Immunopathogenesis of olmesartan-associated enteropathy

E. V. Marietta, A. M. Nadeau, A. K. Cartee, I. Singh, A. Rishi, R. S. Choung, T. T. Wu, A. Rubio-Tapia, Joseph A Murray

Research output: Contribution to journalArticle

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Abstract

Background: Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are resolved after discontinuation of olmesartan medoximil. Aim: To determine the mechanistic similarities of OAE with coeliac sprue. Methods: Duodenal biopsies were extracted from OAE patients before (n = 11) or after (n = 17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were seven 'on/off' paired samples. Formalin-fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R and ZO-1. Results: In the 'on olmesartan medoxomil' duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T-cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells. Conclusions: Olmesartan-associated enteropathy shares many features with coeliac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effects of gluten upon the epithelium of coeliac patients.

Original languageEnglish (US)
JournalAlimentary Pharmacology and Therapeutics
DOIs
StateAccepted/In press - 2015

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Interleukin-15
Celiac Disease
Biopsy
Zonula Occludens-1 Protein
Olmesartan Medoxomil
olmesartan
Glutens
Duodenum
Abdomen
Nausea
Abdominal Pain
Formaldehyde
Vomiting
Weight Loss
Diarrhea
Epithelium
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Marietta, E. V., Nadeau, A. M., Cartee, A. K., Singh, I., Rishi, A., Choung, R. S., ... Murray, J. A. (Accepted/In press). Immunopathogenesis of olmesartan-associated enteropathy. Alimentary Pharmacology and Therapeutics. https://doi.org/10.1111/apt.13413

Immunopathogenesis of olmesartan-associated enteropathy. / Marietta, E. V.; Nadeau, A. M.; Cartee, A. K.; Singh, I.; Rishi, A.; Choung, R. S.; Wu, T. T.; Rubio-Tapia, A.; Murray, Joseph A.

In: Alimentary Pharmacology and Therapeutics, 2015.

Research output: Contribution to journalArticle

Marietta, EV, Nadeau, AM, Cartee, AK, Singh, I, Rishi, A, Choung, RS, Wu, TT, Rubio-Tapia, A & Murray, JA 2015, 'Immunopathogenesis of olmesartan-associated enteropathy', Alimentary Pharmacology and Therapeutics. https://doi.org/10.1111/apt.13413
Marietta, E. V. ; Nadeau, A. M. ; Cartee, A. K. ; Singh, I. ; Rishi, A. ; Choung, R. S. ; Wu, T. T. ; Rubio-Tapia, A. ; Murray, Joseph A. / Immunopathogenesis of olmesartan-associated enteropathy. In: Alimentary Pharmacology and Therapeutics. 2015.
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abstract = "Background: Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are resolved after discontinuation of olmesartan medoximil. Aim: To determine the mechanistic similarities of OAE with coeliac sprue. Methods: Duodenal biopsies were extracted from OAE patients before (n = 11) or after (n = 17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were seven 'on/off' paired samples. Formalin-fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R and ZO-1. Results: In the 'on olmesartan medoxomil' duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T-cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells. Conclusions: Olmesartan-associated enteropathy shares many features with coeliac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effects of gluten upon the epithelium of coeliac patients.",
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T1 - Immunopathogenesis of olmesartan-associated enteropathy

AU - Marietta, E. V.

AU - Nadeau, A. M.

AU - Cartee, A. K.

AU - Singh, I.

AU - Rishi, A.

AU - Choung, R. S.

AU - Wu, T. T.

AU - Rubio-Tapia, A.

AU - Murray, Joseph A

PY - 2015

Y1 - 2015

N2 - Background: Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are resolved after discontinuation of olmesartan medoximil. Aim: To determine the mechanistic similarities of OAE with coeliac sprue. Methods: Duodenal biopsies were extracted from OAE patients before (n = 11) or after (n = 17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were seven 'on/off' paired samples. Formalin-fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R and ZO-1. Results: In the 'on olmesartan medoxomil' duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T-cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells. Conclusions: Olmesartan-associated enteropathy shares many features with coeliac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effects of gluten upon the epithelium of coeliac patients.

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