The use of PPIs is generally considered to have a low risk. Micronutrient deficiencies have been reported as possible side effects, and they will be described in the respective subchapters of this literature review. The most notable side effects are sequelae of hypochlor­hydria. Certain bacterial infections, such as those with Clostridioides difficile⁽⁵⁾, Salmonella enteritidis, Salmonella Typhimurium and Campylobacter jejuni, are more likely to occur in people who receive PPI⁽³⁾. Other infections are generally correlated with hypochlorhydria, not specifically with the PPI use. In a review by Johnson et al. from 2017⁽⁵⁾, a consensus was reached that a masking of gastric or esophageal cancer by the use of over-the-counter PPIs is unlikely.

This narrative review aims to sum up the effect of proton pump inhibitors on the minerals, vitamins and macronutrients absorption, to give a comprehensive overview and recommendations for the day-to-day general practice interventions.

Methodology

The state of the art for this topic was based on research on the PubMed and Google Scholar platforms, for studies performed in the last 10 years regarding PPIs, gastric acid treatment, macro- and micronutrients absorption, diet and food supplements. We took into account clinical and preclinical research and systematic reviews.

This article contains basic information about deficiency states, physiology and the mechanism of absorption under the circumstances of aberrant pH for the individual nutrients. The information on deficiency states and physiology was taken from sources which represent the current consensus or have stood the test of time. More focus is placed on finding mechanisms of change in absorption in higher-than-normal pH, or reports of clinical changes in patient population with routine PPI intake.

Results and discussion

Proteins

Protein malabsorption is associated with various conditions, ranging from neuropsychiatric disorders, like depression, anxiety and insomnia⁽⁴⁾, to more evident somatic disorders such as skeletal muscle wasting, fatigue and fluid retention⁽⁶⁾.

Protein digestion begins with its denaturation in the stomach under the influence of gastric acid and pepsins. The inactive precursor of pepsin is pepsinogen. It is released by chief cells and activated by gastric acid at a pH around 1.5 to 2^(7,8). The further breakdown of food proteins occurs in the duodenum, where the denatured oligopeptides from the stomach are hydrolyzed by pancreatic proteases and membrane-associated endo-, amino- and carboxypeptidases, finally resulting in dipeptides, tripeptides and free amino acids⁽⁹⁾.

Most protein absorption occurs in the proximal jejunum, with smaller amounts reaching the ileum and being absorbed there. The amino acids pass into the enterocytic cytoplasm through various⁽¹⁰⁾ enterocytic membrane peptide transporters, such as: neutral and basic amino acid transport complex (b[0,+]AT1-rBAT)‌⁽¹¹⁾, Na⁺ dependent⁽⁹⁾ neutral and basic amino acid transport complex with angiotensin-converting-enzyme 2 (b[0]AT-ACE2)⁽¹²⁾, proton-coupled amino acid transporter (PAT1)⁽¹³⁾ and peptide transporter 1 (PEPT1) for the absorption of di- and tripeptides⁽⁹⁾.

Specifically, PAT1 and PEPT1 are conducted through proton (H⁺) transport and driven by the membrane potential in the form of an inward-directed proton gradient, which is maintained by Na⁺/H⁺ antiporter 3 (NHE3)⁽⁹⁾. Here, PPIs exert their irreversible activity for a duration often exceeding 24 hours^(4,14). Their influence on the effectiveness of the aforementioned proton-dependent protein transporters and, consequently, on patients’ protein levels is to be questioned.

Notably, a 2023 case report by Murthy et al.⁽⁴⁾ describes the presumed cause of depressive symptoms as a consequence of tyrosine deficiency due to chronic PPI use.

Nakamura et al.⁽¹⁵⁾ note a correlation of PPI-related protein malabsorption and suppression of protein assimilation with malnutrition and activities-of-daily-living disability in elderly patients. Sufficient data for other age groups is not available, and protein malabsorption has not been routinely characterized as a common consequence of PPI use⁽¹⁶⁾.

Lipids

Dietary fats are carriers of vitamins (vitamins A, D, E and K), sources of essential fatty acids and a primary energy source of the human body^(17,18). Hyperlipidemia is a major risk factor for atherosclerosis and coronary heart disease⁽¹⁹⁾. Hypolipidemia does not usually have a direct clinical consequence, and can occur in states of low uptake, like malabsorption and malnutrition, as well as hyperthyroidism and liver failure. Hyperlipidemia is much more common than hypolipidemia⁽²⁰⁾.

Digestion of dietary lipids and structured triglycerides in the gastrointestinal tract occurs in the mouth, stomach and small intestine. The major site of absorption is the small intestine. Lipids are hydrophobic substances that need to be dispersed and emulsified for the digestive enzymes to take action at the interface of the emulsified oil and aqueous phases^(21-23).

The enzymatic digestion begins in the upper gastrointestinal tract via acid lipases – namely, lingual and gastric lipase⁽²¹⁾. They mainly target medium-chain fatty acids containing triglycerides, hydrolyzing them into fatty acids and glycerol⁽²⁴⁾. In the small intestine, pancreatic lipase further degrades triglycerides⁽²⁵⁾. The ideal pH for gastric lipase is acidic, around 5.4, and for pancreatic lipase alkaline, the pH should be around 8-9⁽²⁶⁾.

The mechanical action involved in the creation of a dispersion of dietary fats takes place by mastication and churning movements of the stomach, where the gastric chyme is ground under the influence of gastric acid and propelled through the antrum to the pylorus, and further into the duodenum^(21-23).

Subsequently, the lipid emulsion enters the small intestine in the form of fine lipid droplets with less than 0.5 micrometers in diameter⁽²¹⁾, where both bile and pancreatic juice take action. Digestion and absorption depend on the type of lipid.

• Triglycerides: pancreatic lipase affects emulsified triglyceride molecules, which releases 2-monoacylglycerol and free fatty acids^(21,27). An alkaline environment and the presence of bile are important for lipase activity⁽²⁶⁾.
• Phospholipids cannot be digested by the acid lipases (e.g. lingual, gastric). In the small intestine, they are present as micelles containing cholesterol and bile salts or mixed with triglyceride droplets. Phospholipids are hydrolyzed by pancreatic phospholipase A2 (PLA2), producing a fatty acid and lysophospholipids⁽²¹⁾.
• Cholesterol: cholesterol ester must first be hydrolyzed by cholesterol esterase into free cholesterol, which can be absorbed. Sterols are absorbed, for example, ­through Niemann-Pick C1-Like 1 (NPC1L1) receptors^(21,28).

The absorption of fatty acids takes place through the enterocytes⁽²¹⁾. There are several processes that are thought to facilitate fatty acid absorption^(21,29).

• Passive absorption: fatty acids and monoglycerides enter the absorptive cell as monomers at the moment of the micelles’ contact with the brush border of the enterocyte⁽²¹⁾.
• Transport proteins: long-chain and medium-chain fatty acid absorption also implicates fatty acid translocase (CD36), in relation to plasma membrane-associated fatty acid binding protein (FABPpm), as well as fatty acid transport protein 4 (FATP4)⁽²⁹⁾.
• Carrier-mediated process has been hypothesized to take place in situations of lower linoleate concentration by means of fatty acid binding protein⁽²¹⁾.

As previously mentioned, the optimum pH for the respective lipases differs depending on their origin. At higher pH, as resulting from the use of PPIs, the lipid absorption is reportedly increased^(30,31). Ali et al. (2022)⁽³⁰⁾ showed an increase of cholesterol, triglycerides and LDL with high confidence, yet with no connection to HDL.

A study conducted on laboratory animals by Aamir et al. in 2019⁽³¹⁾ has also demonstrated decreases in HDL and increases in total lipids and triglycerides with PPI medication.

Phillips et al. (2025)⁽³²⁾ noted that the increase in lipid absorption has been clinically used to aid patients with cystic fibrosis, as fat malabsorption is one of the symptoms of this disease. This practice is controversially discussed⁽³³⁾.

Carbohydrates

Carbohydrates are saccharide chains that are largely present in our diet as short-chain molecules known as sugars and long-chain molecules such as starch and dietary fiber^(23,24). Only monosaccharides can be absorbed via the intestine; longer chains must be broken down enzymatically by amylases in saliva and pancreatic juice, followed by brush-border digestion by a variety of specific enzymes. The monosaccharides then enter the small intestinal epithelial cells via sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 5 (GLUT 5) and leave the cell into the bloodstream by glucose transporter 2 (GLUT 2)⁽²³⁾.

Contrary to the influence of PPIs on proteins and lipids, where the correlation of PPI with nutrient absorption is mainly based on acid-mediated degradation and receptor activity, their effect on carbohydrates seems to be of a rather endocrinological nature. It is generally noted that this topic is not well researched.

For the endocrinological relations, the reader of this review might recall the relation between gastric acid secretion and gastrin, as well as the interaction of gastric acid secretion and somatostatin. The major pathway goes as follows: gastrin stimulates the enterochromaffin-like cell to produce histamine, which in turn stimulates the parietal cells to produce gastric acid (HCl)⁽³⁵⁾. Gastrin and HCl secretion are regulated by negative feedback. PPI induced low HCl levels, therefore stimulating an increased gastrin production, in a dose-dependent manner, as described by Helgadóttir et al. (2020)⁽³⁶⁾.

Several animal studies show gastrin to be a growth factor for beta cells of the pancreas^(37,38). Suarez-Pinzon et al. administered a combination of gastrin and epidermal growth factor to mice in vivo⁽³⁷⁾ and to isolated cell cultures in vitro⁽³⁹⁾. Both studies reached similar conclusions: when combined with epidermal growth factor, either normoglycemia was restored in the mice, or beta cell expression was significantly increased in vitro. Gastrin given alone prevented a worsening condition during administration without long-lasting effects.

In 2021, a study by Verma et al.⁽⁴⁰⁾ revealed a possible action of gastrin through cholecystokinin 2 (CCK2) receptors in the pancreas, indirectly increasing insulin levels and, thus, possibly decreasing HbA1c values, and this was verified by Ebadi et al.⁽⁴¹⁾ in the same year.

That being said, the realities of PPI influence on carbohydrate metabolism do not seem to be understood in their entirety, with no consensus being reached^(41,42).

Iron

Iron deficiency is well known to potentially lead to iron deficiency anemia, with consequences such as tachycardia, shortness of breath⁽⁴³⁾, fatigue and several other symptoms⁽⁴⁴⁾. Children with iron deficiency anemia might also experience delayed growth and development⁽⁴⁴⁾. 

The primary site of absorption of iron, to the extent of about 1-2 mg per day, is the duodenum and the proximal jejunum⁽⁴⁵⁾. Iron can be absorbed as non-heme or heme iron, with these forms accounting for 90% and 10% of our average diet, respectively. Non-heme iron exists either as ferric iron (Fe³⁺), or as ferrous iron (Fe²⁺)⁽⁴⁵⁾.

Most authors describe two pathways of iron absorption and assume iron to be either heme iron or ferrous iron (Fe²⁺) before absorption, and they agree to describe the absorption of ferrous iron (Fe²⁺) by the divalent metal transporter 1 (DMT-1) pathway⁽⁴⁶⁾. Some authors choose to detail the absorption of ferric iron (Fe³⁺) by the beta3-integrin and mobilferrin (IMP) pathway^(47,48). The latter has been shown to take place in animal models at least, although some authors postulate that the IMP pathway does not take place in the human intestine⁽⁴⁹⁾.

The importance of the DMT1 pathway in dietary research and medical practice is far more extensive. Notably, for ferric iron (Fe³⁺) to be absorbed through DMT1, the iron molecule must first be converted to its ferrous (Fe²⁺) form, either by duodenal cytochrome B on the brush border of enterocytes⁽⁴⁶⁾ or by gastric acid⁽⁵¹⁾. At a pH>3, ferric iron (Fe³⁺) would precipitate⁽⁴⁵⁾. Hence, it needs to be solubilized and chelated in the stomach⁽⁴⁷⁾. Ferrous iron (Fe²⁺) is stable⁽⁴⁵⁾. Chelating factors may be mucins, constituents of the iron-containing food⁽⁴⁷⁾ and other components of the chyme. Most well-known is the positive influence of ascorbic acid, which forms a chelate with ferric iron (Fe³⁺), making it soluble until it reaches the more alkaline environment of the small intestine^(45,46). Ascorbic acid is also a donor of electrons. Phytates, amongst others, are known to inhibit iron absorption⁽⁴⁷⁾.

According to some authors, heme iron is first digested into an intact metalloporphyrin before entering the enterocytes. Inside the cell, heme oxygenases extract the iron⁽⁵²⁾.

Heme carrier protein 1 (HCP1) is hypothesized to be implicated in heme absorption⁽⁵³⁾. PPI use in patients with hemochromatosis reduced the absorption of non-heme iron from test meals by about half⁽⁵¹⁾, and it is explained by the hindered transformation of ferric iron (Fe³⁺) to ferrous iron (Fe²⁺)⁽⁵⁴⁾. An earlier study on patients with hereditary hemochromatosis also demonstrated the administration of a PPI to inhibit the absorption of dietary non-heme iron and limit tissue accumulation of iron⁽⁵⁵⁾. However, neither study found any association between PPI intake and iron deficiency under normal clinical circumstances. A long-term study on patients with Zollinger-Ellison syndrome, who received continuous treatment with omeprazole for six years, could not find signs of iron deficiency⁽⁵⁶⁾.

Hamano et al. (2020)⁽⁵⁷⁾ found a positive association of PPI use and iron deficiency anemia, using the FDA Adverse Event Reporting System (FAERS) self-reported database. The reported odds ratios ranged from 3.9 for omeprazole to 7.29 for rabeprazole. This could be explained by a hypothesized PPI-induced upregulation of hepcidin, a regulator of serum iron concentration.

This hypothesis is further supported by experiments on in vivo mice and in vitro human hepatoma cells, where PPI administration increased hepatic hepcidin mRNA expression and increased plasma hepcidin levels⁽⁵⁷⁾. A UK population-based case-control study from 2018 showed that chronic use of PPI increased the risk of iron deficiency⁽⁵⁸⁾.

Calcium

Hypocalcemia is known to cause bone fragility⁽⁵⁹⁾, muscle cramps up to plain tetany, as well as psychiatric symptoms ranging from confusion and depression to hallucinations⁽⁶⁰⁾. Scaly skin and coarse hair have also been reported. At very low levels, difficulty breathing and seizures may be present as well⁽⁶⁰⁾.

In the digestive tract, calcium is mainly absorbed in its ionized form (Ca²⁺). While some of the calcium in dietary intake is already ionized, most of it needs to be transformed into its soluble, ionized form in the acidic environment of the stomach before absorption. Acid solubilization is needed for calcium absorption⁽⁶¹⁾. After propulsion of the stomach content, more than 90% of the dietary calcium will be absorbed in the small intestine⁽⁶²⁾. A shift of the intraluminal pH to more alkaline levels leads to reformation of less soluble calcium compounds, with only 3-6% of the calcium being absorbed in the colon^(61,62).

On a cellular level, the absorption of calcium has two different mechanisms⁽⁶²⁾:

Vitamin D-independent paracellular calcium transport takes place throughout the intestine. It functions by passive electrochemical gradient diffusion between intercellular tight junctions and is not saturable. Thus, it is of importance in cases with high calcium intake⁽⁶¹⁾.

Vitamin D-dependent transcellular calcium transport takes place by active transport through the apical TRPV6 and TRPV5 (transient receptor potential vanilloid Ca²⁺ channel) calcium channels of the enterocytes. The expression of this channel is regulated by the level of the physiologically active form of vitamin D3^(61-63).

The use of PPI leads directly to achlorhydria. Already in 1985, Recker⁽⁶⁴⁾ described the negative effect of achlorhydria on calcium carbonate absorption. This is supported by Shkembi and Huppertz in 2021⁽⁶¹⁾, describing the connection between acidic gastric environment and solubilization of calcium salts. 

In 2009, a prospective study was performed on 1211 postmenopausal women, trying to discern a correlation between omeprazole use and vertebral fractures. A relative risk of 3.5 for vertebral fractures with omeprazole in their medication regimen was reported, making omeprazole use a statistically significant risk factor for vertebral fracture⁽⁶⁵⁾.

In 2015, Hinson et al.⁽⁶⁶⁾ described a correlation between chronic PPI exposure, lower calcium levels (9.1 mg/dL with PPIs versus 9.4 mg/DL without PPIs; p=0.02) and increased parathyroid hormone levels (65.5 pg/mL with PPI versus 30.3 pg/mL without PPIs; p<0.001).

The hypothesis is that chronic PPI exposure leads to lower calcium levels, subsequently stimulating parathyroid hormone secretion. “Mild hyperparathyroidism” is hypothesized to be a sensitive marker for chronic PPI exposure. Only one study in postmenopausal women (≥5 years into menopause) evaluating fractional calcium absorption following 30 days of continuous PPI administration was found to be contradictory. But with a sample size of 21 patients, further research is needed to evaluate the significance of this study⁽⁵⁹⁾.

Magnesium

Hypomagnesemia has a broad clinical spectrum, both of physical and neuropsychiatric nature. Vomiting, nausea, fatigue, muscle spasms and tremors are amongst the common clinical findings⁽⁶⁷⁾. In states of severe deficiency, seizures⁽⁶⁷⁾, tetany and neuromuscular hyperexcitability may occur⁽⁶⁸⁾. Certain ECG changes are related to hypomagnesemia, such as a widened QT interval and diminished T waves^(68,69).

Hypomagnesemia is arrhythmogenic. Some of the proposed mechanisms of action include a malfunction of the Na⁺/K⁺-ATPase and disturbances of action potentials⁽⁷⁰⁾.

The digestion and absorption of magnesium share certain similarities with those of calcium. Magnesium has a para- and a transcellular pathway of absorption^(71,72). Only the free ionized form of magnesium (Mg²⁺) is usually available for absorption⁽⁷²⁾. An acidic gastric environment is necessary for its solubility⁽⁷³⁾.

The paracellular pathway is the main pathway for magnesium absorption, and occurs in the small intestine via specific proteins, called claudins, located at tight junctions between cells. They determine the selectivity and permeability of the particular paracellular pathway. Research on claudins responsible for magnesium absorption is still ongoing⁽⁷⁴⁾.

The transcellular pathway, minor in comparison to the paracellular one, predominantly takes place in the colon, and it is mediated through the transient receptor potential cation channel subfamily M member 6 and 7 (TRPM6 and TRPM7) on the luminal side of enterocytes^(71,72). TRPM6 is mostly expressed in the distal intestine, whereas TRPM7 is expressed in almost all human tissues⁽⁷⁴⁾.

The homeostasis of magnesium is maintained via renal regulation to a greater extent than magnesium intake⁽⁷¹⁾. Hypomagnesemia is one of the most well-known consequences of long-term PPI usage. This has been confirmed by a systematic analysis of cohort studies made in 2022 by Gommers et al.⁽⁷³⁾ The meta-analysis has shown a correlation of hypomagnesemia with PPI use and the duration of treatment. A PPI usage over six months is associated with an increased risk. The reported odds ratios range from 1 to 5.4^(73,75). This goes in concert with reported cases of hypomagnesemia under PPI regimens^(75,76).

One of the proposed mechanisms of hypomagnesemia due to PPI use is the decreased solubility of Mg²⁺ at more alkaline gastrointestinal pH. A coexisting reason could be a higher affinity of Mg²⁺ to negatively charged ions and forming insoluble salts in an alkaline environment, such as phosphate salts⁽⁷³⁾.

PPIs may also affect the paracellular transport of Mg²⁺ in the small intestine through direct and indirect mechanisms⁽⁷³⁾. The direct mechanism is the reduction of the expression of permeability-related proteins (claudins 7 and 12) and an increase in the transepithelial electrical resistance^(73,77). The indirect mechanism is the reduction of the paracellular permeability by increasing the luminal pH.

No scientific consensus has been reached regarding a direct effect of PPIs on Mg²⁺ absorption in the colon and possible compensation via transcellular colonic Mg²⁺ absorption⁽⁷³⁾. A 2020 study on Sprague-Dawley rats by Suksridechacin et al.⁽⁷⁸⁾ showed no effect of prolonged omeprazole use on the expression of relevant ion channels in the colon.

Zinc

Zinc is an essential microelement for the human body. Zinc deficiency manifests with a loss of appetite and hair, decreased speed of regeneration and an impairment of the immune system⁽⁷⁹⁾, elevating the tumor risk⁽⁸⁰⁾.

Dietary intake is the main source of zinc in the human body⁽⁸¹⁾. The main sites of zinc absorption are the distal duodenum and proximal jejunum. As is the case for calcium and magnesium, the influence of gastric acid might be needed to facilitate the extraction of zinc from food material and transform it into ionic zinc⁽⁸²⁾, although it is currently debated how significant this effect is⁽⁸³⁾. In the proximal small intestine, the transporter protein families zinc/iron-regulated-transporter-like-proteins (ZIP) and zinc transporter proteins (ZnT) are responsible for zinc absorption. The role of DMT-1 (divalent metal transporter-1) in the physiological transport of Zn²⁺ has been debated ever since the discovery of the ZIP4 transporter^(81,82). In any case, ZIP4 seems to be of greater concern regarding absorption. ZIP transporters are responsible for binding the Zn²⁺ ions for their active transport into the cell⁽⁸²⁾. ZnT proteins are responsible for the transport of Zn²⁺ ions inside the cell and into the bloodstream, with the exception of ZnT5B variant, which serves as a bidirectional transporter, also being able to transport Zn²⁺ back into the intestinal lumen⁽⁸¹⁾.

A statistical study by Urbas et al. from 2016⁽⁸⁴⁾ has come to the result that the long-term PPI use was associated with a nearly 20% decrease in plasma zinc levels. A 70% decrease in the absorption of zinc gluconate was observed. However, this decrease has not reached clinically significant levels of zinc deficiency, as the zinc concentration decreased only from 0.9 µg/ml to 0.7 µg/ml.

A separate 2011 study by Farrell et al.⁽⁸⁵⁾ has found a lower baseline zinc level in subjects receiving chronic PPI therapy (mean levels of 0.75 ± 0.03 µg/mL). None of these patients was classically zinc-deficient to a clinically significant level. A 2012 study by the same authors on patients with Barrett’s esophagus with prolonged use of PPIs also found statistically lower Zn²⁺ serum concentrations, but without reaching clinical Zn²⁺ deficiency⁽⁸⁶⁾.

In 2012, Joshaghani et al.⁽⁸⁷⁾ researched the effects of omeprazole consumption on serum levels, and observed a statistically significant decrease in Zn²⁺ absorption in males after omeprazole intake, without reaching clinically significant levels.

The lack of clinical relevance corresponds to the results of a study on rats⁽⁸³⁾, suggesting that low gastric pH may not be necessary for intestinal Zn²⁺ absorption. Further research on intestinal absorption is necessary.

Copper

The consequences of copper deficiency include fatigue, weakness, anemia and, in some cases, nerve damage. Psychiatric symptoms and osteoporosis may also occur⁽⁸⁸⁾. Copper is absorbed as Cu⁺, despite being found in the form of Cu²⁺ in most environments. In order to be absorbed, certain metalloreductases in the intestine have to reduce the copper⁽⁸⁹⁾. Amongst them, the duodenal cytochrome b⁽⁹⁰⁾ and members of the Steap family⁽⁹¹⁾ are of importance.

There are two main Cu⁺ transporters on the apical membrane of the intestinal cells⁽⁹²⁾: copper transporter 1 (CTR1) and divalent metal transporter 1 (DMT1). CTR1 binds to Cu⁺ with high affinity⁽⁹³⁾, while DMT1 plays a role in the absorption of other divalent metals⁽⁵⁰⁾.

A pilot study by Kaczmarczyk et al.⁽⁹⁴⁾ investigated the effects of long-term PPI use, finding a statistically significant increase in serum copper levels in patients taking PPIs. According to the authors, this may be due to an up regulation of Cu⁺ absorption in conditions of reduced Fe²⁺ uptake, as induced by PPIs.

A study by Wu et al. (2021)⁽⁹⁵⁾ revealed a decreased solubility of copper (i.e., a formation of copper precipitates) with an increase in pH. This does not correspond to in vivo results, but would be more like the action of PPI on other micronutrients.

Sodium

Sodium is the major osmolyte of extracellular fluid, regulating extracellular fluid homeostasis. Subsequently, sodium imbalances cause body water disorders, manifesting with thirst, muscle cramps and nausea⁽⁹⁶⁾. Unlike the micronutrients discussed so far, sodium is rarely mentioned in the context of PPI use. The research on interactions between sodium and potassium homeostasis under PPI regimens is limited, yet some noteworthy results warrant a brief discussion. The significance of this data is yet to be determined.

The small and large intestine share the following two main mechanisms of absorption^(97,98):

• electroneutral Na⁺ absorption through Na⁺/H⁺ exchangers (NHE2 and NHE3)⁽⁹⁹⁾ and Cl^-/HCO₃^- exchangers;
• electrogenic Na⁺ absorption by epithelial sodium channels (ENaC) and counter-ion Cl^- secretion by cystic fibrosis transmembrane conductance regulator (CFTR)⁽⁹⁷⁾.

In the small intestine, Na+ absorption can also be nutrient coupled, with glucose via SGLT and amino acids via members of the solute carrier family (Slc6, Slc38 etc.). In the large intestine, absorption may also be amiloride-sensitive through ENaC transporters⁽⁹⁷⁾.

We recommend reviewing Kato and Romero (2011)‌⁽⁹⁷⁾ paper to readers interested in sodium absorption channels and their regulation.

A 2019 postmarketing safety analysis by Makunts et al.⁽¹⁰⁰⁾, focusing on the nephrological risks of prolonged PPI use, found a statistically significant correlating hyponatremia. The following odds ratios (OR) for hyponatremia were given: omeprazole (OR 7), esomeprazole (OR 0.6), pantoprazole (OR 2), lansoprazole (OR 4) and rabeprazole (OR 4.3).

Two case studies from 1994⁽¹⁰¹⁾ and 1996⁽¹⁰²⁾ reported cognitive impairment and electrolyte imbalance after PPI administration.

In conclusion, no comprehensive pathophysiological explanations of the possible underlying mechanisms are available yet. It is unclear whether the effect of PPIs on the sodium balance is of a gastrointestinal or nephrological nature⁽¹⁰³⁾. Despite the statistical significance, the clinical relevance should be evaluated.

Potassium

A significant decrease in potassium can lead to muscle weakness, cramps, abnormal heart rhythms and even paralysis. Prolonged hypokalemia can be a reason for kidney disease^(104,105).

Around 90% of dietary potassium is absorbed in the small intestine through the means of passive transport^(84,106,107). Transcellular potassium channels can be divided into four main groups: voltage-gated channels (Kv), calcium-activated channels (KCa), inwardly rectifying channels (Kir) and two-pore domain channels (K2P)^(99,106). 

The previously mentioned postmarketing safety analysis by Makunts et al.⁽¹⁰⁰⁾ records the odds ratios for hypokalemia occurring under PPI treatment as follows: omeprazole (15.8), esomeprazole (3.1), pantoprazole (6.4), lansoprazole (11), rabeprazole (2.3).

Supporting this observation, a 2023 statistical study by Maideen (2023)⁽¹⁰⁸⁾ found a significant association between hypokalemia and long-term PPI use, analyzing more than 10 million reports from the FDA Adverse Event Reporting System.

One contradicting 2009 statistical study by Gau et al.⁽¹⁰⁹⁾ stated a significantly higher serum K⁺ level in PPI users of advanced age (mean age 79.7 years old; 70% females). However, the study showed completely contradictory results regarding an association between high-dose PPI use and increased serum potassium levels, depending on the statistical model used.

There are various explanations for the specific mechanism of action of PPIs on potassium levels in serum, most of which points to the kidneys rather than the gastrointestinal tract, although the effect is speculative only. Indeed, H⁺/K⁺-ATPases are also present in the kidneys^(84,110). Studies have shown PPI action on non-parietal H⁺/K⁺-ATPases as well⁽¹¹⁰⁾. This leads to the hypothesis that PPIs inhibit potassium reabsorption in the kidney, especially in an acidemic environment, and hence would increase the likelihood of hypokalemia⁽⁸⁴⁾.

At the same time, the presence of hypomagnesemia predisposes to hypokalemia due to an increased loss of K⁺ because of the disinhibition of renal outer medullary potassium channels (ROMK)⁽¹¹¹⁾. The proportion of this mechanism in total potassium loss is yet to be shown. While the use of PPIs predisposes to hypomagnesemia, the importance of this mechanism in secondary renal potassium loss is to be evaluated.

Like hyponatremia, the association of hypokalemia and PPI intake is not yet researched to its fullest. The degree to which its mechanism is nephrological, gastrointestinal or combined is unclear. As before, the statistical significance appears to exceed the clinical importance.

Vitamin B12

Besides mineral deficiencies, PPIs are widely considered a cause of vitamin B12 (cobalamin) deficiency. Vitamin B12 plays a role in erythropoiesis and myelination of nerves⁽¹¹²⁾. It is a cofactor for 5-methyltetrahydrofolate-homocysteine methyltransferase and methylmalonyl-CoA mutase⁽¹¹³⁾. Vitamin B12 deficiency is most typically characterized by the development of megaloblastic anemia^(112,114), causing paleness, weakness and possibly shortness of breath⁽¹¹⁴⁾. Due to its implication in myelination, symptoms such as tingling, muscle weakness, hyporeflexia, and even confusion or dementia are possible consequences⁽¹¹⁴⁾.

After the separation of the vitamin from ingested proteins by gastric acid⁽⁵¹⁾ and pepsin⁽¹¹⁵⁾, the two distinct carrier-proteins, haptocorrin and intrinsic factor, act in binding the vitamin⁽¹¹³⁾ throughout the gastrointestinal tract. Haptocorrin (i.e., R-factor or transcobalamin 1)^(113,114) binds vitamin B12 after having been secreted by the salivary glands⁽¹¹³⁾. With this protection, the cobalamin-haptocorrin complex can safely traverse the stomach and reach the duodenum. At this point, pancreatic proteases degrade haptocorrin⁽¹¹³⁾.  The second carrier-protein, intrinsic factor^(113,116), which is secreted by gastric parietal cells⁽¹¹⁷⁾, binds the vitamin. The complex of vitamin B12 and the intrinsic factor then traverses the small intestine until the absorption by enterocytes of the distal ileum takes place⁽¹¹³⁾. The absorption itself takes place by binding to cubam^(113,117), a receptor which consists of cubilin and the protein named amnionless⁽¹¹³⁾. It is then endocytosed⁽¹¹⁷⁾.

While the general consensus of studies indicates a link between a decreased vitamin B12 absorption and increased gastric pH due to PPI regimens, there is still ongoing debate^{(51,115,118,119)}.

A 2011 case-control study⁽¹¹⁵⁾ did not support the link between PPIs and vitamin B12 deficiency. With a confidence interval of 0.53-1.60 and odds ratios of 1 for short-term PPI use, 0.85 for long-term PPI use, 1.14 for low-dose treatment, and 0.87 for high-dose treatment, the study appears inconclusive.

In 2016, Presse et al.⁽¹¹⁸⁾ came to the distinct conclusion that vitamin B12 deficiency was statistically significantly associated with the use of gastric acid inhibitors (H2-receptor-antagonists included). An odds ratio of 3.12 was reported when no calcium supplements were given at the same time. Interestingly, the same study showed an odds ratio of only 1.30 for this association when calcium supplements were given.

As summarized by McColl (2009)⁽⁵¹⁾, PPIs seem to have the potential to lower vitamin B12 levels under certain circumstances, such as in patients with slow omeprazole metabolism, patients with H. pylori gastritis and a risk of atrophic gastritis, or high-dose, long-term treatment regimens.

Vitamin C

Vitamin C (ascorbic acid) is an antioxidant essential for the formation and maintenance of connective tissue⁽¹²⁰⁾. It is important for proline hydroxylation on procollagen and, thus, for the formation of the finished collagen triple helix⁽¹²¹⁾. It is implicated in wound healing, normal blood vessel function and iron absorption⁽¹²⁰⁾. A deficiency, called scurvy, is marked by bruising, hair and skin problems, including hyperkeratosis⁽¹²¹⁾, and anemia⁽¹²⁰⁾.
In vivo, two forms of vitamin C exist: ascorbic acid, the reduced form, and dehydroascorbic acid, the oxidized form⁽¹²²⁾. Vitamin C absorption occurs in the small intestine. Two distinct mechanisms are found: sodium-dependent vitamin C transporters and hexose transporters⁽¹²¹⁾. Some authors note passive diffusion as a third mechanism⁽¹²²⁾. Passive diffusion would not be easily possible at neutral pH, as almost all (>99.9%) of the vitamin is in its anionic form. At lower pH, such as in the duodenum, a higher percentage of unionised vitamin C (15%) is presumed to play a significant role in absorption, according to the 2019 review by Lykkesfeldt and Tvenden-Nyborg⁽¹²²⁾.

Sodium-dependent vitamin C transporters (SVCTs) account for most vitamin C absorption^(121,122). They are cotransporters for Na+ and vitamin C via gradient-independent active transport. The pathway of absorption by these transporters is mostly concerned with ascorbic acid, as compared to dehydroascorbic acid⁽¹²²⁾.

Hexose transporters⁽¹²¹⁾ – specifically, glucose transporters 1 and 3 (GLUT 1 and 3) – account for the transport of dehydroascorbic acid. Dehydroascorbic acid and glucose compete for absorption through GLUT 1 and GLUT 3, as shown by the inhibition of dehydroascorbic acid absorption in states of excess glucose intake. The transport through GLUT 1 and GLUT 3 is gradient-dependent⁽¹²²⁾.

An experimental 2005 study by Henry et al.⁽¹²³⁾ demonstrates that omeprazole lowers the concentration of vitamin C in fasting gastric juice from 5 µm/l pre-omeprazole to 3 µm/l after ingestion. A slight reduction in serum vitamin C concentration was also observed more pronouncedly in subjects infected with H. pylori.

As described by McColl (2009)⁽⁵¹⁾, increased gastric juice pH due to PPI therapy reduces the proportion of vitamin C, as an increased metabolism to 2,3-diketogulonic acid will occur, and it is not bioavailable. This takes place at a pH>4⁽¹²³⁾.

Another factor could be the lower percentage of dietary vitamin C transforming from a unionised form (with ~99.9% at pH 1) to an anionic form (with >99.9% at pH 7), further reducing its bioavailability through passive diffusion alone, along membranes, even with a substantial concentration gradient⁽¹²²⁾.

Vitamin D

Vitamin D (cholecalciferol) plays a role in regulating human growth and mineral absorption. Vitamin D deficiency can cause muscle spasms, bone pain, bone fractures and weakness in people of all ages. In children, vitamin D deficiency may lead to the condition known as rickets, which is characterized by abnormal bone growth and neurological symptoms⁽¹²⁴⁾.

Dietary vitamin D exists in hydroxylated and non-hydroxylated forms⁽¹²⁵⁾. For a long time, it was believed that vitamin D was absorbed through passive diffusion in micelles with other dietary fats⁽¹²⁶⁾. Newer studies propose more specific methods of vitamin D incorporation as secondary mechanisms of absorption^(126,127).

A 2018 systematic review by Silva and Furlanetto⁽¹²⁶⁾ revealed a similarity between the absorption of vitamin D and cholesterol, involving membrane transport proteins. The most important are Niemann-Pick C1-like 1 carrier (NPC1L1), scavenger-receptor class B type I (SR-BI), cluster determinant 36 (CD36) and ATP-binding cassette transporter A1. This is underlined by the 2011 in vitro study by Reboul et al.⁽¹²⁸⁾, which showed a direct connection between vitamin D absorption and the expression of NPC1L1, SR-BI and CD36 transporters in human intestinal epithelium.

Goncalves et al.⁽¹²⁷⁾ found that long-chain fatty acids, which modulate cholesterol absorption, might also interfere with vitamin D absorption. Possible competitive binding of free fatty acids and vitamin D by the same transporters, especially CD36 and SR-BI, would further support the idea that vitamin D is absorbed by these specific membrane transporters.

According to the 2023 study by Losurdo et al.⁽¹²⁹⁾, pantoprazole use is associated to decreases in vitamin D levels (p<0.001). Earlier studies found similar results^(130,131), with varying significance. In 2024, Smaoui et al.⁽¹³¹⁾ also included omeprazole and esomeprazole.

A potential link between dietary vitamin D bioavailability and chronic PPI use was discussed in the aforementioned study by Losurdo et al. (2023)⁽¹²⁹⁾. Many steps in vitamin D absorption depend on magnesium as a cofactor. The negative influence of PPIs on magnesium levels may indirectly influence vitamin D metabolism. There is a lack of data on the direct effect of gastrointestinal pH on vitamin D absorption.

There appears to be a correlation between PPI use and lower vitamin D levels; however, more research is needed to determine the direct effect of PPIs on vitamin D.

A study by Vinke et al. (2020)⁽¹³⁰⁾ hypothesized a link between the effect of PPI use on the gut microbiota and consecutive effects on magnesium levels, which in turn would influence the active vitamin D levels, but did not provide statistical data supporting this theory.

Vitamin B9

Vitamin B9 (folate) is an essential vitamin for the amino acid metabolism and DNA synthesis⁽¹³²⁾. Folate refers to a class of biologically active compounds related to, and including folic acid, the reduced folates 5-methyltetrahydrofolate and 5-formyltetrahydrofolate^(133,134). 5-methyltetrahydrofolate is the primary form of vitamin B9 found in human blood⁽¹³³⁾. Folate deficiency can lead to megaloblastic anemia, and it is strongly associated with neural tube defects in newborns⁽¹³²⁾.

Vitamin B9 absorption mainly takes place in the small intestine^(133,135). Several mechanisms have been identified for the absorption of the vitamin^(136,137).

Most dietary folate is in the polyglutamate form and needs hydrolysis to the monoglutamate form, by the intestinal glutamate carboxypeptidate II of the small intestinal brush border⁽¹³³⁾. 

The main pathway of absorption of folate into the enterocytes is through the human proton-coupled folate transporter (hPCFT), on the apical brush border membrane^{(133,136,137)}. It has an optimum pH of  4.5⁽¹³⁸⁾ to 5.5⁽¹³³⁾. hPCFT is a proton symporter and, besides folic acid, hPCFT also transports the reduced folates^(136,138) and antifolates⁽¹³³⁾. 

Another transporter that is implicated in folate transport is the reduced folate carrier (RFC)^{(133,136,137)}. It is an organic phosphate antiporter ubiquitously expressed in the human body, yet it cannot be adequately absorbed from the gastrointestinal tract in the absence of hPCFT. This is highlighted in individuals with hereditary folate malabsorption. It has an optimum pH of 7.4. It also transports antifolates and reduced folates⁽¹³³⁾. 

Other transporters of minor importance include the solute-carrying organic anion-transporting polypeptide 2B1 (SLCO2B1). Lastly, some folate is still absorbed in the colon despite suboptimal pH and lower hPCFT expression. In this location, many bacteria of the microbiome might synthesize folate endogenously⁽¹³³⁾.

Changes in pH in the small intestine in several different conditions have shown that an increased pH decreases folate absorption and vice versa^(139-142). Furthermore, Urquhart et al. (2010)⁽¹³⁹⁾ note that PPI use is associated with reduced hPCFT expression in vivo.

However, these results seem to be of little clinical importance as the 2025 systematic review by Parnham et al.⁽¹⁴³⁾, who found no effect of PPI use on vitamin B9 blood concentrations or absorption. The review, using data from the SOPRAN study (“Safety of Omeprazole in Peptic Reflux Esophagitis: A Nordic Open Study”)⁽¹⁴⁴⁾, concluded that vitamin B9 levels in PPI users remained stable over the five years of observation. These findings align with a 2023 study by Losurdo et al.⁽¹²⁹⁾ and with older results from 1998 by Termanini et al.⁽¹⁴⁵⁾

Other vitamins

Vitamins can generally be classified based on their solubility. The lipophilic vitamins are A, D, E and K⁽¹⁴⁶⁾. The hydrophilic vitamins are C and the B complex⁽¹⁴⁷⁾.

Besides the D vitamin, the other lipophilic vitamins (A, E and K) are rarely mentioned in connection to the PPI use. No significant sources associating the use of PPIs to changes in vitamin A and vitamin E serum concentration, their absorption or related deficiency states are to be found at this point^(148,149).

While a direct link to vitamin K was not found, it might be of interest to the reader that PPI use could lead to elevations in INR with simultaneous warfarin intake, albeit this reaction is very rare, with a frequency per package ranging from 0.23:1,000,000 for lansoprazole to only 0.09:1,000,000 for omeprazole^(150,151).

Besides vitamin B12 and B9, no significant sources associating the use of PPI with changes in concentration or absorption of other vitamins of the B complex are to be found at this point.

Conclusions

The literature demonstrated clinically relevant negative changes in the absorption of iron, calcium, magnesium, vitamin B12 and vitamin C, a clinically relevant positive absorptive effect on lipids, and a decreased absorption without clinical relevance for zinc, sodium, potassium, vitamin D and proteins (in the elderly). There is no relevant influence on the absorption of proteins and vitamin B9. No consensus or insufficient data is given for carbohydrates, copper, and proteins (in non-elderly).

It is recommended to evaluate a special supplementation of iron, calcium, magnesium and vitamin C, as well as vitamin B12 for at-risk individuals. The supplementation in these cases should not rely on the action of stomach acids. Furthermore, for patients at risk and in case of chronic treatment, special nutritional counseling for a lipid reduced diet and close monitoring of the relevant blood parameters are advisable.

 

Autor corespondent:  Alexander Karl Merker E-mail: merkeralexander@gmx.de

 

 

 

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.