Editing Proton-pump inhibitor (section)

=== Gastrointestinal ===
Some studies have shown a correlation between use of PPIs and [[Clostridioides difficile infection|''Clostridioides difficile'' infection]]. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI medications.<ref name=Corleto2014 /> Concerns have also been raised about [[spontaneous bacterial peritonitis]] (SBP) in older people taking PPIs and in people with [[irritable bowel syndrome]] taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs.<ref name=Corleto2014 /> PPIs may predispose an individual to developing  [[small intestinal bacterial overgrowth]] or fungal overgrowth.<ref name="SIBO">{{cite journal | vauthors = Fujimori S | title = What are the effects of proton pump inhibitors on the small intestine? | journal = World Journal of Gastroenterology | volume = 21 | issue = 22 | pages = 6817–9 | date = June 2015 | pmid = 26078557 | pmc = 4462721 | doi = 10.3748/wjg.v21.i22.6817 | quote = Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridioides difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. | doi-access = free }}</ref><ref name="SIFO">{{cite journal | vauthors = Erdogan A, Rao SS | title = Small intestinal fungal overgrowth | journal = Current Gastroenterology Reports | volume = 17 | issue = 4 | pages = 16 | date = April 2015 | pmid = 25786900 | doi = 10.1007/s11894-015-0436-2 | quote = Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive number of fungal organisms in the small intestine associated with gastrointestinal (GI) symptoms. Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those receiving steroids or antibiotics. However, only recently, there is emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Two recent studies showed that 26% (24/94) and 25.3% (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms. | s2cid = 3098136 }}</ref>

In [[Cirrhosis|cirrhotic patients]], large volume of ascites and reduced esophageal motility by varices can provoke [[Gastroesophageal reflux disease|GERD]].<ref>{{cite journal | vauthors = Li B, Zhang B, Ma JW, Li P, Li L, Song YM, Ding HG | title = High prevalence of reflux esophagitis among upper endoscopies in Chinese patients with chronic liver diseases | journal = BMC Gastroenterology | volume = 10 | issue = 1 | pages = 54 | date = June 2010 | pmid = 20525368 | pmc = 2889852 | doi = 10.1186/1471-230X-10-54 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Passaretti S, Mazzotti G, de Franchis R, Cipolla M, Testoni PA, Tittobello A | title = Esophageal motility in cirrhotics with and without esophageal varices | journal = Scandinavian Journal of Gastroenterology | volume = 24 | issue = 3 | pages = 334–8 | date = April 1989 | pmid = 2734592 | doi = 10.3109/00365528909093056 }}</ref><ref>{{cite journal | vauthors = Reilly JJ, Schade RR, Van Thiel DS | title = Esophageal function after injection sclerotherapy: pathogenesis of esophageal stricture | journal = American Journal of Surgery | volume = 147 | issue = 1 | pages = 85–8 | date = January 1984 | pmid = 6606991 | doi = 10.1016/0002-9610(84)90039-4 }}</ref> Acidic irritation, in return, may induce the rupture of varices.<ref>{{cite journal | vauthors = Lo GH, Perng DS, Chang CY, Tai CM, Wang HM, Lin HC | title = Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitor in the control of acute esophageal variceal bleeding | journal = Journal of Gastroenterology and Hepatology | volume = 28 | issue = 4 | pages = 684–9 | date = April 2013 | pmid = 23278466 | doi = 10.1111/jgh.12107 | s2cid = 5205186 }}</ref> Therefore, PPIs are often routinely prescribed for cirrhotic patients to treat GERD and prevent variceal bleeding. However, it has been recently shown that long term use of PPIs in patients with [[cirrhosis]] increases the risk of SBP and is associated with the development of clinical decompensation and liver-related death during long-term follow-up.<ref>{{cite journal | vauthors = Janka T, Tornai T, Borbély B, Tornai D, Altorjay I, Papp M, Vitális Z | title = Deleterious effect of proton pump inhibitors on the disease course of cirrhosis | language = en-US | journal = European Journal of Gastroenterology & Hepatology | volume = 32 | issue = 2 | pages = 257–264 | date = February 2020 | pmid = 31464790 | doi = 10.1097/MEG.0000000000001499 | doi-access = free }}</ref>

There is evidence that PPI use alters the composition of the bacterial populations inhabiting the [[Gastrointestinal tract|gut]], the [[gut microbiota]].<ref>{{cite journal | vauthors = Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ | title = Proton pump inhibitors alter the composition of the gut microbiota | journal = Gut | volume = 65 | issue = 5 | pages = 749–756 | date = May 2016 | pmid = 26719299 | pmc = 4853574 | doi = 10.1136/gutjnl-2015-310861 }}</ref> Although the mechanisms by which PPIs cause these changes are yet to be determined, they may have a role in the increased risk of bacterial infections with PPI use.<ref name=":1" /> These infections can include ''Helicobacter pylori'' due to this species not favouring an acid environment, leading to an increased risk of ulcers and gastric cancer risk in genetically susceptible patients.<ref name=":1">{{cite journal | vauthors = Hagiwara T, Mukaisho K, Nakayama T, Hattori T, Sugihara H | title = Proton pump inhibitors and helicobacter pylori-associated pathogenesis | journal = Asian Pacific Journal of Cancer Prevention | volume = 16 | issue = 4 | pages = 1315–1319 | year = 2015 | pmid = 25743791 | doi = 10.7314/APJCP.2015.16.4.1315 | doi-access = free }}</ref>

PPI use in people who have received attempted ''H. pylori'' eradication may also be associated with an increased risk of gastric cancer.<ref name="pmid29089382">{{cite journal | vauthors = Cheung KS, Chan EW, Wong AY, Chen L, Wong IC, Leung WK | title = Long-term proton pump inhibitors and risk of gastric cancer development after treatment for ''Helicobacter pylori'': a population-based study | journal = Gut | volume = 67 | issue = 1 | pages = 28–35 | date = January 2018 | pmid = 29089382 | doi = 10.1136/gutjnl-2017-314605 | doi-access = free }}</ref> The validity and robustness of this finding, with the lack of causality, have led to this association being questioned.<ref name="PMID31294357">{{cite journal | vauthors = Leontiadis GI, Veldhuyzen Van Zanten S, Hookey L, Armstrong D, Jones N, Moayyedi P | title = Canadian Association of Gastroenterology Statement on the Putative Link Between Proton Pump Inhibitor Treatment and Gastric Cancer after ''Helicobacter pylori'' Eradication | journal = Journal of the Canadian Association of Gastroenterology | volume = 1 | issue = 4 | pages = 155–158 | date = December 2018 | pmid = 31294357 | pmc = 6542241 | doi = 10.1093/jcag/gwy040 }}</ref>  It is recommended that long-term PPIs should be used judiciously after considering individual's risk–benefit profile, particularly among those with history of ''H. pylori'' infection, and that further, well-designed, prospective studies are needed.<ref>{{cite journal | vauthors = Cheung KS, Leung WK | title = Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence | journal = Therapeutic Advances in Gastroenterology | volume = 12 | pages = 1756284819834511 | date = January 2019 | pmid = 30886648 | pmc = 6415482 | doi = 10.1177/1756284819834511 | doi-access = free }}</ref>

Long-term use of PPIs is associated with the development of benign [[polyp (medicine)|polyp]]s from [[fundic gland]]s (which is distinct from [[fundic gland polyposis]]); these polyps do not cause cancer and resolve when PPIs are discontinued.<ref name="Corleto2014" /> There is concern that use of PPIs may mask [[gastric]] cancers or other serious gastric problems.<ref name="Corleto2014" />

PPI use has also been associated with the development of [[microscopic colitis]].<ref name="pmid22704658">{{cite journal | vauthors = Münch A, Aust D, Bohr J, Bonderup O, Fernández Bañares F, Hjortswang H, Madisch A, Munck LK, Ström M, Tysk C, Miehlke S | title = Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group | journal = Journal of Crohn's & Colitis | volume = 6 | issue = 9 | pages = 932–45 | date = October 2012 | pmid = 22704658 | doi = 10.1016/j.crohns.2012.05.014 | doi-access = free }}</ref>