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Mechanisms and pathophysiology of Barrett oesophagus

Abstract

Barrett oesophagus, in which a metaplastic columnar mucosa that can predispose individuals to cancer development lines a portion of the distal oesophagus, is the only known precursor of oesophageal adenocarcinoma, the incidence of which has increased profoundly over the past several decades. Most evidence suggests that Barrett oesophagus develops from progenitor cells at the oesophagogastric junction that proliferate and undergo epithelial–mesenchymal transition as part of a wound-healing process that replaces oesophageal squamous epithelium damaged by gastroesophageal reflux disease (GERD). GERD also seems to induce reprogramming of key transcription factors in the progenitor cells, resulting in the development of the specialized intestinal metaplasia that is characteristic of Barrett oesophagus, probably through an intermediate step of metaplasia to cardiac mucosa. Genome-wide association studies suggest that patients with GERD who develop Barrett oesophagus might have an inherited predisposition to oesophageal metaplasia and that there is a shared genetic susceptibility to Barrett oesophagus and to several of its risk factors (such as GERD, obesity and cigarette smoking). In this Review, we discuss the mechanisms, pathophysiology, genetic predisposition and cells of origin of Barrett oesophagus, and opine on the clinical implications and future research directions.

Key points

  • Barrett oesophagus is defined conceptually as the condition in which a metaplastic mucosa that can predispose to cancer development lines a portion of the distal oesophagus.

  • Patients with Barrett oesophagus can have an inherited predisposition to its development, involving germline susceptibility to reflux oesophagitis, to risk factors such as gastroesophageal reflux disease (GERD) and obesity, and to tissue-specific gene expression that might favour oesophageal metaplasia.

  • Barrett oesophagus seems to develop when oesophageal squamous cells destroyed by GERD are replaced by columnar progenitor cells at the oesophagogastric junction that proliferate as part of a wound-healing process.

  • Potential cells of origin for Barrett metaplasia include basal cells of oesophageal squamous epithelium, oesophageal submucosal gland cells, transitional basal cells, residual embryonic cells, gastric gland cells and cells of compact mucous glands.

  • GERD induces the reprogramming of key transcription factors in progenitor cells to produce the specialized intestinal metaplasia with goblet cells, which is characteristic of Barrett oesophagus, probably through an intermediate step of metaplasia to cardiac mucosa.

  • Short and long segments of the specialized intestinal metaplasia seem to develop through the same pathophysiological mechanisms.

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Fig. 1: Histology of human oesophageal squamocolumnar junction region.
Fig. 2: Potential progenitor cells for Barrett oesophagus at the oesophagogastric junction.
Fig. 3: Re-epithelialization of the ulcer crater via epithelial–mesenchymal transition in adjacent cells.
Fig. 4: Specialized intestinal metaplasia develops as a result of reflux-induced molecular reprogramming of progenitor cells.

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Acknowledgements

The authors acknowledge funding from the US National Institutes of Health (R01-DK124185 to R.F.S. and S.J.S.) and the Baylor Scott & White Research Institute.

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Correspondence to Rhonda F. Souza.

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R.F.S. has served as a consultant for Interpace Diagnostics, Castle Biosciences, Ironwood Pharmaceuticals, Phathom Pharmaceuticals, IsoThrive, CDx Diagnostics and AstraZeneca and receives research support from Phathom Pharmaceuticals and Sanofi. S.J.S. has served as a consultant for Interpace Diagnostics, Castle Biosciences, Phathom Pharmaceuticals, IsoThrive, Takeda Pharmaceuticals and Ironwood Pharmaceuticals and receives royalties as an author for UpToDate.

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Souza, R.F., Spechler, S.J. Mechanisms and pathophysiology of Barrett oesophagus. Nat Rev Gastroenterol Hepatol 19, 605–620 (2022). https://doi.org/10.1038/s41575-022-00622-w

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