short-term LC diet supplementation promotes procarcinogenic signaling involving PGE2 synthesis. However, this does not translate to an increased risk of EAC with long-term LC diet supplementation. A possible explanation for the bimodal effect of LC diet is the marked weight reduction & low IGF1 levels with long-term LC diet, which may negate the effects of procarcinogenic signaling. This is clinically relevant because most people use Low-Carb diet for short term rather than long term, which may increase their risk of EAC. Studies to examine the opposing effects of IGF-1/weight reduction & PGE2 pathway are currently being investigated.