Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection

doi:10.1016/j.surg.2014.06.074

Surgery

Volume 156, Issue 4, October 2014, Pages 972-978

Presented at on Friday March 7, 2014, Indianapolis, Indiana.

https://doi.org/10.1016/j.surg.2014.06.074 Get rights and content

Background

Proton pump inhibitors seem to promote Clostridium difficile infection (CDI). Although the current literature suggests that this association is mediated through gastric acid suppression, there has been little investigation into whether a direct effect on expression of colonocyte genes may also have a role. The aim of this study was to investigate the effect of omeprazole on genome-wide gene expression in a human colonic cell line.

Methods

T84 cell monolayers were treated with acid-activated omeprazole at 0, 1, 10, or 100 μmol/L for 48 hours. Cells were lysed and total RNA samples were reverse transcribed and used to generate biotinylated cRNA. Whole-genome transcript expression levels were then quantified using an Illumina HT-12 BeadChip microarray targeting 25,440 genes. Transcripts with a stringent minimum absolute fold change of 1.5 and an adjusted nominal P value <.05 (false discovery) were identified as being differentially expressed.

Results

Significant changes in expression were observed for 322 colonocyte transcripts, including genes with potential implications for susceptibility to CDI. These genes include roles in cell junctions, toxin susceptibility, and bile acid metabolism and transport.

Conclusion

Omeprazole treatment decreases the expression of genes that have important functions in colonocyte integrity. Such impairment in colonocyte function may promote CDI.

Section snippets

Materials and methods

This study was performed at the authors' institution using C. difficile isolates from an institutional review board–approved tissue biobank.

Colonocyte gene expression

Illumina HT-12 BeadChips provided genome-wide transcriptional coverage for 48,000 transcripts and known splice variants, including 25,440 annotated genes, using probes derived from the RefSeq (Build 36.2, rel22) and UniGene (Build 99) databases. The BeadChip experiment was conducted using biological triplicates and the resulting data were found to be consistent across all replicates. Genes whose expression would be expected to be affected, such as those in the aryl hydrocarbon receptor and

Discussion

The use of PPIs is associated with increased rates of CDI—1.7-fold with once-daily use and 2.4-fold with more than once-daily use.8, 9 Recent studies have noted such noncanonical effects of PPIs as an nuclear factor-κB–mediated antiinflammatory effect, which is mediated in cells where the primary biologic target of PPIs is missing.10, 11 This finding suggests that, outside their intended target (parietal cells), the pharmacologic activities of PPIs may be linked to biologic processes unrelated

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Cited by (25)

Thesaurus of pharmacist interventions associated with inappropriate proton pump inhibitors prescriptions
2023, Annales Pharmaceutiques Francaises
Les inhibiteurs de la pompe à protons (IPP) sont les médicaments les plus efficaces dans les troubles gastro-œsophagiens liés à l’acidité. Malgré une bonne tolérance à court terme, de nombreuses études ont rapporté des effets indésirables liés à une prise au long cours. Afin de réduire le taux de prescriptions inappropriées d’IPP et d’améliorer la sécurité thérapeutique des patients, un outil d’aide à l’analyse pharmaceutique a été développé. Il s’agit d’un thésaurus d’interventions pharmaceutiques associées aux prescriptions injustifiées d’inhibiteurs de la pompe à protons.
Dans un service d’hépato-gastro-entérologie, de chirurgie viscérale, de médecine interne et d’oncologie d’un centre hospitalo-universitaire, les situations cliniques pour lesquelles la prescription d’un IPP était injustifiée ont été identifiées par quatre pharmaciens. Chaque situation a fait l’objet d’une recherche bibliographique visant à objectiver le caractère inapproprié des prescriptions.
Le thésaurus a été divisé en deux parties, la première contient 12 situations pour lesquelles un IPP n’est pas indiqué (pancréatite aiguë, cholécystectomie…), tandis que la deuxième comporte 22 situations pour lesquelles l’IPP expose à des risques iatrogènes particuliers (infection à Clostridium difficile, déficits en micronutriments…). Elles ont été illustrées par une intervention pharmaceutique s’appuyant sur les données de la littérature avec 81 références bibliographiques recensées.
Le thésaurus est un outil d’aide à l’analyse pharmaceutique des prescriptions ayant pour objectif de convaincre les médecins hésitants à arrêter ou à ne pas initier un IPP pour une indication injustifiée.
Proton pump inhibitors (PPI) are the most effective drugs in the treatment of acid-related gastrointestinal disorders. Yet, many studies reported potential adverse drug reactions associated with long-term use. In order to reduce the rates of inappropriate PPI prescriptions and to improve patient safety, a tool aimed at guiding pharmacists to analyze PPI prescriptions was designed. It results in a thesaurus of clinical situations designed to argue about the inappropriateness of some PPI prescriptions and to highlight the risk associated with them.
Clinical situations in which PPIs are inappropriate were identified by four pharmacists in one gastroenterological, one surgery/liver transplantation, one internal medicine and one oncology units. A scientific literature search was performed for each clinical situation in order to corroborate the pharmacist interventions.
The thesaurus comprises two parts, the first one is dedicated to 12 clinical situations in which a PPI is not required (acute pancreatitis, cholecystectomy etc.), while the second one focus on 22 situations in which PPIs are associated with specific adverse drug reactions (Clostridium difficile infection, vitamin deficiency etc.). Eighty-one articles were used to support the pharmacist interventions.
This thesaurus is an analysis tool aimed at guiding pharmacists identify and argue about the inappropriateness of some PPI prescriptions in order to convince doctors to discontinue or not to initiate PPI prescriptions.
All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance
2018, International Journal of Pharmaceutics
Citation Excerpt :
Stewart and Hegarty (2013) demonstrated that the expression of toxin genes and their regulators were different following PPI administration in some C. diff ribotypes. Another in vitro study identified that PPIs decreased the expression of coloncyte genes leading to the reduced production of proteins associated with the protection of intestinal epithelium and loss of maintenance of cell junctions (Hegarty et al., 2014). CDI is a growing concern, particularly as resistance to treatments increases.
The term “disease” conjures a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic and pharmacodynamic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. This knowledge, however, applies less so in the context of drug absorption and distribution for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases and surgical effects on the functionality of the gastrointestinal tract, their implications for drug delivery and attempt to uncover significant links for clinical practice.
Side Effects and Complications of Proton Pump Inhibitors: A Pediatric Perspective
2016, Journal of Pediatrics
Citation Excerpt :
In addition to bacteria growth and variety, a retrospective case-control study of 102 patients with cirrhosis suggested that PPIs might facilitate bacterial translocation across gastrointestinal epithelium.19 Beyond the gastrointestinal system, there is growing evidence that PPI use alters the microbiome and possibly the secretory and antimicrobial properties of other mucosal surfaces.20,21 Several in vitro studies provide evidence that PPIs can suppress immune cell surveillance, activation, migration, and function.22
Proton pump inhibitor use and hearing loss in patients with type 2 diabetes: Evidence from a hospital-based case-control study and a population-based cohort study
2022, British Journal of Clinical Pharmacology
Incidence of Clostridioides difficile in patients post loop ileostomy reversal in an Australian tertiary hospital: a retrospective study
2022, ANZ Journal of Surgery
Clostridioides difficile infection among cirrhotic patients with variceal bleeding
2021, Antibiotics

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Central Surgical AssociationProton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection

Background

Methods

Results

Conclusion

Section snippets

Materials and methods

Colonocyte gene expression

Discussion

Clin Gastroenterol Hepatol

J Biol Chem

Gastroenterology

Biochem Pharmacol

Gastric acid suppression by proton pump inhibitors as a risk factor for clostridium difficile-associated diarrhea in hospitalized patients

Am J Gastroenterol

Drug safety communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs)

Correlation between virulence gene expression and proton pump inhibitors and ambient pH in Clostridium difficile: results of an in vitro study

J Med Microbiol

Omeprazole inhibits IL-4 and IL-13 signaling signal transducer and activator of transcription 6 activation and reduces lung inflammation in murine asthma

J Allergy Clin Immunol

Pharmacokinetic profile of immediate-release omeprazole in patients with gastro-oesophageal reflux associated with gastroparesis

Aliment Pharmacol Ther

WebGestalt: an integrated system for exploring gene sets in various biological contexts

Nucleic Acids Res

PANTHER: A library of protein families and subfamilies indexed by function

Genome Res

Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection

Arch Intern Med

Central Surgical Association
Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection