How One of the Largest Selling Drug Classes Disrupts the Microbiome and Impacts Liver Function
Proton Pump Inhibitors (PPIs) are among the most commonly prescribed medications in the United States with nearly 10% of the population taking one of these drugs on a daily basis.[1] Although PPIs are used to treat gastric acid related disorders such as gastroesophageal reflux disease (GERD), estimates indicate that only approximately 30% of PPI users get significant benefit from them.[2] PPI medications are also often used “off-label” for conditions such as coronary heart disease, gastritis, even tumors.[3] And while PPIs can be effective for some indicated conditions such as those related to excess gastric acid (stomach acid), as with many medications, there are significant risks associated with their long-term use.
According to a 2021 publication in the journal BMJ Open Gastroenterology,[4] long-term PPI utilization is defined as continuous use between 8 weeks and 6+ months. This extended use is associated with myriad health consequences such as: impaired absorption of calcium and magnesium leading to potential bone fractures,[5] increased risk and progression of kidney damage,[6] development of neurodegenerative disorders such as Alzheimer’s DIsease,[7],[8] and gastric cancer.[9] PPI use also increases the risk of intestinal infection including small intestinal bacterial overgrowth (SIBO).[10] It is this impact on the gut microbiome and its association with liver damage that we will discuss in this post.
Impact on the Microbiome
Proton pump inhibitors work to decrease acid production in the stomach by reducing the activity of hydrogen-potassium “pumps” in the gastric lining. It is thought that under normal circumstances, stomach acid destroys organisms that inhabit the oral cavity and are otherwise ingested, but which cannot tolerate the low pH of gastric (stomach) acids.[11] When acid production is reduced with PPI use, that barrier to intestinal entry is diminished, allowing microorganisms that would not normally inhabit the intestines to take up residence there. This so-called “oralization” can then result in gut microbiome disruptions or dysbiosis including SIBO and Leaky Gut.[12]
Small Intestinal Bacterial Overgrowth (SIBO)
The small intestine includes the duodenum, jejunum, and ileum. Its primary role is nutrient digestion, which is accomplished by digestive enzymes and other secretions such as the liver’s bile acids. Although the small intestine does have its own distinct microbiome, the bacterial population is much lower here than further along the GI tract in the large intestine, or colon.[13]
SIBO occurs when an abnormally high number of microbes inhabit the small intestine. Because PPI use reduces the gastric acid’s ability to prevent ingested microbes from migrating into the intestinal tract, chronic use is one of the predisposing factors of this condition[14] which is characterized by weight loss, bloating, diarrhea, and malnutrition.
Intestinal Hyperpermeability (Leaky Gut)
The gastrointestinal lining serves as a barrier between what passes through our intestinal tract (lumen) and our body’s internal systems. This intestinal barrier includes the gut microbiota, a protective mucus layer, antimicrobial peptides (AMPs), and the various components that regulate the semi-permeable tight junctions between cells that allow nutrients to enter circulation.[15]
The largest microbiome population in the body resides in the large intestine. Migration of undesirable microbes into the colonic microbiome can be seen with chronic PPI and many other conditions– all of which deleteriously impacts the balance of friendly bugs.[16] This disruption, or dysbiosis, can result in a weakening of the intestinal barrier allowing bacteria and toxins to leak into circulation. So-called “leaky gut” will then trigger the body’s immune system (approximately 70% of which is located in the gut itself), setting off a systemic inflammatory response leading to a wide range of symptoms from bloating and gas to inflammatory bowel disease, autoimmune disease, and depression.[17] The impact on the liver is also considerable and considering that people diagnosed with cirrhosis are commonly prescribed PPIs,[18] it is worth exploring the relationship and risks more closely.
Liver Cirrhosis, The Gut Microbiome, and PPIs
The gut and the liver have a uniquely close relationship with a direct link through the portal vein. This connection provides the liver with nutrients and healthful microbial byproducts as well as providing access to undesirable microbes which have made their way into the intestines. The liver itself performs a protective function clearing potential harmful intestinal products.[19] In the case of intestinal hyperpermeability however, the liver can get overloaded with foreign microbes and toxins, resulting in their leakage into circulation.
PPIs are frequently utilized in the management of liver cirrhosis. Their benefits include elimination of H. pylori infection (gastric ulcers) as well as reduced endoscopy-related complications.[20] Unfortunately, PPI use in liver patients is also related to a number of negative outcomes including Clostridium difficile infection resulting from a higher gastric pH, spontaneous bacterial peritonitis (SBP) associated with SIBO, and hepatic encephalopathy (HE) related to bacterial overgrowth–each contributing to higher mortality rates.15
On a positive note however, use of targeted probiotics to help repair and rebalance the gut microbiome can be an effective prevention tool. In a recent study, the gut microbiome of cirrhotic patients (with and without long-term PPI use) were evaluated using 16S rDNA sequencing and compared with the microbiome population of cirrhotic patients who had been taking a daily multi-strain probiotic for six months. Those who took the probiotic experienced an increase in healthful gut microbes– both those in the probiotic formulation as well as an organic increase in helpful resident microbes. These patients also demonstrated positive shifts in biomarkers (e.g. neopterin, zonulin) indicative of intestinal barrier strengthening.[21]
Given the complications associated with chronic PPI use, consideration of other, more holistic approaches to balancing gastric secretions makes all the sense in the world. For example, Deglycyrrhizinated Licorice, a form of licorice that has been processed so that it contains smaller amounts of glycyrrhizin (the natural sweetener in licorice), has been studied and used for decades to relieve symptoms related to GERD, gastritis, peptic ulcers, duodenal ulcers, canker sores, and inflammatory bowel disease.[22]
Dr. Nicole Cain is a licensed Naturopathic Doctor with a masters in clinical psychology She has been interviewed as a mental health expert in Forbes, published in Well+Good and in journals such as NDNR, and has been a national speaker for PESI. Dr. Nicole’s mission is to introduce a new paradigm for understanding and treating our mental health. As an anxiety warrior herself, she has a special interest in sharing her experiences with anxiety.
References
[1] Torres-Bondia, F., de Batlle, J., Galván, L. et al. Evolution of the consumption trend of proton pump inhibitors in the Lleida Health Region between 2002 and 2015. BMC Public Health 22, 818 (2022). https://doi.org/10.1186/s12889-022-13217-6
[2] https://www.drugwatch.com/proton-pump-inhibitors/
[3] Hu, X et al., Off Label Use of Proton Pump Inhibitors and Economic Burden in Chinese Population: A Retrospective Analysis Using Claims Database, Value in Health, Volume 21, S82 – S83, 2018.
[4] Haastrup PF, Jarbøl DE, Thompson W, Hansen JM, Søndergaard J, Rasmussen S. When does proton pump inhibitor treatment become long term? A scoping review. BMJ Open Gastroenterol. 2021 Feb;8(1):e000563. doi: 10.1136/bmjgast-2020-000563. PMID: 33589415; PMCID: PMC7887363.
[5] Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010;12:448–457. doi: 10.1007/s11894-010-0141-0. https://pubmed.ncbi.nlm.nih.gov/20882439/
[6] Adverse effects of proton pump inhibitors—evidence and plausibility. Fossmark R, Martinsen TC, Waldum HL. Int J Mol Sci. 2019;20:5203 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829383/
[7] Haenisch B., von Holt K., Wiese B., Prokein J., Lange C., Ernst A., Brettschneider C., Konig H.H., Werle J., Weyerer S., et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur. Arch. Psychiatry Clin. Neurosci. 2015;265:419–428. doi: 10.1007/s00406-014-0554-0. https://pubmed.ncbi.nlm.nih.gov/25341874/
[8] Choi, H.G., Kim, JH., Kim, J.H. et al. Associations between proton pump inhibitors and Alzheimer’s disease: a nested case–control study using a Korean nationwide health screening cohort. Alz Res Therapy 14, 91 (2022). https://doi.org/10.1186/s13195-022-01032-5
[9] Abrahami D, McDonald EG, Schnitzer ME, et alProton pump inhibitors and risk of gastric cancer: population-based cohort studyGut 2022;71:16-24.
[10] Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11:483–490. doi: 10.1016/j.cgh.2012.12.011. https://pubmed.ncbi.nlm.nih.gov/23270866/
[11] Horvath A, Rainer F, Bashir M, Leber B, Schmerboeck B, Klymiuk I, Groselj-Strele A, Durdevic M, Freedberg DE, Abrams JA, Fickert P, Stiegler P, Stadlbauer V. Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis. Sci Rep. 2019 Aug 19;9(1):12000. doi: 10.1038/s41598-019-48352-5. PMID: 31427714; PMCID: PMC6700098. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700098/#CR21
[12] Di Tommaso N, Gasbarrini A, Ponziani FR. Intestinal Barrier in Human Health and Disease. Int J Environ Res Public Health. 2021 Dec 6;18(23):12836. doi: 10.3390/ijerph182312836. PMID: 34886561; PMCID: PMC8657205.
[13] Judkins, T.C., Archer, D.L., Kramer, D.C. et al. Probiotics, Nutrition, and the Small Intestine. Curr Gastroenterol Rep 22, 2 (2020). https://doi.org/10.1007/s11894-019-0740-3 https://link.springer.com/article/10.1007/s11894-019-0740-3
[14] Su T, Lai S, Lee A, He X, Chen S. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol. 2018 Jan;53(1):27-36. doi: 10.1007/s00535-017-1371-9. Epub 2017 Aug 2. PMID: 28770351. https://pubmed.ncbi.nlm.nih.gov/28770351/
[15] Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017;11(9):821–34. https://doi.org/10.1080/17474124.2017.1343143. https://www.tandfonline.com/doi/abs/10.1080/17474124.2017.1343143?journalCode=ierh20
[16] Shanahan F. The colonic microbiota and colonic disease. Curr Gastroenterol Rep. 2012 Oct;14(5):446-52. doi: 10.1007/s11894-012-0281-5. PMID: 22941733. https://pubmed.ncbi.nlm.nih.gov/22941733/
[17] Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019 Aug;68(8):1516-1526. doi: 10.1136/gutjnl-2019-318427. Epub 2019 May 10. PMID: 31076401; PMCID: PMC6790068. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
[18] De Roza MA, Kai L, Kam JW, Chan YH, Kwek A, Ang TL, Hsiang JC. Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis. World J Gastroenterol. 2019 Sep 7;25(33):4933-4944. doi: 10.3748/wjg.v25.i33.4933. PMID: 31543684; PMCID: PMC6737311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737311/
[19] Brandl K, Kumar V, Eckmann L. Gut-liver axis at the frontier of host-microbial interactions. Am J Physiol Gastrointest Liver Physiol. 2017 May 1;312(5):G413-G419. doi: 10.1152/ajpgi.00361.2016. Epub 2017 Feb 23. PMID: 28232456; PMCID: PMC5451561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451561/
[20] Zhu J, Yu H, Mancuso A, Qi X. Proton pump inhibitors in liver cirrhosis: a review of benefits and harms. AME Med J 2017;2:36.
[21] Horvath A, Durdevic M, Leber B, di Vora K, Rainer F, Krones E, Douschan P, Spindelboeck W, Durchschein F, Zollner G, Stauber RE, Fickert P, Stiegler P, Stadlbauer V. Changes in the Intestinal Microbiome during a Multispecies Probiotic Intervention in Compensated Cirrhosis. Nutrients. 2020 Jun 23;12(6):1874. doi: 10.3390/nu12061874. PMID: 32585997; PMCID: PMC7353185. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353185/
[22] Murray MT. Glycyrrhiza glabra (Licorice). Textbook of Natural Medicine. 2020:641–647.e3. doi: 10.1016/B978-0-323-43044-9.00085-6. Epub 2020 Jul 10. PMCID: PMC7348626.
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