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Proton Pump Inhibitors, Migraine, and the Microbiome

By Heather Davis, MS, RDN, LDN

Proton pump inhibitors (PPIs) such as omeprazole are among the most frequently prescribed drugs throughout the world.1 These drugs are commonly used to treat conditions like gastroesophageal reflux disease through their modulation of the acid-producing function of the parietal cells of the stomach.2 Many nutrition professionals may already be familiar with their potential side effects, including nutrient interactions involving B12, calcium, iron, vitamin C, and magnesium.3 Long-term use of PPIs may come with some additional health concerns, researchers say. Among these concerns is a higher incidence and likelihood of migraine headaches.4

A recent cross-sectional analysis published in April 2024 in Neurology Clinical Practice found that people taking PPIs were 70% more likely to experience migraine than people not taking PPIs. They also looked at the impact of taking other acid-suppressive medications, such as H2 receptor antagonists like cimetidine and generic antacids, whose use revealed a 40% and 30% higher likelihood for migraine, respectively. The authors adjusted for magnesium intake as well as age, sex, and use of caffeine and alcohol.4

This isn’t the first study to explore the possible connection between acid-suppressive medication and migraine. However, most studies examining the relationship, including this one, have been correlational and unable to determine a direct cause-and-effect relationship. Nonetheless, authors of the 2017 Clinical Practice Update from the American Gastroenterological Association say there’s cause for hesitancy in recommending these drugs long-term for patients, and in those who may require long-term use, the lowest effective dose should be used to reduce risk for side effects.5

PPIs and the Gut-Brain Axis 
Other researchers have discussed the possibility that PPI use may enhance an individual’s susceptibility to several enteric infections, including small intestinal bacterial overgrowth (SIBO), Salmonella, Campylobacter jejuni, and Clostridium difficile.5 The authors from the American Gastroenterological Association’s report also say that although PPIs have no direct effect on pH in the colon, they appear to have a significant downstream effect on colonic bacteria.

Neurology study author Margaret Slavin, PhD, RDN, of the University of Maryland in College Park, says, "These drugs are often considered to be overprescribed, and new research has shown other risks tied to long-term use of proton pump inhibitors, such as an increased risk of dementia."6

PPI use is also associated with an array of neurological adverse events, including impaired hearing, vision, and memory.7

Researchers are digging for deeper answers about how PPI use may alter gut function, including the impact on intestinal microbiome, and how these alterations may, in turn, influence clinical symptoms and conditions such as migraine.

Migraine and gastrointestinal (GI) diseases have a connection worth exploring. Authors investigating this mechanism say that many GI diseases involve the sensitization of nerve fibers by nerve signals, endocrine signals, or the immune system, which may increase the risk of migraine. Studies on the topic often reveal that as the number of GI diseases increases, the prevalence of migraine also increases.8

Probiotics and PPIs
To the extent that PPIs may negatively impact the gut microbiome, what role might probiotics play in curbing risk of dysbiosis? The research is promising.

A three-year prospective study published in 2018 revealed that administration of probiotics not only decreased the rate of SIBO among children with gastroesophageal reflux disease treated with PPI but also significantly reduced the presence of digestive symptoms in the group with positive glucose hydrogen breath test.9

In a randomized, double-blind, placebo-controlled trial published in 2022 in Clinical Nutrition ESPEN, healthy participants ages 18-56 were given either a PPI (n = 15) or a placebo (n = 15) over 6 weeks. All subjects consumed multi-strain probiotics from weeks 2-6, with metagenomic and metabolomic analysis performed on stool samples at week 0, 2, and 6. The authors found that probiotics in combination with PPI use suppressed undesirable PPI-mediated intestinal microbial alterations.10

Prior studies, such as a human intervention pilot published earlier in the Journal of Clinical Gastroenterology, also demonstrated a significant improvement in gastric and duodenal bacteria overgrowth and reduced impairment of the gastric barrier effect with concomitant probiotic and PPI use compared with PPI alone. The authors note a decrease in undesirable fecal enterococci, total coliforms, E. coli, molds, and yeasts in subjects treated with PPIs in conjunction with probiotic supplementation. Probiotic strains used included Lactobacillus rhamnosus LR06 (DSM 21981), Lactobacillus pentosus LPS01 (DSM 21980), Lactobacillus plantarum LP01 (LMG P-21021), and Lactobacillus delbrueckii LDD01 (DSM 22106).11

But what about probiotic use in cases of migraine?

Probiotics and Migraine 
Researchers have hypothesized that dysbiosis may drive inflammation and present a burden for optimal gut-brain axis function in a way that may increase risk for migraine.12

A randomized double-blind controlled trial published in 2019 evaluated the effects of supplementation with a 14-strain probiotic on 40 episodic and 39 chronic migraine patients over the span of 10 weeks. Among both episodic and chronic migraineurs taking the probiotic, the frequency and severity of migraine attacks were significantly reduced. In chronic migraineurs, the duration of attacks was also reduced.13

Study authors say that an improvement in gut microbiota and reduction of inflammation may have positive effects on strengthening gut and brain function. However, more large-scale randomized, placebo-controlled studies are needed to determine clinical efficacy and safety.12

For care teams and their patients suffering from migraine in the presence of PPIs, these findings may take us one step closer to understanding some of the mechanisms involved and perhaps provide additional clinical tools worth adding to the arsenal.

— Heather Davis, MS, RDN, LDN, is the editor at Today’s Dietitian and has a background in nutrition research, education, integrative clinical nutrition, and medical writing.

References

  1. Shanika LGT, Reynolds A, Pattison S, Braund R. Proton pump inhibitor use: systematic review of global trends and practices. Eur J Clin Pharmacol. 2023;79(9):1159-1172.
  2. Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages of long-term proton pump inhibitor use. J Neurogastroenterol Motil. 2018;24(2):182-196.
  3. Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Ther Adv Drug Saf. 2013;4(3):125-133.
  4. Slavin M, Frankenfeld CL, Guirguis AB, Seng EK. Use of acid-suppression therapy and odds of migraine and severe headache in the National Health and Nutrition Examination Survey. Neurol Clin Pract. 2024;14(3):e200302.
  5. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715. 
  6. American Academy of Neurology. Use of acid reflux drugs linked to higher risk of migraine. ScienceDaily website. https://www.sciencedaily.com/releases/2024/04/240424182453.htm. Published April 24, 2024. Accessed July 2, 2024.
  7. Makunts T, Alpatty S, Lee KC, Atayee RS, Abagyan R. Proton-pump inhibitor use is associated with a broad spectrum of neurological adverse events including impaired hearing, vision, and memory. Sci Rep. 2019;9(1):17280. 
  8. Kim J, Lee S, Rhew K. Association between gastrointestinal diseases and migraine. Int J Environ Res Public Health. 2022;19(7):4018. 
  9. Belei O, Olariu L, Dobrescu A, Marcovici T, Marginean O. Is it useful to administer probiotics together with proton pump inhibitors in children with gastroesophageal reflux? J Neurogastroenterol Motil. 2018;24(1):51-57. 
  10. Singh G, Haileselassie Y, Briscoe L, et al. The effect of gastric acid suppression on probiotic colonization in a double blinded randomized clinical trial. Clinical Nutrition ESPEN. 2022; 47:70-77.
  11. Del Piano M, Anderloni A, Balzarini M, et al. The innovative potential of Lactobacillus rhamnosus LR06, Lactobacillus pentosus LPS01, Lactobacillus plantarum LP01, and Lactobacillus delbrueckii Subsp. delbrueckii LDD01 to restore the "gastric barrier effect" in patients chronically treated with PPI: a pilot study. J Clin Gastroenterol. 2012;46 Suppl:S18-26. 
  12. Dai YJ, Wang HY, Wang XJ, Kaye AD, Sun YH. Potential beneficial effects of probiotics on human migraine headache: a literature review. Pain Physician. 2017;20(2):E251-E255.
  13. Martami F, Togha M, Seifishahpar M, et al. The effects of a multispecies probiotic supplement on inflammatory markers and episodic and chronic migraine characteristics: a randomized double-blind controlled trial. Cephalalgia. 2019;39(7):841-853.