Proton pump inhibitors (PPIs) are drugs commonly prescribed by your doctor for the treatment of heartburn. You can also skip the doctor visit and buy them over the counter at the supermarket or pharmacy. Since you can buy PPIs without a prescription then they must be safe, right?  Wrong. Recent work suggests that PPIs are harmful, even deadly.

Xie and colleagues recently published an article in BMC Open, Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. They report that PPIs increase the risk of death in long term users – by about 1.5x. In patients without gastrointestinal conditions, PPI use increased the risk of death even higher, almost 2 fold. These differences existed even when PPIs were compared to H2 blockers (think Zantac), antacids that employ a different mechanism and are not quite as potent as PPIs.

What about proton pump inhibitors causes harm? People take PPIs for heartburn, acid reflux, a painful condition in which stomach acid travels backwards into the esophagus, causing chest pain. By increasing the pH of the stomach contents, PPIs are effective in reducing pain from acid reflux. Remarkably, though, some 20-30% of PPIs are taken by people who have no gastrointestinal symptoms. The popularity of PPIs – they are the 9th most commonly prescribed medication in the US – is a clue that physicians and patients think these drugs are benign. More broadly, the story of PPIs betrays a mindset that the body is a simple machine, that symptoms indicate malfunction, and that blocking the mechanisms that cause symptoms is an unalloyed good. This is not so.

As I like to point out to my students: nothing is free in medicine.  You can’t block an evolved cellular function in a large percentage of the population and think that nothing will go wrong. Adaptive, fitness-enhancing processes are also blocked, along with symptoms. Unintended consequences are guaranteed. In this instance ignorance is not bliss. If you are blind to adaptation and evolution, it can literally kill you.

Let’s first examine what PPIs do and how they work. PPIs potently block the gastric proton pump in parietal cells of the stomach. Normally, this cellular pump moves H+ ions into the lumen (the inner part) of the stomach, thereby decreasing the pH of gastric juice. Proton pumps are responsible for acidic stomach contents, but also cause the relatively low pH in the small intestine. Why is low pH important? Many people think that stomach acid is important for digestion of food. Nope. The primary reason we have evolved strongly acidic gastric juice is to kill microbes entering the gut along with food. That’s right – stomach acid is a gatekeeper to the microbiome.

Low pH generally kills microbes by destabilizing the cell membranes of bacteria. Acid has synergistic effects along with high temperature in rupturing the cell membranes of pathogens. Parenthetically, that is why infected patients with sepsis often have a high temperature (fever) plus low pH in tissues and blood (lactic acidosis).

Acid killing of bacteria is the reason why some scientists refer to stomach juice as an acid barrier. It is also why the manufacturers of probiotics – living microbes with health benefits when consumed – must go to great lengths to protect their products from sterilization in the stomach. Thus, a consequence of normal activity of proton pump inhibitors is to prevent microbial growth in the stomach and protect us from food-borne infection.

Now we turn to the ways that PPI users die. Since the main function of the proton pump is to protect us from harmful microbes, we would predict that PPI users would have more gut infections. Do they? Indeed the answer is yes. Observational studies have shown that PPIs increase infection by the virulent gut pathogen Clostridium difficile in hospitalized patients. Interestingly C. diff spores are pretty acid resistant, which raises questions about the exact mechanims. However, it is postulated that the change in pH from PPIs changes the microbiome, reducing commensal bacteria that otherwise inhibit C. diff. This sets the stage for out of control growth of this deadly pathogen.

The acid barrier works both ways, since the gut can be a source of extra-intestinal infections. PPIs are also associated with pneumonia in hospitalized patients. Since PPIs eliminate the acid barrier, harmful pathogens that take up residence in the gut can more easily travel upwards to the pharynx, airway, and lung. Another potential explanation for increased pneumonia is that the same H+/K+ ATPase proton pump in the gut also exists in the airway. PPIs impair acidification of the respiratory tract, which is probably what allows pathogens to colonize the lung.

It gets worse. PPIs also inhibit the bactericidal function of immune cells like macrophages. How do they do that? Macrophages consume (phagocytose) errant microbes and destroy them in internal lysosomes. These lysosome compartments are loaded with antibacterial peptides, free radicals and… wait for it… acid. The acid pump is a little different. It is a H+ATPase, but it is also inhibited by proton pump inhibitor drugs. It makes sense, then, that PPIs are going to have widespread effects on your immune system’s ability to manage infectious threats.

What about the microbiome? I mentioned earlier that stomach acid barrier is the gateway to the microbome. It follows that PPIs would affect the body’s community of commensal microbes, known as the microbiome. Do they? Yes. After taking PPIs, the stomach, esophagus, and small intestine grow a thick carpet of unfriendly microbes – a condition known as small intestinal bacterial overgrowth. Let’s pause here for a moment and reflect on the fact that your microbiome is profoundly affected by PPIs. This is important. Here is why: The microbiome is plugged into virtually every part of your body’s functions. Microbiomes that are out of whack (aka dysbiosis) can cause chronic low grade inflammation. Chronic inflammation is important because it is a slow smoldering immune process that increases the risk for heart attacks, strokes, and some cancers.

So, it should not come as a surprise that PPIs drive a variety of chronic inflammatory diseases, like chronic kidney disease, also heart attacks, strokes and congestive heart failure. If that is no enough to convince you that PPIs are dangerous, note also that PPIs are associated with excessive weight gain and obesity (also a chronic inflammatory condition).

I will make a prediction here: we will soon see a variety of studies that will showing that the microbiome is central in the otherwise inexplicable links between PPIs and chronic inflammatory diseases.

I could go on and on, but you should wait for the podcast coming soon on PPIs for that. For now, I will leave you with these summary points:

1. PPIs are dangerous drugs. They have some legit indications, but current widespread use is completely irrational, unsupported by evidence, and counter to public health.
2. PPIs disable a a key adaptation (control of pH) that is central in infection-fighting and control of the microbiome.
3. The cautionary tale of PPIs overuse is repeated in a variety of other medical domains and for many other drugs. Biomedicine has not yet learned its evolutionary lessons.
4. Ignore adaptation at your peril – what you don’t know about evolution might kill you.

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine