Abstract
Esophageal adenocarcinoma (EAC) incidence has been rapidly increasing, potentially associated with the prevalence of the risk factors gastroesophageal reflux disease (GERD), obesity, high-fat diet (HFD), and the precursor condition Barrett’s esophagus (BE). EAC development occurs over several years, with stepwise changes of the squamous esophageal epithelium, through cardiac metaplasia, to BE, and then EAC. To establish the roles of GERD and HFD in initiating BE, we developed a dietary intervention model in C57/BL6 mice using experimental HFD and GERD (0.2% deoxycholic acid, DCA, in drinking water), and then analyzed the gastroesophageal junction tissue lipidome and microbiome to reveal potential mechanisms. Chronic (9 months) HFD alone induced esophageal inflammation and metaplasia, the first steps in BE/EAC pathogenesis. While 0.2% deoxycholic acid (DCA) alone had no effect on esophageal morphology, it synergized with HFD to increase inflammation severity and metaplasia length, potentially via increased microbiome diversity. Furthermore, we identify a tissue lipid signature for inflammation and metaplasia, which is characterized by elevated very-long-chain ceramides and reduced lysophospholipids. In summary, we report a non-transgenic mouse model, and a tissue lipid signature for early BE. Validation of the lipid signature in human patient cohorts could pave the way for specific dietary strategies to reduce the risk of BE in high-risk individuals.
Highlights
There are two main forms of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma (EAC) [1]
We hypothesized that obesity induced by chronic high-fat diet (HFD) will replicate the chronic inflammation due to interleukin-1β overexpression, and leads to Barrett’s-like epithelium development in wild-type mice
We examined the impact of the dietary treatments on tissue morphology of the gastroesophageal junction, where Barrett’s esophagus (BE) arises
Summary
There are two main forms of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma (EAC) [1]. Over a period of three decades, the incidence of EAC has risen sixfold, while esophageal squamous cell carcinoma has remained relatively stable [2,3]. In the United States, incidence of EAC was estimated to increase from 0.40 to 2.58 cases per 100,000 between 1975 and 2009 [4]. EAC is widely accepted to develop via a stepwise sequence, as a consequence of gastroesophageal reflux disease (GERD). BE itself has limited adverse health effects, patients with BE have a 30–60-fold increased risk of developing EAC [11], with estimated annual progression rate of ~0.1%–0.5% per year [12,13]
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