Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms and pathophysiology of Barrett oesophagus

Nature Reviews Gastroenterology & Hepatology volume 19, pages 605–620 (2022)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Spechler, S. J. & Souza, R. F. Barrett’s esophagus. N. Engl. J. Med. 371, 836–845 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Cook, M. B. & Thrift, A. P. Epidemiology of Barrett’s esophagus and esophageal adenocarcinoma: implications for screening and surveillance. Gastrointest. Endosc. Clin. North. Am. 31, 1–26 (2021).

    Article  Google Scholar 

  3. Sawas, T. et al. Identification of prognostic phenotypes of esophageal adenocarcinoma in 2 independent cohorts. Gastroenterology 155, 1720–1728.e4 (2018).

    Article  PubMed  Google Scholar 

  4. Curtius, K., Rubenstein, J. H., Chak, A. & Inadomi, J. M. Computational modelling suggests that Barrett’s oesophagus may be the precursor of all oesophageal adenocarcinomas. Gut 70, 435–1440 (2021).

    Article  Google Scholar 

  5. Nowicki-Osuch, K. et al. Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition. Science 373, 760–767 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Ek, W. E. et al. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett’s esophagus, and gastroesophageal reflux. J. Natl Cancer Inst. 105, 1711–1718 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Palles, C. et al. Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett’s esophagus. Gastroenterology 148, 367–378 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Levine, D. M. et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat. Genet. 45, 1487–1493 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gharahkhani, P. et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett’s oesophagus: a large-scale meta-analysis. Lancet Oncol. 17, 1363–1373 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dong, J. et al. Sex-specific genetic associations for barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology 159, 2065–2076.e1 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Sun, X. et al. Genomic regions associated with susceptibility to Barrett’s esophagus and esophageal adenocarcinoma in African Americans: the cross BETRNet admixture study. PLoS ONE 12, e0184962 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Su, Z. et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat. Genet. 44, 1131–1136 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Spechler, S. J. Cardiac mucosa: the heart of the problem. Gut 64, 1673–1674 (2015).

    Article  PubMed  Google Scholar 

  14. Noffsinger, A. E. in Fenoglio-Preiser’s Gastrointestinal Pathology 136–223 (Wolters Kluwer, 2017).

  15. Chandrasoma, P. Pathophysiology of Barrett’s esophagus. Semin. Thorac. Cardiovasc. Surg. 9, 270–278 (1997).

    CAS  PubMed  Google Scholar 

  16. Chandrasoma, P., Makarewicz, K., Wickramasinghe, K., Ma, Y. & Demeester, T. A proposal for a new validated histological definition of the gastroesophageal junction. Hum. Pathol. 37, 40–47 (2006).

    Article  PubMed  Google Scholar 

  17. Chandrasoma, P., Wijetunge, S., Demeester, S. R., Hagen, J. & Demeester, T. R. The histologic squamo-oxyntic gap: an accurate and reproducible diagnostic marker of gastroesophageal reflux disease. Am. J. Surg. Pathol. 34, 1574–1581 (2010).

    Article  PubMed  Google Scholar 

  18. Park, Y. S., Park, H. J., Kang, G. H., Kim, C. J. & Chi, J. G. Histology of gastroesophageal junction in fetal and pediatric autopsy. Arch. Pathol. Lab. Med. 127, 451–455 (2003).

    Article  PubMed  Google Scholar 

  19. Kilgore, S. P. et al. The gastric cardia: fact or fiction? Am. J. Gastroenterol. 95, 921–924 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Dunn, L. J., Burt, A. D., Hayes, N. & Griffin, S. M. Columnar metaplasia in the esophageal remnant after esophagectomy: a common occurrence and a valuable insight into the development of Barrett esophagus. Ann. Surg. 264, 1016–1021 (2016).

    Article  PubMed  Google Scholar 

  21. Dias Pereira, A. & Chaves, P. Columnar-lined oesophagus without intestinal metaplasia: results from a cohort with a mean follow-up of 7 years. Aliment. Pharmacol. Ther. 36, 282–289 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Ellison, E., Hassall, E. & Dimmick, J. E. Mucin histochemistry of the developing gastroesophageal junction. Pediatr. Pathol. Lab. Med. 16, 195–206 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Hahn, H. P. et al. Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus. Am. J. Surg. Pathol. 33, 1006–1015 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Liu, W., Hahn, H., Odze, R. D. & Goyal, R. K. Metaplastic esophageal columnar epithelium without goblet cells shows DNA content abnormalities similar to goblet cell-containing epithelium. Am. J. Gastroenterol. 104, 816–824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robertson, E. V. et al. Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa. Gastroenterology 145, 730–739 (2013).

    Article  PubMed  Google Scholar 

  26. Robertson, E. V. et al. Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux. Gut 66, 1208–1215 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Odze, R. et al. Histologic study of the esophagogastric junction of organ donors reveals novel glandular structures in normal esophageal and gastric mucosae. Clin. Transl. Gastroenterol. 12, e00346 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Paull, A. et al. The histologic spectrum of Barrett’s esophagus. N. Engl. J. Med. 295, 476–480 (1976).

    Article  CAS  PubMed  Google Scholar 

  29. Chen, W. et al. Significance of Paneth cell metaplasia in Barrett esophagus: a morphologic and clinicopathologic study. Am. J. Clin. Pathol. 143, 665–671 (2015).

    Article  PubMed  Google Scholar 

  30. Evans, J. A. et al. Clonal transitions and phenotypic evolution in Barrett’s esophagus. Gastroenterology 162, 1197–1209 (2022).

    Article  PubMed  Google Scholar 

  31. McClave, S. A., Boyce, H. W. Jr. & Gottfried, M. R. Early diagnosis of columnar-lined esophagus: a new endoscopic diagnostic criterion. Gastrointest. Endosc. 33, 413–416 (1987).

    Article  CAS  PubMed  Google Scholar 

  32. Ishimura, N. et al. Questionnaire-based survey conducted in 2011 concerning endoscopic management of Barrett’s esophagus in East Asian countries. Digestion 86, 136–146 (2012).

    Article  PubMed  Google Scholar 

  33. Sharma, P., Morales, T. G. & Sampliner, R. E. Short segment Barrett’s esophagus — the need for standardization of the definition and of endoscopic criteria. Am. J. Gastroenterol. 93, 1033–1036 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Shaheen, N. J., Falk, G. W., Iyer, P. G. & Gerson, L. B. ACG clinical guideline: diagnosis and management of Barrett’s esophagus. Am. J. Gastroenterol. 111, 30–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Fitzgerald, R. C. et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut 63, 7–42 (2014).

    Article  PubMed  Google Scholar 

  36. Weusten, B. et al. Endoscopic management of Barrett’s esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy 49, 191–198 (2017).

    Article  PubMed  Google Scholar 

  37. Merlo, L. M., Kosoff, R. E., Gardiner, K. L. & Maley, C. C. An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition. BMC Cancer 11, 461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Spechler, S. J., Sharma, P., Souza, R. F., Inadomi, J. M. & Shaheen, N. J. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology 140, 1084–1091 (2011).

    Article  PubMed  Google Scholar 

  39. Iascone, C., DeMeester, T. R., Little, A. G. & Skinner, D. B. Barrett’s esophagus. Functional assessment, proposed pathogenesis, and surgical therapy. Arch. Surg. 118, 543–549 (1983).

    Article  CAS  PubMed  Google Scholar 

  40. Zaninotto, G., DeMeester, T. R., Bremner, C. G., Smyrk, T. C. & Cheng, S. C. Esophageal function in patients with reflux-induced strictures and its relevance to surgical treatment. Ann. Thorac. Surg. 47, 362–370 (1989).

    Article  CAS  PubMed  Google Scholar 

  41. Gray, M. R., Donnelly, R. J. & Kingsnorth, A. N. Role of salivary epidermal growth factor in the pathogenesis of Barrett’s columnar lined oesophagus. Br. J. Surg. 78, 1461–1466 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Johnson, D. A., Winters, C., Spurling, T. J., Chobanian, S. J. & Cattau, E. L. Jr. Esophageal acid sensitivity in Barrett’s esophagus. J. Clin. Gastroenterol. 9, 23–27 (1987).

    Article  CAS  PubMed  Google Scholar 

  43. Spechler, S. J. The columnar lined oesophagus: a riddle wrapped in a mystery inside an enigma. Gut 41, 710–711 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Spechler, S. J., Zeroogian, J. M., Antonioli, D. A., Wang, H. H. & Goyal, R. K. Prevalence of metaplasia at the gastro-oesophageal junction. Lancet 344, 1533–1536 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Johnston, M. H., Hammond, A. S., Laskin, W. & Jones, D. M. The prevalence and clinical characteristics of short segments of specialized intestinal metaplasia in the distal esophagus on routine endoscopy. Am. J. Gastroenterol. 91, 1507–1511 (1996).

    CAS  PubMed  Google Scholar 

  46. Nandurkar, S., Talley, N. J., Martin, C. J., Ng, T. H. & Adams, S. Short segment Barrett’s oesophagus: prevalence, diagnosis and associations. Gut 40, 710–715 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chalasani, N., Wo, J. M., Hunter, J. G. & Waring, J. P. Significance of intestinal metaplasia in different areas of esophagus including esophagogastric junction. Dig. Dis. Sci. 42, 603–607 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Kahrilas, P. J. et al. The acid pocket: a target for treatment in reflux disease? Am. J. Gastroenterol. 108, 1058–1064 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Fletcher, J., Wirz, A., Henry, E. & McColl, K. E. Studies of acid exposure immediately above the gastro-oesophageal squamocolumnar junction: evidence of short segment reflux. Gut 53, 168–173 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pandolfino, J. E. et al. Comparison of esophageal acid exposure at 1 cm and 6 cm above the squamocolumnar junction using the Bravo pH monitoring system. Dis. Esophagus 19, 177–182 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Iijima, K. et al. Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 122, 1248–1257 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Spechler, S. J. Are we underestimating acid reflux? Gut 53, 162–163 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tosh, D. & Slack, J. M. How cells change their phenotype. Nat. Rev. Mol. Cell Biol. 3, 187–194 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Wang, D. H. The Esophageal squamous epithelial cell-still a reasonable candidate for the Barrett’s esophagus cell of origin? Cell. Mol. Gastroenterol. Hepatol. 4, 157–160 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Que, J., Garman, K. S., Souza, R. F. & Spechler, S. J. Pathogenesis and cells of origin of Barrett’s esophagus. Gastroenterology 157, 349–364.e1 (2019).

    Article  PubMed  Google Scholar 

  56. Willet, S. G. et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J. 37, e98311 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jin, R. U. & Mills, J. C. Are gastric and esophageal metaplasia relatives? The case for Barrett’s stemming from SPEM. Dig. Dis. Sci. 63, 2028–2041 (2018).

    Article  PubMed  Google Scholar 

  58. Brown, J. W., Cho, C. J. & Mills, J. C. Paligenosis: cellular remodeling during tissue repair. Annu. Rev. Physiol. 84, 461–483 (2022).

    Article  PubMed  CAS  Google Scholar 

  59. Zhang, W. & Wang, D. H. Origins of metaplasia in Barrett’s esophagus: is this an esophageal stem or progenitor cell disease? Dig. Dis. Sci. 63, 2005–2012 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Agoston, A. T. et al. Columnar-lined esophagus develops via wound repair in a surgical model of reflux esophagitis. Cell. Mol. Gastroenterol. Hepatol. 6, 389–404 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Asanuma, K. et al. In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-Box 2) expression. Gut 65, 1416–1426 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Minacapelli, C. D. et al. Barrett’s metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G615–G622 (2017).

    Article  PubMed  Google Scholar 

  63. Wang, D. H. et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology 138, 1810–1822 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, D. H. et al. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J. Clin. Invest. 124, 3767–3780 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Roudebush, C., Catala-Valentin, A., Andl, T., Le Bras, G. F. & Andl, C. D. Activin A-mediated epithelial de-differentiation contributes to injury repair in an in vitro gastrointestinal reflux model. Cytokine 123, 154782 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhou, G. et al. Acid and bile salt up-regulate BMP4 expression in human esophageal epithelium cells. Scand. J. Gastroenterol. 44, 926–932 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Glickman, J. N. et al. Multilayered epithelium in mucosal biopsy specimens from the gastroesophageal junction region is a histologic marker of gastroesophageal reflux disease. Am. J. Surg. Pathol. 33, 818–825 (2009).

    Article  PubMed  Google Scholar 

  68. Chen, X. et al. Multilayered epithelium in a rat model and human Barrett’s esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol. 8, 1 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Shields, H. M. et al. Prospective evaluation of multilayered epithelium in Barrett’s esophagus. Am. J. Gastroenterol. 96, 3268–3273 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Abdulnour-Nakhoul, S. et al. Characterization of esophageal submucosal glands in pig tissue and cultures. Dig. Dis. Sci. 52, 3054–3065 (2007).

    Article  PubMed  Google Scholar 

  71. Zhang, X. et al. The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury. Ann. NY Acad. Sci. 1434, 304–318 (2018).

    Article  PubMed  Google Scholar 

  72. Leedham, S. J. et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut 57, 1041–1048 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Coad, R. A. et al. On the histogenesis of Barrett’s oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts. J. Pathol. 206, 388–394 (2005).

    Article  PubMed  Google Scholar 

  74. Garman, K. S. Origin of Barrett’s epithelium: esophageal submucosal glands. Cell. Mol. Gastroenterol. Hepatol. 4, 153–156 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Owen, R. P. et al. Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands. Nat. Commun. 9, 4261 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Gillen, P., Keeling, P., Byrne, P. J., West, A. B. & Hennessy, T. P. Experimental columnar metaplasia in the canine oesophagus. Br. J. Surg. 75, 113–115 (1988).

    Article  CAS  PubMed  Google Scholar 

  77. Li, H. et al. Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett’s esophagus. Surgery 115, 176–181 (1994).

    CAS  PubMed  Google Scholar 

  78. Krüger, L. et al. Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G180–G191 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Van Nieuwenhove, Y. & Willems, G. Gastroesophageal reflux triggers proliferative activity of the submucosal glands in the canine esophagus. Dis. Esophagus 11, 89–93 (1998).

    Article  PubMed  Google Scholar 

  80. von Furstenberg, R. J. et al. Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation. Cell. Mol. Gastroenterol. Hepatol. 4, 385–404 (2017).

    Article  Google Scholar 

  81. Sayin, S. I., Baumeister, T., Wang, T. C. & Quante, M. Origins of metaplasia in the esophagus: is this a GE junction stem cell disease? Dig. Dis. Sci. 63, 2013–2021 (2018).

    Article  PubMed  Google Scholar 

  82. Quante, M. et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21, 36–51 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, Y. et al. Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett’s-like esophagus. Oncotarget 8, 203–214 (2017).

    Article  PubMed  Google Scholar 

  84. Wang, X. et al. Residual embryonic cells as precursors of a Barrett’s-like metaplasia. Cell 145, 1023–1035 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jiang, M. et al. Transitional basal cells at the squamous-columnar junction generate Barrett’s oesophagus. Nature 550, 529–533 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Vercauteren Drubbel, A. et al. Reactivation of the Hedgehog pathway in esophageal progenitors turns on an embryonic-like program to initiate columnar metaplasia. Cell Stem Cell 28, 1411–1427 (2021).

    Article  CAS  PubMed  Google Scholar 

  87. Sarosi, G. et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett’s esophagus. Dis. Esophagus 21, 43–50 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Hutchinson, L. et al. Human Barrett’s adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant. Stem Cell Dev. 20, 11–17 (2011).

    Article  CAS  Google Scholar 

  89. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Armstrong, D. et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 111, 85–92 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Mills, J. C. & Sansom, O. J. Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract. Sci. Signal. 8, re8 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Slack, J. M. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat. Rev. Mol. Cell Biol. 8, 369–378 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Oberg, S., Johansson, J., Wenner, J. & Walther, B. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann. Surg. 235, 338–345 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Vega, K. J. et al. Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett’s esophagus and esophageal adenocarcinoma. J. Gastroenterol. Hepatol. 27, 773–780 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yang, J. et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Zhang, Q. et al. Acidic bile salts induce epithelial to mesenchymal transition via VEGF signaling in non-neoplastic Barrett’s cells. Gastroenterology 156, 130–144.e110 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Kunze, B. et al. Notch signaling mediates differentiation in Barrett’s esophagus and promotes progression to adenocarcinoma. Gastroenterology 159, 575–590 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Peters, Y. et al. Barrett oesophagus. Nat. Rev. Dis. Primers 5, 35 (2019).

    Article  PubMed  Google Scholar 

  100. Cameron, A. J. et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 122, 55–59 (2002).

    Article  PubMed  Google Scholar 

  101. Mohammed, I., Cherkas, L. F., Riley, S. A., Spector, T. D. & Trudgill, N. J. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 52, 1085–1089 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. An, J. et al. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases. Nat. Commun. 10, 4219 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Dai, J. Y. et al. A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett’s esophagus. Cancer Epidemiol. Biomark. Prev. 24, 1739–1747 (2015).

    Article  CAS  Google Scholar 

  104. Thrift, A. P. et al. Obesity and risk of esophageal adenocarcinoma and Barrett’s esophagus: a Mendelian randomization study. J. Natl Cancer Inst. 106, dju252 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Böhmer, A. C. et al. Shared genetic etiology of obesity-related traits and Barrett’s esophagus/adenocarcinoma: insights from genome-wide association studies. Cancer Epidemiol. Biomark. Prev. 29, 427–433 (2020).

    Article  Google Scholar 

  106. Singh, S. et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 11, 1399–1412.e7 (2013).

    Article  PubMed  Google Scholar 

  107. Dighe, S. G. et al. Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma. Carcinogenesis 42, 369–377 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. Consortium, G. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).

    Article  CAS  Google Scholar 

  109. Schröder, J. et al. Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data. PLoS ONE 14, e0227072 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Jin, E. H. et al. A novel susceptibility locus near GRIK2 associated with erosive esophagitis in a Korean cohort. Clin. Transl. Gastroenterol. 11, e00145 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Wu, C. S. et al. Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer. Int. J. Cancer 126, 2542–2552 (2010).

    CAS  PubMed  Google Scholar 

  112. Brassai, A., Suvanjeiev, R. G., Bán, E. G. & Lakatos, M. Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Brain Res. Bull. 112, 1–6 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Browning, K. N. & Travagli, R. A. Plasticity of vagal brainstem circuits in the control of gastric function. Neurogastroenterol. Motil. Soc. 22, 1154–1163 (2010).

    Article  CAS  Google Scholar 

  114. Tack, J. & Pandolfino, J. E. Pathophysiology of gastroesophageal reflux disease. Gastroenterology 154, 277–288 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Mittal, R. K., Holloway, R. H., Penagini, R., Blackshaw, L. A. & Dent, J. Transient lower esophageal sphincter relaxation. Gastroenterology 109, 601–610 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Buas, M. F. et al. Germline variation in inflammation-related pathways and risk of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 66, 1739–1747 (2017).

    Article  CAS  PubMed  Google Scholar 

  117. Feagins, L. A. et al. Mechanisms of oxidant production in esophageal squamous cell and Barrett’s cell lines. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G411–G417 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Banerjee, B. et al. Clinical study of ursodeoxycholic acid in Barrett’s esophagus patients. Cancer Prev. Res. 9, 528–533 (2016).

    Article  CAS  Google Scholar 

  119. Battle, A., Brown, C. D., Engelhardt, B. E. & Montgomery, S. B. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article  PubMed  Google Scholar 

  120. Zhang, H. Y. et al. In non-neoplastic Barrett’s epithelial cells, acid exerts early antiproliferative effects through activation of the Chk2 pathway. Cancer Res. 67, 8580–8587 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Huo, X. et al. Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett’s oesophagus. Gut 67, 606–615 (2018).

    CAS  PubMed  Google Scholar 

  122. Souza, R. F. et al. Differences in ERK activation in squamous mucosa in patients who have gastroesophageal reflux disease with and without Barrett’s esophagus. Am. J. Gastroenterol. 100, 551–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Yang, L. et al. Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 137, 588–597 (2009).

    Article  PubMed  Google Scholar 

  124. Verbeek, R. E. et al. Toll-like receptor 4 activation in Barrett’s esophagus results in a strong increase in COX-2 expression. J. Gastroenterol. 49, 1121–1134 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Jakszyn, P. & Gonzalez, C. A. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World J. Gastroenterol. 12, 4296–4303 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Endo, H. et al. Exogenous luminal nitric oxide exposure accelerates columnar transformation of rat esophagus. Int. J. Cancer 127, 2009–2019 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Souza, R. F. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 137, 1776–1784 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Dunbar, K. B. et al. Association of acute gastroesophageal reflux disease with esophageal histologic changes. JAMA 315, 2104–2112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lind, A., Koenderman, L., Kusters, J. G. & Siersema, P. D. Squamous tissue lymphocytes in the esophagus of controls and patients with reflux esophagitis and Barrett’s esophagus are characterized by a non-inflammatory phenotype. PLoS ONE 9, e106261 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Sen, M. et al. Flow based single cell analysis of the immune landscape distinguishes Barrett’s esophagus from adjacent normal tissue. Oncotarget 10, 3592–3604 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Kong, J. et al. Immature myeloid progenitors promote disease progression in a mouse model of Barrett’s-like metaplasia. Oncotarget 6, 32980–33005 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Moons, L. M. et al. Barrett’s oesophagus is characterized by a predominantly humoral inflammatory response. J. Pathol. 207, 269–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Somja, J. et al. Dendritic cells in Barrett’s esophagus carcinogenesis: an inadequate microenvironment for antitumor immunity? Am. J. Pathol. 182, 2168–2179 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Jeong, Y. et al. Identification and genetic manipulation of human and mouse oesophageal stem cells. Gut 65, 1077–1086 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Dobson, H., Pignatelli, M., Hopwood, D. & D’Arrigo, C. Cell adhesion molecules in oesophageal epithelium. Gut 35, 1343–1347 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ali, I. et al. Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett’s patients and healthy controls. Am. J. Gastroenterol. 101, 1437–1448 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Zhang, H. Y. et al. Differences in activity and phosphorylation of MAPK enzymes in esophageal squamous cells of GERD patients with and without Barrett’s esophagus. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G470–G478 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Qu, Z. et al. Proteomic quantification and site-mapping of S-nitrosylated proteins using isobaric iodoTMT reagents. J. Proteome Res. 13, 3200–3211 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gu, Z., Nakamura, T. & Lipton, S. A. Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases. Mol. Neurobiol. 41, 55–72 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Macfarlane, S., Furrie, E., Macfarlane, G. T. & Dillon, J. F. Microbial colonization of the upper gastrointestinal tract in patients with Barrett’s esophagus. Clin. Infect. Dis. 45, 29–38 (2007).

    Article  PubMed  Google Scholar 

  141. Sharma, P. et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology 131, 1392–1399 (2006).

    Article  PubMed  Google Scholar 

  142. Spechler, S. J. Intestinal metaplasia at the gastroesophageal junction. Gastroenterology 126, 567–575 (2004).

    Article  PubMed  Google Scholar 

  143. Jung, K. W. et al. Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett’s esophagus: a population-based study. Am. J. Gastroenterol. 106, 1447–1455 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Itskoviz, D. et al. Risk of neoplastic progression among patients with an irregular Z line on long-term follow-up. Dig. Dis. Sci. 63, 1513–1517 (2018).

    Article  PubMed  Google Scholar 

  145. Thota, P. N. et al. Low risk of high-grade dysplasia or esophageal adenocarcinoma among patients with Barrett’s esophagus less than 1cm (irregular Z line) within 5 years of index endoscopy. Gastroenterology 152, 987–992 (2017).

    Article  PubMed  Google Scholar 

  146. Pohl, H. et al. Length of Barrett’s oesophagus and cancer risk: implications from a large sample of patients with early oesophageal adenocarcinoma. Gut 65, 196–201 (2016).

    Article  PubMed  Google Scholar 

  147. Barrie, J., Yanni, F., Sherif, M., Dube, A. K. & Tamhankar, A. P. Length of Barrett’s esophagus in the presence of low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Surg. Endosc. 35, 4756–4762 (2021).

    Article  PubMed  Google Scholar 

  148. Wani, S. et al. An analysis of the GIQuIC nationwide quality registry reveals unnecessary surveillance endoscopies in patients with normal and irregular Z-Lines. Am. J. Gastroenterol. 115, 1869–1878 (2020).

    Article  PubMed  Google Scholar 

  149. Evans, J. A. et al. The role of endoscopy in Barrett’s esophagus and other premalignant conditions of the esophagus. Gastrointest. Endosc. 76, 1087–1094 (2012).

    Article  PubMed  Google Scholar 

  150. Whiteman, D. C. et al. Australian clinical practice guidelines for the diagnosis and management of Barrett’s esophagus and early esophageal adenocarcinoma. J. Gastroenterol. Hepatol. 30, 804–820 (2015).

    Article  PubMed  Google Scholar 

  151. Virchow, R. Ueber metaplasie: vortrag, gehalten auf dem internationalen medicinischen Congress in Kopenhagen. Virchows Arch. 97, 21 (1884).

    Article  Google Scholar 

  152. Spechler, S. J. Screening for Barrett’s oesophagus: are we looking for the right thing? Gut 70, 1426–1427 (2021).

    Article  Google Scholar 

  153. Krishnamoorthi, R. et al. Factors associated with progression of Barrett’s esophagus: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 16, 1046–1055.e8 (2018).

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Center for Oesophageal Diseases, Baylor University Medical Center, Dallas, TX, USA

    Rhonda F. Souza & Stuart J. Spechler

  2. Center for Oesophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA

    Rhonda F. Souza & Stuart J. Spechler

Authors
  1. Rhonda F. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stuart J. Spechler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to all aspects of the manuscript.

Corresponding author

Correspondence to Rhonda F. Souza.

Ethics declarations

Competing interests

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.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Gary Falk, Michael Quante and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-022-00622-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing