Controlled bile acid exposure to oesophageal mucosa causes up-regulation of nuclear γ-H2AX possibly via iNOS induction.

Bo Jiang,Yancheng Yang,Jin Wen,Aimin Gao,Hongling Yan,Shengqian Zhao,Zhen Tao,Yin Zheng,Ying Sheng

doi:10.1042/bsr20160124

Bo Jiang, Yancheng Yang + Show 7 more

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https://doi.org/10.1042/bsr20160124

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Abstract

Using an invitro model in which flatmounts of oesophagus was periodically exposed to bile acids, we demonstrate, using multiple methods, that the bile acid receptor TGR5, inducible nitric oxide synthase (iNOS) and γ-histone family 2A variant (γ-H2AX) are up-regulated. This indicates that bile acids cause up-regulation of iNOS, which further causes genotoxic stress as evidenced by increase of the highly sensitive marker, phosphorylated histone. Invitro nitric oxide (NO) assays showed increased production of nitric acid in the oesophageal epithelium exposed to the bile acids. This increase was inhibited in the presence of the nonspecific iNOS inhibitor aminoguanidine (AG). Cumulatively, the results of the present study provide suggestion that not only acid reflux, but also non-acid reflux of bile may cause genotoxic stress. These aspects merit to be tested in wide spectrum of Barrett epithelial tissues.

Highlights

Barrett oesophagus is a premalignant condition and molecular aspects have been characterized from numerous perspectives [1,2,3,4]
H2O2 cannot induce the TGR5 expression, suggesting bile acid induces oxidative stress, which activates inducible nitric oxide synthase (iNOS), at least bile acid affects the downstream signalling through TGR5, which is independent of oxidative stress
Our results in Figure 2(D) show knockdown TGR5 could decrease the expression of iNOS with the treatments of bile acid at 8 and 24 h, indicating TGR5 is required in the bile acid-TGR5-iNOS pathway

Summary

Introduction

Barrett oesophagus is a premalignant condition and molecular aspects have been characterized from numerous perspectives [1,2,3,4]. Non-acid refluxate can result from ongoing acid suppression therapy in subjects with gastroesophageal reflux disease (GERD). It is identified that the hypotensive sphincters and other mechanical factors like obesity commonly results in backward flow of contents even from the first part of the duodenum [2]. This results in significant exposure of the luminal oesophageal mucosa to duodenal contents, which include biliary fluid [10]

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