Simvastatin Inhibits Histologic Changes Associated with Gastroduodenal Reflux in a Murine Model

Dig Dis Sci. 2022 Oct;67(10):4732-4741. doi: 10.1007/s10620-021-07344-0. Epub 2022 Jan 10.


Background: Observational studies demonstrate a protective effect of statins on the development and progression of esophageal adenocarcinoma. The role of statins in the prevention of reflux-induced esophageal changes remains unknown.

Aims: Using a mixed gastroduodenal reflux mouse model, we hypothesized that oral administration of simvastatin would attenuate reflux-induced mucosal changes of the distal esophagus.

Methods: Human Barrett's (CPB) and esophageal adenocarcinoma (FLO1 and OE19) cells were treated with simvastatin. Cell proliferation and apoptosis were evaluated using the MTS proliferation and annexin V apoptosis assays, respectively. A reflux mouse model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and first portion of the duodenum (duodeno-gastroesophageal anastomosis, DGEA). DGEA mice were fed a standard or simvastatin-containing diet following surgery. Mice were euthanized 6 weeks post-operatively.

Results: Simvastatin significantly decreased proliferation and increased apoptosis in all cell lines. Compared to control animals, mice undergoing DGEA who were fed a standard diet demonstrated a fourfold increase in mucosal thickness and significant increase in proliferating cells (p < 0.0001). DGEA mice fed a simvastatin-containing diet had an attenuated response to reflux, with a significant reduction in mucosal hyperplasia and proliferation (p < 0.0001). DGEA mice fed a simvastatin-containing diet demonstrated significant upregulation of procaspase-3 (p = 0.009) and cleaved caspase-3 (p = 0.034) in the distal esophagus.

Conclusions: We demonstrate for the first time a reduction in reflux-induced histologic changes of the distal esophagus following oral administration of simvastatin in vivo. These findings identify simvastatin as a potential preventative agent to inhibit the development and progression of reflux-induced esophageal injury.

Keywords: Gastroesophageal reflux disease; Reflux; Simvastatin; Statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / pathology
  • Animals
  • Annexin A5
  • Barrett Esophagus* / drug therapy
  • Barrett Esophagus* / pathology
  • Caspase 3
  • Disease Models, Animal
  • Esophageal Neoplasms* / pathology
  • Esophagitis, Peptic*
  • Gastroesophageal Reflux* / drug therapy
  • Gastroesophageal Reflux* / pathology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Mice
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use


  • Annexin A5
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Simvastatin
  • Caspase 3

Supplementary concepts

  • Adenocarcinoma Of Esophagus