Long-term effects of PPIs on immunity
What are PPIs?
It may be natural to confuse PPIs with those hidden fees that banks charged you for years without disclosing those fees to you. But the acronym “PPIs” stands for proton-pump inhibitors, a class of drugs that cause a profound and prolonged reduction of stomach acid production. They do so by inhibiting the stomach's gastric hydrogen-potassium ATPase proton pump, a process that is reversible upon discontinuity.
Schematic representation of acid-producing stomach cells and pathways involved in hydrochloric acid (HCl) production, and proton-pump inhibitors mode of action.
The role of PPIs in chronic disorders
Inhibiting the hydrogen-potassium pump (H+/K+-ATPase) to decrease stomach acid production has been the most common method of treating gastroesophageal reflux disease (GERD/GORD) and peptic ulcer disease.[1] While this may be a quick fix, it doesn’t address the actual cause.[2]
Common PPIs like Omeprazole have a short half-life of approximately 90 minutes, meaning that the short treatment duration requires repeated intake to match common feeding patterns.[3] Some individuals may also take another tablet before bed so heartburn or reflux doesn’t wake them up or prevent them to fall asleep. This type of behaviour can lead to addiction, making it very difficult to ever come off the drug. Especially if no changes are made to the diet and lifestyle and reduce stress.
Since their release 25 years ago, the use of proton-pump inhibitors has increased progressively with approximately 5% of the developed world taking this type of drug at any given time.[4]
Several factors are likely to be contributing to this increase, but research suggests that these drugs may be causing or aggravating the disease process they are supposed to treat. A study published in the peer-reviewed journal Gastroenterology (2009), under the following title: “Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat,” showed that 44% of previously asymptomatic patients experienced significant heartburn, acid reflux, or dyspepsia after discontinuing the recommended 6–8-week course of esomeprazole — suggesting a rebound acid hyper-secretion once treatment is discontinued.[5]
A large body of research has also demonstrated that the inactivation of the proton pump can lead to many other health problems. One of the key issues associated with PPIs is nutrient malabsorption because stomach acid is required to break down protein, fat and minerals and also to secrete the intrinsic factor, a chaperone molecule required to ensure the safe passage of B12 throughout the intestinal tract and its assimilation in the bowel. Recognised deficiencies provoked by achlorhydria include iron, potentially leading to anaemia (poor oxygenation of the blood), and other essential minerals [6,7]
Current research is also showing an association between the use of PPIs and dementia.[8,9,10] Theories include the non-selective blockade of sodium-potassium pumps also found in the brain causing fluid imbalances and/or swelling.
Additionally, PPIs are also known to interact with other drugs affecting the sodium-potassium pump (e.g., digoxin and warfarin).[11] PPIs may also affect astrocytes (a star-shaped glial cell found in the brain) and adenosine receptors found in hydrogen/Sodium-potassium pumps, which may also be involved in the development of dementia.[12,13,14]
Considering that PPIs are among the best-selling drugs, now also available outside pharmacies following its reclassification to a general sales list, this is a global problem.
The role of PPIs in gut disorders and lower immunity
It is well-documented that malnutrition is associated with a wide range of conditions, which can affect the entire body. It is recognised that low stomach acid may prevent the assimilation of essential nutrients and lead to symptoms ranging in severity, like bloating, intestinal discomfort and/or pain, constipation and/or diarrhoea, skin problems, fatigue and poor sugar management, lower cognitive capabilities, as well as other symptoms linked to food hypersensitivities and allergies, and gut dysbiosis. Gut dysbiosis is implicated in most metabolic disorders and brain inflammation and neurodegeneration. Take an example, Akkermansia muciniphila, a type of bacteria found in the mucous layer of the intestinal tract, is directly implicated in gut integrity (via the release of short-chain acids, particularly acetate). Other bacteria feed on acetate and in turn produce butyrate, a vital energy source for gut-lining cells. Therefore, A. muciniphila is a key player in our gut health.
In healthy individuals, the abundance of A. muciniphila is high, accounting for up to 4% of your intestinal bacteria. Numbers seem to be low in people with obesity or IBD, and it may also be involved in non-alcoholic fatty liver disease (NAFLD), type-2 diabetes and many other symptoms of metabolic dysfunction, demonstrating the direct impact of A. muciniphila on our health and the role they play in our metabolism.
PPIs are also directly implicated in type-2 diabetes. People who had taken proton pump inhibitors for more than five years showed an excess of cardiovascular events and heart failure.[15,16]
Because A. muciniphila feeds on mucin, a protein found in mucous, they do not rely much on the food we eat. Considering that many pathogenic and opportunistic bacteria can devour the mucous lining when they do not receive their favourite food, sugar, then this may be a pathway leading to the reduction in the numbers of A. muciniphila. Another important factor is that by encouraging our gut cells to produce more mucous they not only strengthen the gut barrier (short-chain fatty acids are used to support tight junctions, and protein complexes holding cells closely together) but also help to modulate the immune system.
Research has shown that low stomach acid can influence gut microbial distribution and diversity, via gut inflammation. Remember that indigested food entering the intestinal tract is identified as a problem, and our gut immune cells tag each piece of food as an enemy to destroy. This can lead to inflammation of the gut lining. Additionally, undigested sugar-rich food fermenting in the intestinal tract and protein putrefying, as a direct result of low stomach acid, create a lot of gas that can lead to bloating and abdominal distention, often leading to discomfort and, in severe cases, pain. Further to this, this constant banquet attracts a multitude of opportunistic and, often, pathogenic microbes that also release gas, making the gut a fermentation chamber, which inflames the gut even further. Inevitably leading to increased intestinal permeability (leaky gut syndrome). Increasing the risk of food hypersensitivities and allergies, as undesirable molecules cross into the bloodstream. This also leads to disproportionate immune responses anywhere in the body, with the potential to establish an autoimmune disorder. Autoimmunity occurs when the immune cells confuse our own tissues with some of those problematic molecules (which may closely match that of any of our tissues).[17]
In Energise - 30 Days to vitality, Olivier Sanchez writes:
“Acid reflux (GERD) is often associated with regular grain consumption. Proton-pump inhibitors (PPIs) reduce the production of stomach acid and so discomfort. However, protein breakdown starts in the stomach. Poorly or undigested proteins may participate in gut inflammation and leaky gut by promoting gas and distension, and disturbing the gut microbiome.
Dependence on all these drugs has a cost. The intestines may become chronically inflamed and prevent the absorption of nutrients. As a result, immune cells release inflammatory chemicals, as well as histamine. A large daily intake of grains, therefore, may exacerbate the severity of symptoms and the feeling of pain.
Inflammation also dysregulates sugar metabolism and participates in visceral fat accumulation (fat around the middle), obesity and type-2 diabetes. Red blood cell aggregation and inflammation in the arteries lead to poor oxygenation of tissues, hypertension and heart disease, and poorer healing because the blood cannot supply vital nutrients to the tissues, as it is also the case in diabetes.“[18]
Low stomach acid and malnutrition
We already know that low stomach acid leads to malnutrition (nutrient deficiencies), which may be further exacerbated by microbes ‘stealing’ our food as they grow in number and possibly found in parts of the gastrointestinal where they shouldn’t (for example, H. pylori in the stomach, and several microbes migrating and establishing themselves in the small intestine as observed in SIBO, SIYO and SIFO. SI- stands for short-intestinal and -O for overgrowth. B is for bacterial, Y for yeast (i.e. candida) and F for fungal. Depending on the type and species of microbes, symptoms may differ, but the most common ones are constipation and/or diarrhoea, bloating and visible distention (some individuals may refer to it as being 6 months pregnant after eating food), abdominal pain, fatigue, low cognition and mood, and a general sense of malaise.
Essential nutrients like magnesium, iron and zinc play a key role in our immunity. Any deficiencies will, therefore, impact our health at the deepest levels. We may be more prone to colds and flu and longer recovery period, and also experience skin outbreaks (including rosacea) ass our cells and organs struggle to detoxify metabolic waste, toxins and problematic compounds (like BPA and heavy metals, and other contaminants found in the air we breathe, the food we eat and the water we drink, and the products we lather onto our skin). We are exposed to several toxicants that today have reached critical levels. Never in our existence have we ever had to deal with that much working against our bodies. Never have we also experienced that level of stress and anxiety than today. Those past years are just proof that we are no longer part of nature and that disconnection has made us the prey of forces that want to keep the status quo for their own benefit.
We must have a fully-operational immune system to survive. If we don’t have strong defences to resist our environment, we will experience dis-ease. There will be little the body can do to prevent infection, because of the lack of resources but also because the immune system is fighting on all fronts. This may be a contributing factor explaining why many people experienced very few (or even an absence of) symptoms even though they ‘caught’ or tested ‘positive’ for COVID. Their bodies were efficiently prepared and had adequate resources to deal with the problem.
One of the first lines of defence is stomach acid; virtually, a caustic bath that destroys bacteria, viruses and other pathogens and parasites. It is not surprising that they can survive if levels are low as a direct effect of taking PPIs. These are provoking an immune response as they travel through the intestinal tract. They may also wreak havoc and lead to gastroenteritis, a decisive factor in the pathophysiology of SIBO.
As the gut wall breaks apart to flood the intestinal tract in an attempt to flush the culprits (this is what health practitioners referred to as ‘leaky gut’), it allows undesirable substances to enter the bloodstream. You may now experience hypersensitivities to certain foods. Food intolerances also lead to leaky gut syndrome, creating a very vicious cycle, where the gut is constantly inflamed and in crisis, more sensitive to its environment and microbial pressures. Now imagine you ingest gluten. Gluten is proven to provoke leaky gut in anyone eating it. Gluten, therefore, makes everything worse and unmanageable.[19,20,21]
“The main effect of partially digested wheat proteins is the immediate (and transient) increase in gut permeability, which occurs in anyone who ingests gluten.”
Removing gluten from the diet completely makes sense when taking PPIs. Removing any food to which you may react, including dairy products, and certain problematic compounds like phytic acid and lectins, which may be a greater problem in people with increased intestinal permeability and also because they may participate further in nutrient defences, particularly minerals. Lectins and phytic acid bind to minerals present in the food you eat and trap them, so those minerals are no longer available for the body to use.
The idea is to remove the problems, the cause of dysfunction in the body, but the main problem, in this case, is taking a drug that causes more problems than it solves but also provokes the problems it is supposed to prevent.
Are you sure taking Omeprazole, antacids or similar acid-suppressing drugs is the best route of action to deal with GERD (reflux) and heartburn?
Is GERD not the result of a bad diet and chronic exposure to stress?
If so, can an acid-lowering drug reduce your levels of stress and anxiety? Can this type of drug make up for a bad diet made of poorly nutritious foods, trans fats and toxic substances (e.g., gluten, taste enhancers (MSG), petrochemical derivatives additives, and heavy metals, among a multitude of others)?
Probably not.
Consuming wholesome foods now makes sense. Learn to reconnect with food and understand the power of food on your health. If you don’t know how to cook, there is no better time to learn.
The aim is to take control of what you put at the end of your fork so that you don’t need to pop a pill to rectify the problem. Do not be misled by the food industry. So-called healthier alternatives like gluten-free products or even vegan meals may be worse than the foods they are supposed to replace — food manufactured by the same companies selling you junk on every other aisle in your favourite supermarket. Read labels. This should become an automatism. If you can’t pronounce it or you see a lot of E numbers, and additives or the main ingredients are cheap refined foods like rice and maize/corn, then it is best to leave this product where it belongs: back on display.
You have the power in your hands.
References
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Shin, JM. Sachs, G. (2009). Long-lasting inhibitors of the gastric H,K-ATPase. Expert Review of Clinical Pharmacology. 2(5), pp. 461–468. doi:10.1586/ecp.09.33
Forgacs, I. Loganayagam, A. (2008). Overprescribing proton pump inhibitors. BMJ. 336(7634), pp. 2–3. doi:10.1136/bmj.39406.449456.BE
McColl, KEL. Gillen, D. (2009). Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology. 137, pp. 20 –39. doi:10.1053/j.gastro.2009.05.015
Krieg, L. et al. (2011). Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice. Blood. 118(24): pp. 6418–6425.
https://www.nutrunity.com/updates/nutrients-depleted-by-ppis
Gomm, W. et al. (2016). Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis. JAMA Neurology. 73 (4), pp. 410–416. doi:10.1001/jamaneurol.2015.4791
Rojo, LE. et al. (2010). Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease. Journal of Alzheimer's Disease. 19(2), pp. 573–89. doi:10.3233/JAD-2010-1262
Fawaz, MV. et al. (2014). High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chemical Neuroscience. 5(8), pp. 718–30. doi:10.1021/cn500103u
Björklund O, Shang M, Tonazzini I, Daré E, Fredholm BB (2008). Adenosine A1 and A3 receptors protect astrocytes from hypoxic damage. European Journal of Pharmacology. 596(1–3), pp. 6–13. doi:10.1016/j.ejphar.2008.08.002
Carmona, MA. et al. (2009). Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proceedings of the National Academy of Sciences of the United States of America. 106(30), pp. 12524–12529. doi:10.1073/pnas.0903328106
Ben Haim, L. et al. (2015). Elusive roles for reactive astrocytes in neurodegenerative diseases. Frontiers in Cellular Neuroscience. 9: 278. doi:10.3389/fncel.2015.00278
Sakai, H. Fujii, T. Takeguchi, N. (2016). "Chapter 13. Proton-Potassium (H+/K+) ATPases: Properties and Roles in Health and Diseases". In Astrid, Sigel; Helmut, Sigel; Roland K.O., Sigel (eds.). The Alkali Metal Ions: Their Role in Life. Metal Ions in Life Sciences. Vol. 16. Springer. pp. 459–483.
Loosen, SH. et al. (2021). Long-term use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes. Gut. doi:10.1136/gutjnl-2021-326297. Epub ahead of print. PMID: 34725199.
BMJ 2021;375:n2740. https://doi.org/10.1136/bmj.n2740
Xu, Y. et al. (2020) Function of Akkermansia muciniphila in Obesity: Interactions With Lipid Metabolism, Immune Response and Gut Systems. Frontiers in Microbiology. 11:219. doi:10.3389/fmicb.2020.00219
Sanchez, O (2021). Energise - 30 Days to Vitality. Energise - 30 Days to Vitality: Reset Your Body to its Natural Rhythm. Manage Blood Sugar and Energy Levels. Stamp Down Inflammation. Gain Clarity. Develop resilience and becomes the person you have always dreamed to be. London: Nutrunity Publishing. pp. 123–152.
Hollon, J. et al. (2015). Effect of gliadin in permeability of intestinal biopsy explants from celiac disease patients with non-celiac gluten sensitivity. Nutrients. 7(3), pp. 1565–1576. doi:10.3390/nu7031565
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De Punder, K. Pruimboom, L. (2013). The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients. 5(3), pp. 771–787. doi:10.3390/nu5030771
Other references H/K ATPase function and impact of PPIs:
Shin, JM. et al. (2009). The gastric HK-ATPase: Structure, function and inhibition. Pflügers Archiv: European Journal of Physiology. 457(3), pp. 609–622. doi:10.1007/s00424-008-0495-4
Berg, JM. Tymoczko, JL. Stryer, L. (2012). Biochemistry (7th ed.). New York: W.H. Freeman and Company.
Chourasia, M. Sastry, GM. Sastry. GN. (2005). Proton binding sites and conformational analysis of H+K+-ATPase. Biochemical and Biophysical Research Communications. 336(3), pp. 961–966. doi:10.1016/j.bbrc.2005.08.205
Scheirlinckx, F. et al. (2004). Conformational changes in gastric H+/K+-ATPase monitored by difference Fourier-transform infrared spectroscopy and hydrogen/deuterium exchange. Biochemical Journal (Pt 1 ed.). 382 (Pt 1), pp. 121–129. doi:10.1042/BJ20040277
Prinz, C. et al. (1992). Acid secretion and the H,K ATPase of stomach. The Yale Journal of Biology and Medicine. 65(6), pp. 577–596.
Sachs, G. et al. (2007). The gastric H,K ATPase as a drug target: Past, present and future. Journal of Clinical Gastroenterology. 41(Suppl 2), S226–S242. doi:10.1097/MCG.0b013e31803233b7. PMC 2860960. PMID 17575528.
Shin J. M.; Sachs G. (2008). Pharmacology of Proton Pump Inhibitors. Current Gastroenterology Reports. 10(6), pp. 528–534. doi:10.1007/s11894-008-0098-4