Top

Published in:

05-03-2025 | Proton Pump Inhibitors | REVIEW

Why think twice before prescribing proton pump inhibitors

Authors: An-Sofie Lemmens, Koen Huysentruyt, Yvan Vandenplas

Published in: European Journal of Pediatrics | Issue 3/2025

Abstract

Proton pump inhibitors (PPIs) represent a class of drugs most prominently known for their use in acid-related disorders. Omeprazole, a drug belonging to this class, is among the top 10 most prescribed drugs in the USA. PPIs have a direct effect on the gastric pH and therefore on the gastric mucosa. This review aims to present the most common adverse effects PPIs have on the gastric mucosa in particular.

Conclusion: PPIs affect the composition of gut and gastric microbiota and will eventually modulate the immune response.

What is known:

• Proton-pump inhibitors are amonth the most frequent prescirbed drugs becasue of their well demonstrated efficacy in acid-related disorders.

• Because of their mode of action and their metabolism, a large spectrum of adversee effects have been reported.

What is new:

• Although the well-known success of PPIs in the wide spectrum of all acid-related conditions should not refrain health care professionals to use them when indicated, insufficient attention is given to the multiple adverse effects reported for this class of drugs.

• Well designed prospective trials collecting adverse effects are required, since most studies reporting adverse effects are retrospective, are biassed and have methodological issues.

Shin JM, Kim N (2013) Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 19(1):25–35. https://doi.org/10.5056/jnm.2013.19.1.25CrossRefPubMedPubMedCentral

Sachs G, Shin JM, Howden CW (2006) Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 23(Suppl 2):2–8. https://doi.org/10.1111/j.1365-2036.2006.02943.xCrossRefPubMed

Strand DS, Kim D, Peura DA (2017) 25 years of proton pump inhibitors: a comprehensive review. Gut Liver 11(1):27–37. https://doi.org/10.5009/gnl15502CrossRefPubMed

Kiecka A, Szczepanik M (2023) Proton pump inhibitor-induced gut dysbiosis and immunomodulation: current knowledge and potential restoration by probiotics. Pharmacol Rep 75(4):791–804. https://doi.org/10.1007/s43440-023-00489-xCrossRefPubMedPubMedCentral

Bartlett JG, Dowell SF, Mandell LA et al (2000) Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 31(2):347–382. https://doi.org/10.1086/313954CrossRefPubMed

Pham C, Sadowski-Hayes L, Regal R (2006) Prevalent prescribing of proton pump inhibitors: prudent or pernicious? P&T 31:159–167

Savarino V, Di Mario F, Scarpignato C (2009) Proton pump inhibitors in GORD an overview of their pharmacology, efficacy and safety. Pharmacol Res 59(3):135–153. https://doi.org/10.1016/j.phrs.2008.09.016CrossRefPubMed

Hagymási K, Müllner K, Herszényi L et al (2011) Update on the pharmacogenomics of proton pump inhibitors. Pharmacogenomics 12:873–888CrossRefPubMed

Litalien C, Théorêt Y, Faure C (2005) Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet 44(5):441–466. https://doi.org/10.2165/00003088-200544050-00001CrossRefPubMed

10.

Wedemeyer RS, Blume H (2014) Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 37(4):201–211. https://doi.org/10.1007/s40264-014-0144-0CrossRefPubMedPubMedCentral

11.

Díaz-Ordóñez L, Ramírez-Montaño D, Candelo E et al (2021) Evaluation of CYP2C19 gene polymorphisms in patients with acid peptic disorders treated with esomeprazole. Pharmgenomics Pers Med 14:509–520. https://doi.org/10.2147/PGPM.S285144CrossRefPubMedPubMedCentral

12.

Wolfe MM, Sachs G (2000) Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology 118(2 Suppl 1):S9-31. https://doi.org/10.1016/s0016-5085(00)70004-7CrossRefPubMed

13.

Arthur Shulkes, Andrew S. Giraud (2006) Physiology of the gastrointestinal tract (Fourth Edition)

14.

Hojo M, Asaoka D, Shimada Y et al (2022) Strategies for discontinuation of proton pump inhibitors (PPIs) in patients with long-term PPI administration: a randomized controlled trial. BMC Gastroenterol 22(1):21. https://doi.org/10.1186/s12876-021-02086-9CrossRefPubMedPubMedCentral

15.

Wang YH, Wintzell V, Ludvigsson JF et al (2020) Association between proton pump inhibitor use and risk of fracture in children. JAMA Pediatr 174(6):543–551. https://doi.org/10.1001/jamapediatrics.2020.0007CrossRefPubMed

16.

Yang J, Zhou TJ, Yang J et al (2022) Use of acid-suppressive drugs and risk of fracture in children and young adults: a meta-analysis of observational studies. Eur J Clin Pharmacol 78(3):365–373. https://doi.org/10.1007/s00228-021-03245-3CrossRefPubMed

17.

Steingoetter A, Sauter M, Curcic J et al (2015) Volume, distribution and acidity of gastric secretion on and off proton pump inhibitor treatment: a randomized double-blind controlled study in patients with gastro-esophageal reflux disease (GERD) and healthy subjects. BMC Gastroenterol 15:111. https://doi.org/10.1186/s12876-015-0343-xCrossRefPubMedPubMedCentral

18.

Guslandi M, Franceschi M, Fanti L et al (1992) Omeprazole-induced changes in gastric mucus secretion. Methods Find Exp Clin Pharmacol 14(3):219–223PubMed

19.

Jaworski T, Sarosiek I, Sostarich S et al (2005) Restorative impact of rabeprazole on gastric mucus and mucin production impairment during naproxen administration: its potential clinical significance. Dig Dis Sci 50(2):357–365. https://doi.org/10.1007/s10620-005-1611-3CrossRefPubMed

20.

Jalving M, Koornstra JJ, Wesseling J et al (2006) (2006) Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 24(9):1341–1348. https://doi.org/10.1111/j.1365-2036.2006.03127.xCrossRefPubMed

21.

Abraham SC (2010) Fundic gland polyps: common and occasionally problematic lesions. Gastroenterol Hepatol (N Y) 6(1):48–51PubMed

22.

Kuiper J, Herk‐Sukel M, Lemmens V et al (2020) Proton pump inhibitors are not associated with an increased risk of colorectal cancer. GastroHep. 2. https://doi.org/10.1002/ygh2.409.

23.

Richman CM, Leiman DA (2023) Can we stop worrying about long-term PPIs and gastric vancer risk? Cancer Epidemiol Biomarkers Prev 32(9):1127–1129. https://doi.org/10.1158/1055-9965CrossRefPubMed

24.

Song H, Zhu J, Lu D (2014) Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. Cochrane Database Syst Rev 2014(12):CD010623. https://doi.org/10.1002/14651858.CD010623.pub2CrossRefPubMedPubMedCentral

25.

Imhann F, Bonder MJ, Vich Vila A et al (2016) Proton pump inhibitors affect the gut microbiome. Gut 65(5):740–748. https://doi.org/10.1136/gutjnl-2015-310376CrossRefPubMed

26.

Minalyan A, Gabrielyan L, Scott D et al (2017) The gastric and intestinal microbiome: role of proton pump inhibitors. Curr Gastroenterol Rep 19(8):42. https://doi.org/10.1007/s11894-017-0577-6CrossRefPubMedPubMedCentral

27.

Freedberg DE, Kim LS, Yang YX (2017) The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology 152:706–715CrossRefPubMed

28.

Stockbruegger RW (1985) Bacterial overgrowth as a consequence of reduced gastric acidity. Scand J Gastroenterol Suppl 111:7–16. https://doi.org/10.3109/00365528509093749CrossRefPubMed

29.

Ruddell WS, Axon AT, Findlay JM et al (1980) Effect of cimetidine on the gastric bacterial flora. Lancet 1(8170):672–674CrossRefPubMed

30.

Sharma BK, Santana IA, Wood EC et al (1984) Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. Br Med J (Clin Res Ed) 289(6447):717–719. https://doi.org/10.1136/bmj.289.6447.717CrossRefPubMed

31.

Verdu E, Viani F, Armstrong D et al (1994) Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds. Gut 35(4):455–460. https://doi.org/10.1136/gut.35.4.455CrossRefPubMedPubMedCentral

32.

Fossmark R, Olaisen M (2024) Changes in the gastrointestinal microbiota induced by proton pump inhibitors: a review of findings from experimental trials. Microorganisms 12(6):1110. https://doi.org/10.3390/microorganisms12061110CrossRefPubMedPubMedCentral

33.

Serrano C, Harris PR, Smith PD et al (2021) Interactions between H. pylori and the gastric microbiome: impact on gastric homeostasis and disease. Curr Opin Physiol 21:57–64. https://doi.org/10.1016/j.cophys.2021.04.003CrossRefPubMedPubMedCentral

34.

Jagdish BR, Kilgore WR 3rd (2021) The relationship between functional dyspepsia, PPI therapy, and the gastric microbiome. Kans J Med 14:136–140. https://doi.org/10.17161/kjm.vol1414831CrossRefPubMedPubMedCentral

35.

Yadlapati R, Kahrilas PJ (2018) The “dangers” of chronic proton pump inhibitor use. J Allergy Clin Immunol 141(1):79–81. https://doi.org/10.1016/j.jaci.2017.06.017CrossRefPubMed

36.

Mitre E, Susi A, Kropp LE et al (2018) Association between use of acid-suppressive medications and antibiotics during infancy and allergic diseases in early childhood. JAMA Pediatr 172(6):e180315. https://doi.org/10.1001/jamapediatrics.2018.0315CrossRefPubMedPubMedCentral

37.

Räisänen L, Viljakainen H, Kolho KL (2023) Exposure to proton pump inhibitors is associated with the development of pediatric autoimmune diseases. Front Pediatr 11:1157547. https://doi.org/10.3389/fped.2023.1157547CrossRefPubMedPubMedCentral

38.

Stark CM, Susi A, Emerick J et al (2019) Antibiotic and acid-suppression medications during early childhood are associated with obesity. Gut 68(1):62–69. https://doi.org/10.1136/gutjnl-2017-314971CrossRefPubMed

39.

Lassalle M, Zureik M, Dray-Spira R (2023) Proton pump inhibitor use and risk of serious infections in young children. JAMA Pediatr 177(10):1028–1038. https://doi.org/10.1001/jamapediatrics.2023.2900CrossRefPubMedPubMedCentral

40.

De Bruyne P, Ito S (2018) Toxicity of long-term use of proton pump inhibitors in children. Arch Dis Child 103(1):78–82. https://doi.org/10.1136/archdischild-2017-314026CrossRefPubMed

41.

Su T, Lai S, Lee A et al (2018) Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol 53(1):27–36. https://doi.org/10.1007/s00535-017-1371-9CrossRefPubMed

42.

Weitsman S, Celly S, Leite G et al (2022) Effects of proton pump iInhibitors on the small bowel and stool microbiomes. Dig Dis Sci 67(1):224–232. https://doi.org/10.1007/s10620-021-06857-yCrossRefPubMed

43.

Sieczkowska A, Landowski P, Zagozdzon P et al (2015) Small bowel bacterial overgrowth associated with persistence of abdominal symptoms in children treated with a proton pump inhibitor. J Pediatr 166(5):1310-1312.e1. https://doi.org/10.1016/j.jpeds.2015.01.004CrossRefPubMed

44.

Lam JR, Schneider JL, Quesenberry CP et al (2017) Proton pump inhibitor and histamine-2 receptor antagonist use and iron deficiency. Gastroenterology 152(4):821-829.e1. https://doi.org/10.1053/j.gastro.2016.11.023CrossRefPubMed

45.

Jung SB, Nagaraja V, Kapur A et al (2015) Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis. Intern Med J 45(4):409–416. https://doi.org/10.1111/imj.12697CrossRefPubMed

46.

Lam JR, Schneider JL, Zhao W et al (2013) Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 310(22):2435–2442. https://doi.org/10.1001/jama.2013.280490CrossRefPubMed

47.

Recart DA, Ferraris A, Petriglieri CI et al (2021) Prevalence and risk factors of long-term proton pump inhibitors-associated hypomagnesemia: a cross-sectional study in hospitalized patients. Intern Emerg Med 16(3):711–717. https://doi.org/10.1007/s11739-020-02501-1CrossRefPubMed

48.

Kim SG, Cho JM, Han K et al (2024) Non-indicated initiation of proton pump inhibitor and risk of adverse outcomes in patients with underlying chronic kidney disease: a nationwide, retrospective, cohort study. BMJ Open 14(1):e078032. https://doi.org/10.1136/bmjopen-2023-078032.CrossRefPubMedPubMedCentral

49.

Keszthelyi D, Jansen SV, Schouten GA et al (2010) Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 32(9):1124–1128. https://doi.org/10.1111/j.1365-2036.2010.04453.xCrossRefPubMed

50.

Wang YH, Wintzell V, Ludvigsson JF et al (2022) Proton pump inhibitor use and risk of depression and anxiety in children: nationwide cohort study. Clin Transl Sc 15(5):1112–1122. https://doi.org/10.1111/cts.13225CrossRef

51.

Pourhadi N, Janbek J, Jensen-Dahm C et al (2024) Proton pump inhibitors and dementia: a nationwide population-based study. Alzheimers Dement 20(2):837–845. https://doi.org/10.1002/alz.13477CrossRefPubMed

52.

Park JY, Yoo J, Jeon J et al (2022) Proton pump inhibitors and risk of cardiovascular disease: a self-controlled case series study. Am J Gastroenterol 117(7):1063–1071. https://doi.org/10.14309/ajg.0000000000001809CrossRefPubMed

53.

Savarino V, Dulbecco P, Savarino E (2016) Are proton pump inhibitors really so dangerous? Dig Liver Dis 48(8):851–859. https://doi.org/10.1016/j.dld.2016.05.018CrossRefPubMed

Title: Why think twice before prescribing proton pump inhibitors
Authors: An-Sofie Lemmens
Koen Huysentruyt
Yvan Vandenplas
Publication date: 05-03-2025
Publisher: Springer Berlin Heidelberg
Keywords: Proton Pump Inhibitors
Medical Side Effect
Gastroesophageal Reflux Disease
Gastritis
Gastrointestinal Microbiota
Gastrointestinal Infection
Gastroesophageal Reflux Disease in Pediatrics
Gastritis in Pediatrics
Respiratory Microbiota
Pediatric Pneumology
Bronchial Asthma
Published in: European Journal of Pediatrics / Issue 3/2025
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI: https://doi.org/10.1007/s00431-025-06058-z

Correction to: Elective thoracoscopic surgery for congenital lung malformations: what age to operate?

Pediatric Surgery
Correction

Enhanced mortality prediction in pediatric sepsis using NGAL: A comparison with PRISM III scores in critical care settings

Open Access
Septicemia
RESEARCH

Investigation of dysmenorrhea in adolescent girls with familial Mediterranean fever: a comparative study with healthy controls

Open Access
Familial Mediterranean Fever
RESEARCH

Effect of earmuff use on physiological and behavioral responses in preterm neonates: a non-randomized, controlled, before-after, quality improvement, observational prospective cohort study

RESEARCH

Parameters associated with the development of autoimmune diseases in pediatric onset celiac disease

Celiac Disease
RESEARCH

Febrile Infection-Related Epilepsy Syndrome (FIRES) in children: a retrospective cohort study

Epilepsy
RESEARCH

Navigating neuroimaging in Alzheimer disease care

Springer Medicine

Why think twice before prescribing proton pump inhibitors

Abstract

Other articles of this Issue 3/2025

Correction to: Elective thoracoscopic surgery for congenital lung malformations: what age to operate?

Enhanced mortality prediction in pediatric sepsis using NGAL: A comparison with PRISM III scores in critical care settings

Investigation of dysmenorrhea in adolescent girls with familial Mediterranean fever: a comparative study with healthy controls

Effect of earmuff use on physiological and behavioral responses in preterm neonates: a non-randomized, controlled, before-after, quality improvement, observational prospective cohort study

Parameters associated with the development of autoimmune diseases in pediatric onset celiac disease

Febrile Infection-Related Epilepsy Syndrome (FIRES) in children: a retrospective cohort study

Navigating neuroimaging in Alzheimer disease care

Springer Medicine

Abstract

Please log in to get access to this content

Correction to: Elective thoracoscopic surgery for congenital lung malformations: what age to operate?

Enhanced mortality prediction in pediatric sepsis using NGAL: A comparison with PRISM III scores in critical care settings

Investigation of dysmenorrhea in adolescent girls with familial Mediterranean fever: a comparative study with healthy controls

Effect of earmuff use on physiological and behavioral responses in preterm neonates: a non-randomized, controlled, before-after, quality improvement, observational prospective cohort study

Parameters associated with the development of autoimmune diseases in pediatric onset celiac disease

Febrile Infection-Related Epilepsy Syndrome (FIRES) in children: a retrospective cohort study