Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis

Abstract

AIMTo elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined.METHODSCollagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry.RESULTSCT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease.CONCLUSIONFrom these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.

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“…The pathogenesis of collagenous colitis appears to be related to myofibroblast dysfunction 48 and fibrolysis imbalance, 49 either as a primary process or as a response to microbiome changes or underlying lymphocytic infiltration. [50][51][52] Indeed, there is increased expression of transforming growth factor-beta [TGF-β] and tissue inhibitor of metalloproteinase-1 [TIMP-1], important regulators of extracellular matrix breakdown and fibrosis, in the colonic mucosa of patients with collagenous colitis as compared to healthy controls. 49,53 The hypothesis that fibrosis may occur as a reaction to underlying inflammatory or microbiome changes is supported by rat models of chronic colitis, in which colonic inoculation of anaerobic bacterial strains led to upregulation of TGF-β and an increase in collagen deposition.…”

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“…37 Although the pathogenetic mechanism of PPI-related as well as that of non-drug-related collagenous colitis has yet to be clarified, PPI-induced augmentation of collagen gene expression in colonocytes may partially be responsible for it. 38 PPIs-related collagenous colitis usually resolves spontaneously after cessation of the drug. 39 Therefore, when patients complain of diarrhea after starting a PPI,…”

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“…PPIs impair important elements of magnesium absorption (13), and pH variations impair the function of the channels and tight junctions. PPI also increases fibrosis-promoting factors such as TGF-beta, fibroblast growth factor 2 and collagen types III and IV (27).…”