Could the Gut Microbiome Be the Link Between PPIs and Dementia?

Understanding the potential biological mechanism of PPIs' effect on memory and cognition could establish safe clinical guidelines for long-term prophylactic use.

Proton pump inhibitors (PPIs) are potent drugs capable of reducing gastric acid secretion by more than 90% of normal physiological levels, allowing for the treatment of peptic ulcers.1

Presently, PPIs are widely used worldwide because of their OTC availability, unparalleled efficacy, and relative safety.2 The latter 2 could be attributed to the drugs’ unique selective accumulation into the acidic canaliculus of the stomach parietal cells, where they undergo acid-mediated chemical activation into a highly reactive intermediate that reacts irreversibly with the gastric hydrogen potassium ATPase (also known as the proton pump of the stomach), resulting in complete disruption of the terminal step of acid production and secretion.3

Current clinical evidence suggests that long-term PPI use is associated with serious adverse events because it alters the stomach pH, which interferes with the absorption of key vitamins, minerals, nutrients, and other drugs.4 Recently, a study published in JAMA Neurology suggested that long-term use could also be associated with dementia, although it did not establish a causative relationship.5

Understanding the potential biological mechanism of PPIs’ effect on memory and cognition could establish safe clinical guidelines for long-term prophylactic use.

Despite the fact that several studies have shown PPIs can cross the blood-brain barrier,6 it is less plausible that the drugs’ effect on cognition results from a direct effect on the brain alone. Several studies have shown that long-term PPI use could significantly alter the gut microbiome, resulting in an increased rate of enteric infections.7

The human microbiome has lately been under intense investigation.8 For instance, the gut microbiome was recently implicated in influencing the central nervous system through secretion of psychoactive molecules involved in mood control as well as cognition and development of Alzheimer’s disease.9

Based on these research findings, the association between long-term PPI use and dementia could be related to alteration of the gut microbiome. Proving such a hypothesis would raise additional questions about the pathogenesis of PPI-associated dementia and the condition’s reversibility.

Clearly, more work needs to be done to understand the mechanism behind PPI-associated dementia and provide more effective patient counseling. In the meantime, pharmacists may caution against long-term prophylactic PPI use and advise patients to consider alternative prophylactic approaches for long-term control of acid secretion, such as other antacid classes in combination with lifestyle changes.


1. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011 Dec;34(11-12):1269-1281. doi: 10.1111/j.1365-2036.2011.04874.x. Epub 2011 Oct 17.

2. Durand C, Willett KC, Desilets AR. Desilets. Proton pump inhibitor use in hospitalized patients: is overutilization becoming a problem? Clin Med Insights Gastroenterol. 2012 Oct 15;5:65-76. doi: 10.4137/CGast.S9588. eCollection 2012.

3. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep. 2008 Dec;10(6): 528-534.

4. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012 Jul;5(4):219-32. doi: 10.1177/1756283X12437358.

5. Gomm W, von Holt K, Thomé F, Broich K, Maier W, et al. Association of proton pump inhibitors with risk of dementia. JAMA Neurol. 2016 Feb 15. doi: 10.1001/jamaneurol.2015.4791. [Epub ahead of print]

6. Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther. 2010 Apr;35(2):125-6. doi: 10.1111/j.1365-2710.2009.01100.x.

7. Imhann F, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2015;0: 1-9. doi:10.1136/gutjnl-2015-310376.

8. Devkota S. Prescription drugs obscure microbiome analyses. Science. 2016 Jan 29;351(6272):452-3. doi: 10.1126/science.aaf1353.

9. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014 Nov 12;34(46):15490-6. doi: 10.1523/JNEUROSCI.3299-14.2014.