Effects of proton pump inhibitors on inflammatory bowel disease: An updated review

Abstract

Inflammatory bowel disease (IBD) is believed to be caused by various factors, including abnormalities in disease susceptibility genes, environmental factors, immune factors, and intestinal bacteria. Proton pump inhibitors (PPIs) are the primary drugs used to treat acid-related diseases. They are also commonly prescribed to patients with IBD. Recent studies have suggested a potential association between the use of certain medications, such as PPIs, and the occurrence and progression of IBD. In this review, we summarize the potential impact of PPIs on IBD and analyze the underlying mechanisms. Our findings may provide insights for conducting further investigations into the effects of PPIs on IBD and serve as an important reminder for physicians to exercise caution when prescribing PPIs to patients with IBD.

Key Words: Drug safety, Proton pump inhibitor, Inflammatory bowel disease, Ulcerative colitis, Crohn’s disease

Core Tip: Inflammatory bowel disease (IBD) can be induced by multiple factors. Incidentally, several drugs, including proton pump inhibitors (PPIs), may also be involved in the occurrence and development of IBD. This study is an updated review of the literature. It summarizes the potential impact of PPIs on the risk, severity, and pharmacotherapy of IBD and analyzes the possible mechanisms through which PPIs may contribute to the development of IBD.

INTRODUCTION

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a non-infectious chronic inflammatory disorder of the gastrointestinal tract. UC is chiefly limited to the inflammation of the colonic mucosa, while CD can affect any part of the gastrointestinal tract from the mouth to the anus[1]. IBD has now become a global health concern owing to the lifestyle and food habits of the 21^st century. Recent epidemiological studies indicate that nearly 6.8 million people worldwide are affected by IBD[1]. In North America and Europe alone, the number of IBD cases exceeds 1.5 million and 2 million, respectively[2]. Additionally, newly industrialized countries in South America, Asia, and Africa are also reporting a significant increase in the incidence of IBD[3]. Although the exact etiology of IBD remains unknown, it is believed a complex interplay of factors, including genetic susceptibility, environmental factors, immune dysregulation, and alterations in the gut microbiota, is responsible for the condition. Furthermore, certain medications have also been implicated in the development of IBD, including oral contraceptives, nonsteroidal anti-inflammatory drugs, rituximab, and antibiotics[4,5]. More recently, proton pump inhibitors (PPIs) have emerged as potential risk factors for IBD[5].

PPIs have been widely used as acid-suppressive agents since their introduction in the mid-1980s[6]. By irreversibly inhibiting the H⁺/K⁺ ATPase proton pumps in the gastric mucosa, PPIs effectively reduce both basal and stimulated gastric acid secretion[6]. Consequently, PPIs have become the first-line treatment for conditions such as gastroesophageal reflux disease, peptic ulcer disease, and Zollinger-Ellison syndrome[7]. They are also frequently prescribed empirically to manage nonspecific upper gastrointestinal symptoms[8-10]. Moreover, PPIs are among the most commonly prescribed long-term medications in clinical practice worldwide. In the United States, it is estimated that approximately 8% of adults were prescribed a PPI in the past 30 d during 2011-2012[11]. Similar trends were reported in Denmark too, where the prevalence of PPI use increased fourfold from 2002 to 2014, reaching 7.4%[12]. Nationwide studies in Iceland and France have also reported a significant rise in PPI utilization, with instances of overuse that do not always align with clinical guidelines[13,14]. Given the widespread use of PPIs, there is growing concern regarding their safety, particularly with long-term use.

Some recent observational studies have shown an association between PPI use and an increased risk of various diseases, including kidney disease, dementia, bone fractures, myocardial infarction, pneumonia, enteric infections, and gastrointestinal and hepato-biliary-pancreatic malignancies[15-18]. Some studies have also suggested a potential link between PPI use and IBD[19,20]. This study aims to summarize the effects of PPIs on IBD and explore potential mechanisms of action, in order to suggest guidelines for the safe and appropriate use of PPIs in patients with IBD.

OVERVIEW OF THE PHARMACEUTICAL CHARACTERISTICS OF PPIS

At present, the following seven types of PPIs have been approved for clinical use: Omeprazole, lansoprazole, pantoprazole, rabeprazole, stereo-isomeric compounds esomeprazole and dexlansoprazole, and ilaprazole (approved in most Asian countries)[21,22]. All PPIs share a common parent nucleus comprising pyridine and benzimidazole with different substituents (Figure 1). Therefore, the pharmacological properties of all PPIs are similar. Once absorbed into the circulation, they are rapidly transported to gastric parietal cells and concentrated in secretory canaliculi, where they undergo protonation and structural rearrangement to generate active metabolites[21]. These active compounds irreversibly bind to the cysteine residues of H⁺/K⁺ ATPase through covalent bonds and inhibit the final stage of gastric acid secretion, resulting in a strong acid-inhibiting effect that lasts until new proton pumps are generated (up to 36 h)[23].

Figure 1 Mother nucleus structure of proton pump inhibitors. Omeprazole (R₁: OCH₃, R₃: OCH₃, R₂R₄: CH₃), lansoprazole (R₁: H, R₃: CF₃CH₂O, R₂R₄: CH₃), pantoprazole (R₁: F₂CHO, R₂R₃: CH₂O, R₄: H), rabeprazole (R₁R₄: H, R₂: CH₃, R₃: CH₃-O-CH₂-CH₂-CH₂O), ilaprazole (R₁: pyrrole, R₂: CH₃, R₃: OCH₃, R₄: H). Esomeprazole is the S-isomer of omeprazole and dexlansoprazole is the R-isomer of lansoprazole.

PPIs are acid-labile weak bases that are typically packaged in enteric-coated delivery systems to make sure that they are released in the intestine, and not in the stomach. The serum half-life of single-release PPIs is only 1-2 h, except for ilaprazole, which has a half-life of 8-10 h[24]. PPIs mainly degrade through hepatic P450 cytochrome (CYP) enzymes. The CYP2C19 pathway is dominant in overall PPI metabolism, although different PPIs show slight variations. This may result in different drug efficacies and drug-drug interactions. Omeprazole and its stereo-isomer esomeprazole are almost entirely metabolized by CYP2C19. Rabeprazole and lansoprazole/dexlansoprazole are also metabolized by CYP2C19; however, they exhibit significant affinity for CYP3A4 as well. Pantoprazole is primarily metabolized by CYP2C19 O-demethylation and sulfate conjugation, while ilaprazole is mainly metabolized by CYP3A4/5[21,25]. Therefore, omeprazole and esomeprazole exhibit the highest potential for drug interactions, while other PPIs may have fewer interactions. Additionally, differences in the genotypes of CYP2C19 are responsible for variability in PPI plasma concentrations and intragastric pH. When these effects cause subtherapeutic concentrations, they may contribute to the risk of treatment failure. Conversely, if they give rise to sustained supratherapeutic concentrations, they may lead to adverse effects[26]. Furthermore, we must also consider the potential effects of PPI-induced elevation in gastric pH, such as the potential impact on the absorption of drugs that require acidic conditions or the promotion of excessive growth of bacteria in the human body.

MECHANISMS FOR POTENTIAL EFFECTS OF PPIS ON IBD

The impact of a PPI on IBD may involve a complex biological process, potentially contributing to the occurrence and progression of IBD. Here, we focus on the specific impact of PPIs on the intestinal microbiota, mucosal barrier, immune cell function, and potential drug interactions in an attempt to elucidate the underlying mechanisms through which PPIs affect IBD.

Impact of PPIs on the intestinal microbiota

IBD has a multifactorial pathogenesis. There is increasing evidence to suggest that the gut microbiome plays a crucial role in the development of IBD[27]. Under normal circumstances, the gut microbiota and the host mutually regulate each other, maintaining a symbiotic relationship and intestinal barrier function through immune regulatory mechanisms[28,29]. However, the use of PPIs may cause dysbiosis of the microbiota. Several studies have indicated a link between the use of PPIs and the development of IBD[30-32]. An extensive analysis of the microbiota has revealed significant similarities in the changes observed in the intestinal microbiota of both IBD patients and PPI users, suggesting that the intestinal microbiota may play a major role in PPI-induced IBD[33].

Firstly, the use of PPIs can lead to the translocation of the intestinal microbiota and increase the risk of intestinal infection, which are considered important triggers for the development of IBD[33]. By inhibiting gastric acid secretion and increasing the pH level of the gastric juices, PPIs enhance the survival rate of ingested microorganisms. This phenomenon facilitates the migration of bacteria from the oral cavity to the intestinal lumen (Figure 2). A previous study conducted genomic sequencing and showed that extensive use of PPIs may enrich the intestine with oral-associated bacteria. This phenomenon may serve as a potential microbial signature of IBD[34]. Oral-associated bacteria, particularly Klebsiella pneumoniae, Fusobacterium nucleatum, and Campylobacter concisus, can actively colonize the intestinal mucosal niche, protected by gastric acid inhibitors, such as PPIs[34]. Additionally, Read et al[34] demonstrated the involvement of the T helper type 17 inflammatory axis in both periodontitis and IBD, suggesting shared inflammatory mechanisms that may contribute to the intestinal expansion of oral disease-associated bacteria in IBD. Furthermore, a low stomach-acid environment promotes excessive growth of small intestinal bacteria, exacerbating the imbalance of the intestinal microbiota (Figure 2). Prolonged acid suppression due to long-term PPI use, resulting in hypochlorhydria, can alter the intestinal environment and promote the growth of small intestinal bacteria[35,36]. Several studies have suggested that the continuous use of PPIs is associated with excessive growth and incidence of small intestinal bacteria owing to hypochlorhydria[37,38]. Notably, within the first few days of PPI use, intestinal infections associated with Campylobacter and nontyphoidal Salmonella spp. have been shown to increase threefold[38]. A self-controlled case series study also demonstrated a threefold increase in the risk of enteric infection among IBD patients using PPIs[39]. Furthermore, PPIs can directly affect the gastric microenvironment by attacking bacterial proton pumps (Figure 2), which decreases the normal gastric microbiota. As a result, acid-resistant pathogens proliferate, which, in turn, increases the number of bacteria reaching the small intestine[40,41].

Figure 2 Impact of proton pump inhibitors on the gastrointestinal microbiota. Proton pump inhibitors (PPIs) inhibit gastric acid secretion by irreversibly binding to H⁺/K⁺ ATPase in gastric parietal cells. An increased pH level facilitates the migration of bacteria from the oral cavity to the intestinal lumen and promotes excessive growth of small intestinal bacteria, exacerbating the imbalance of the intestinal microbiota. PPIs can also directly affect the gastric microenvironment by attacking the P-type ATPase of some bacteria. Additionally, a high gastric pH caused by PPIs can facilitate the survival of the vegetative form of Clostridioides difficile (C. difficile), enhance the survival of germinated spores in the stomach, and increase the number of actively dividing C. difficile cells colonizing the intestinal tract. This PPI-induced dysbiosis of the microbiota may contribute to the occurrence and progression of inflammatory bowel disease. C. difficile: Clostridioides difficile; PPI: Proton pump inhibitor.

Secondly, PPIs may contribute to various bacterial infections, such as those caused by Clostridioides difficile (C. difficile), which can also be involved in the pathogenesis of IBD. C. difficile infections can trigger flares of IBD and worsen the disease course[42,43]. A recent study suggested PPI use as an independent risk factor for C. difficile infection in IBD patients[44]. Multiple mechanisms may underlie this association. Although the ingested spores of C. difficile are likely resistant to gastric acid, PPIs may predispose to colonic bacterial overgrowth and dysbiosis by upregulating gastric pH, particularly by decreasing the prevalence of symbiotic Clostridium spp. that typically compete with C. difficile in the same niche[39]. Moreover, a PPI-induced elevation in gastric pH (generally pH > 5) can facilitate the survival of the vegetative form of C. difficile[45]. The newly emerged vegetative forms can enhance the survival of germinated spores in the stomach and increase the number of actively dividing C. difficile cells colonizing the intestinal tract (Figure 2)[45]. Additionally, PPIs can directly affect C. difficile by promoting toxin production or inducing other virulence behaviors. They can also inhibit the activation of neutrophil cells, thereby decreasing bactericidal activity by reducing the calcium influx[46].

Finally, PPIs can affect the population of gut microbiota in IBD patients by increasing the number of bacteria that cause inflammatory reactions and significantly decreasing those with anti-inflammatory effects. Previous studies have shown that PPIs may decrease the abundance of Faecalibacterium, SMB53, Clostridium, Turicibacter, Slackia, Defluviitalea, unclassified Dehalobacteriaceae, and Oribacterium, while increasing the abundance of Streptococcus, Ruminococcus (Lachnospiraceae), Megasphaera, Actinomyces, and Granulicatella[40,47]. Imhann et al[48] suggested that the impact of PPIs on the gut microbiota is more significant than that of antibiotics or other commonly used drugs. Their study has demonstrated that in long-term PPI users, the abundance of genera Enterococcus, Streptococcus, Staphylococcus, and the potentially pathogenic species Escherichia coli significantly increased, while that of Bifidobacterium decreased.

Impact of PPIs on the intestinal mucosal barrier

It is necessary to maintain the complete composition and function of the intestinal mucosal barrier for normal physiological and immune homeostasis in the intestine. Increasing evidence suggests that defects in the intestinal barrier may contribute to inflammatory activation, particularly in IBD[49,50]. The disruption of the intestinal mucosal barrier, such as that of the tight junction (TJ) barrier, plays a significant role in the pathogenesis of IBD[51,52]. Nighot et al[52] demonstrated that long-term use of PPIs could increase the permeability of the intestinal TJ and exacerbate experimental colitis. Myosin light chain kinase (MLCK) is a key regulator of barrier dysfunction[53]. MLCK can increase the permeability of TJ by rearranging the actin cytoskeleton[52,53]. PPI-induced increase in extracellular pH activates and upregulates MLCK expression via p38 MAPK, leading to an increase in the permeability and disruption of the TJ barrier (Figure 3). This increased extracellular pH may also promote an increase in the concentration of intracellular calcium, which plays a crucial role in MLCK activation (Figure 3)[54-56]. However, some experts also believe that PPIs can block calcium-ion channels in smooth muscles, inhibit the influx of calcium ions into cells, and result in dose-dependent relaxation of smooth muscles[57]. This PPI-induced inhibition of the contractile activity of smooth muscles may have a significant impact on intestinal permeability and the gut microbiota. This PPI-induced alteration of intracellular calcium concentration needs to be further evaluated. A decrease in pH can inhibit the growth of pathogenic Escherichia coli under simulated intestinal conditions[58]. However, the PPI-induced increase in pH may alter the intestinal microbiome by increasing the number of Gram-negative bacteria[59]. Therefore, PPI-induced alteration of the gastrointestinal luminal pH can cause dysbiosis of the intestinal microbiome, resulting in increased intestinal permeability (Figure 3)[52].

Figure 3 Impact of proton pump inhibitors on the intestinal mucosal barrier. Proton pump inhibitors (PPIs) can increase the permeability of the intestinal tight junction (TJ) by activating myosin light chain kinase (MLCK). Increased extracellular pH induced by PPIs activates and upregulates MLCK expression via p38 MAPK. PPIs may promote an increase in intracellular calcium concentration, which also plays a crucial role in MLCK activation. Additionally, the PPI-induced increase in pH may increase the number of Gram-negative bacteria and cause dysbiosis of the intestinal microbiome, resulting in increased intestinal permeability. The intestinal microbiota translocases through the TJ and stimulates the immune system to induce or exacerbate inflammatory bowel disease. PPI: Proton pump inhibitor; MLCK: Myosin light chain kinase.

Son et al[60], through an animal experiment using the dextran sodium sulfate-induced colitis model, demonstrated that tegoprazan, a new potassium-competitive acid blocker, could reduce intestinal permeability and upregulate the expression of TJ proteins zonula occludens 1 and occludin. In contrast, rabeprazole did not alleviate the damage to the intestinal barrier. In fact, it tended to deteriorate the barrier function in a dose-dependent manner. Son et al[60] emphasized that, contrary to rabeprazole, tegoprazan could directly protect the intestinal barrier function. However, another animal experiment showed that lansoprazole could alleviate intestinal mucosal damage in IBD rats by reducing the levels of myeloperoxidase and superoxide dismutase and by restoring the levels of colonic nitric oxide[61]. At present, these studies are limited to animal experiments. Further research and observation are needed to determine whether the same effects occur in humans as well and to explore possible mechanisms involved.

Impact of PPIs on immune cell function

Immune cells play a crucial role in maintaining intestinal homeostasis. Any alterations or imbalances in their function may contribute to the development of IBD. The major players in IBD include intestinal epithelial cells, macrophages, dendritic cells, adaptive immune cells, and innate lymphoid cells, all of which are critical for maintaining the immune function at mucosal surfaces[62]. PPIs have antioxidant and anti-inflammatory properties and can act on various types of cells, including immune, vascular endothelial, and epithelial cells[63]. PPIs can affect the functions of neutrophils, such as chemotaxis and degranulation, and reduce the production of reactive oxygen species both inside and outside the neutrophils, which reduces their bactericidal activity[64,65]. Additionally, PPIs can inhibit the expression of adhesion molecules, thereby weakening the adherence of neutrophils to endothelial cells and suppressing their inflammatory activity[66]. PPIs can also decrease the number of peripheral blood monocytes and intercellular adhesion molecule-1-positive mononuclear cells, affecting the transmigration of leukocytes from blood vessels to inflammatory sites[23,64,65]. Furthermore, it should be noted that H⁺/K⁺ ATPase is not only found in parietal cells but also in neutrophils, myelomonocytes, and the colon[23]. PPIs may directly or indirectly affect these ATPases through various processes.

Impact of PPIs on IBD treatment drugs

Drug interactions can significantly affect the efficacy of IBD drug therapy, particularly in elderly individuals who are often on multiple medications[67]. PPIs can also alter the concentration of other pharmacologically active molecules in the blood by affecting the pharmacodynamics or pharmacokinetics of these drugs[68]. One possible mechanism underlying the interactions between PPIs and other drugs is the increase in gastric pH caused by PPI administration. For instance, mesalazine, a basic drug used to treat IBD, requires reaching the lower segments of the gut to exert its therapeutic effects. The delivery systems for mesalazine include pH-dependent release, time-dependent release, and combined mechanisms[69]. Van Camp et al[70] demonstrated that pre-treatment with PPIs could accelerate the absorption of mesalazine (pH-dependent release) and increase its systemic exposure (time-dependent release). The faster release of mesalazine in the gastrointestinal tract and/or its increased systemic absorption following PPI pre-treatment may hinder its ability to reach the colon. It is also important to consider potential drug interactions involving the CYP system because PPIs are metabolized through this system. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are primarily metabolized by the CYP3A4/5 enzyme system in the liver. Omeprazole, a substrate and inhibitor of the CYP2C19 and CYP3A4 enzymes, may increase the plasma concentration of tacrolimus because of the competition for CYP3A4 or genetic polymorphism of the CYP2C19 isoform[71]. Additionally, PPIs may generate drug interactions by affecting transporters or the P-glycoprotein pathway. Methotrexate (MTX), which is commonly used in IBD patients with thiopurine intolerance, is eliminated through active tubular secretion via organic anion transporter 3 (OAT3). PPIs can increase the plasma MTX levels by inhibiting OAT3[72,73].

CLINICAL EPIDEMIOLOGY OF THE EFFECTS OF PPIS ON IBD

Effect of PPIs on the risk of IBD

In 2006, Aberra et al[74] proposed that the suppression of gastric acid could increase the risk of flares in patients with IBD. Although this case-crossover study was only published as an abstract, it suggested a significant impact of the widespread use of PPIs on the development of UC. Increasingly more studies, including observational studies, are now investigating the relationship between PPIs and the risk of IBD. However, the conclusions remain somewhat controversial.

A nested case-control study conducted in 2019 included 285 new cases of pediatric IBD aged ≤ 21 years and 4 matched control groups from 1996 to 2016. The study explored the relationship between acid-suppression therapy and the risk of developing pediatric IBD[75]. Logistic regression model calculations revealed that early-life PPI use was significantly correlated with the subsequent increase in the risk of developing IBD [adjusted odds ratio (OR) = 3.6, 95% confidence interval (CI): 1.1-11.7]. However, the association between histamine-2 receptor antagonists (H₂RAs) and IBD was weak (adjusted OR = 1.6, 95%CI: 0.7-3.7), despite similar indications for PPIs and H₂RAs[75]. In addition, the limited sample size and inclusion of only pediatric cases weakened the conclusiveness of the findings. Similarly, Xia et al[30] conducted a large-scale prospective cohort study on 647407 individuals from the Nurses’ Health Study and the United Kingdom Biobank. They demonstrated that regular PPI users had a higher risk of developing IBD compared to non-users [hazard ratio (HR) = 1.42, 95%CI: 1.22-1.65], with PPI use being associated with a higher risk of developing IBD than H₂RA use (HR = 1.38, 95%CI: 1.16-1.65)[30]. The authors adjusted for lifestyle factors, PPI indications, comorbidities, and other medications to mitigate confounding and bias. A population-based study involving 45586150 patients and using multivariate regression analysis showed a significant association between PPI use and the risk of developing UC and CD, after adjusting for common risk factors[31]. Shastri et al[32] conducted a meta-analysis of eight observational studies comprising 157758 participants to evaluate the use of PPIs and the risk of IBD. They revealed that PPI users have a significantly higher risk of IBD (adjusted OR = 2.43, 95%CI: 1.18-5.02). A subgroup analysis showed that collagenous colitis (CC) and lymphocytic colitis (LC) can be considered attenuated forms of IBD[76]. The significant correlations between PPI exposure and the risk of CC and LC were 4.73 (95%CI: 1.99-11.22) and 3.77 (95%CI: 2.91-4.87), respectively. All the evidence presented above strongly supports the significant link between PPI use and the risk of developing IBD.

However, some researchers hold different perspectives. Abrahami et al[77] argue that the previous observational study[30] may have had methodological shortcomings resulting in bias, which may have potentially altered the conclusion. Abrahami et al[77] studied 1498416 individuals who initiated PPIs and 322474 individuals who initiated H₂RAs from 1990 to 2018. To specifically address any protopathic bias, they conducted an early-event analysis for a maximum of 2 years after cohort entry and repeated the analysis after a 2-year lag of cohort entry for late-event analysis. The early-event analysis showed that the use of PPIs was associated with an increased risk of IBD within the first 2 years of treatment initiation compared to that observed with H₂RAs (HR = 1.39, 95%CI: 1.14-1.69). In contrast, the late-event analysis did not show a significant association between PPI use and IBD incidence (HR = 1.05, 95%CI: 0.90-1.22). The second analysis involving duration-response and dose-response relations, PPI type-specific effect, effect measure modification analysis by age and impact of smoking did not yield significant findings. The findings of the sensitivity analysis were consistent with those of the primary analysis. Therefore, Abrahami et al[77] concluded that PPIs were not associated with the incidence of IBD after accounting for protopathic bias. Singh et al[47] studied 5920 individuals to investigate the link between PPI use and the diagnosis of IBD. They found that patients with IBD had higher rates of PPI use, reaching 17% within 1 year before IBD diagnosis [relative risk (RR) = 3.08, 95%CI: 2.9-3.3]. Hence, they suggested that PPI use might increase the risk of IBD, or patients with IBD might have more upper gastrointestinal complaints that led to increased use of PPIs, or PPIs might be prescribed to manage certain IBD symptoms, whether clinically warranted or not.

The conclusions drawn from the current research are not entirely consistent. The reasons for these differences are not completely clear, although it is suggested that these differences could arise owing to variations in the research methods applied, sample sizes, and other potential confounding factors. However, it is necessary to remind clinical physicians to exercise caution when prescribing PPIs, as they may be associated with a risk of developing IBD. This relationship needs to be further confirmed through rigorous, large-scale, multicenter, and prospective studies.

Effect of PPIs on the severity of IBD

IBD is characterized by a chronic relapse of inflammation of the intestines. However, the factors associated with IBD flares are not yet well understood. The use of concurrent medications for non-IBD indications may affect the clinical course of UC or CD[64]. Multiple observational studies have reported that the use of acid inhibitors, such as PPIs, may alter the course of IBD, resulting in increased disease severity and a lower remission rate[64,78]. A case-control study conducted in the United States, which included 58459 IBD patients, suggested an association between PPIs and an increased risk of IBD-related hospitalization or surgery in patients with UC [adjusted incidence density ratio (IDR) = 1.11, 95%CI: 1.02-1.21] as well as in those with CD (adjusted IDR = 1.12, 95%CI: 1.02-1.22) after adjusting for multiple variables, such as age, gender, race, and other medications[78]. However, another cohort study involving 16151 patients with IBD showed no significant correlation between the use of PPIs and severe events related to IBD (hospitalization/surgery) (RR = 1.20, 95%CI: 0.80-1.81); however, it did suggest a link between PPI use and medication change in UC (RR = 1.39, 95%CI: 1.20-1.62)[64]. Although the reason for this discrepancy is unclear, the larger sample size and nested case-control design may have efficiently identified the exposure before the outcome and reduced the impact of confounding factors. More prospective studies are needed to confirm these findings. A recent real-world study conducted in the US evaluated the influence of PPI use on the clinical outcomes of IBD patients[79]. This US study identified 46234 IBD patients, of whom 6488 used PPIs, while the remaining (39746 patients) did not use them. Compared to patients not on PPI therapy, those on concurrent PPI therapy were at a higher risk of developing undesirable clinical outcomes, such as new biologic initiation (OR = 1.11, 95%CI: 1.04-1.18), IBD-related admissions (OR = 1.95, 95%CI: 1.74-2.19), and surgeries (OR = 1.46, 95%CI: 1.26-1.71). Additionally, a dose-response relationship was noted between the number of PPI prescriptions and an increased risk of new biologic use and IBD-related admissions[79]. Hence, caution should be exercised when prescribing PPIs to IBD patients.

Calprotectin is a damage-associated molecular-pattern protein with antimicrobial protective properties. It is mainly found in the cytosol of human neutrophils and macrophages[80]. Fecal calprotectin (FC) is a sensitive marker of colonic inflammation. FC levels are closely related to the degree of inflammatory activity in IBD patients. In 2003, Poullis et al[81] proposed that the use of PPIs may significantly elevate FC levels, adversely affecting the specificity of the FC test in detecting gastrointestinal inflammation. A cross-sectional study involving 590 subjects demonstrated a significant relationship between PPI use and elevated FC levels (> 50 μg/g) (adjusted OR = 3.843, 95%CI: 2.338-6.316)[82]. PPI-induced elevation in FC levels might lead to a false-positive indication of IBD activity. Hence, it is essential to understand whether the increased FC level is caused by IBD activity or PPI use in clinical practice.

Effect of PPIs on the therapeutic impact of IBD

Significant progress has been made in the treatment of IBD in the last two decades. The development of novel biologics that can target key pathways in the inflammatory response has been instrumental in this progress. This has brought new hope for the treatment of IBD. The introduction of infliximab (IFX), the first anti-tumor necrosis factor on the market, has greatly improved the clinical remission rate of IBD, leading to the widespread use of biologics in IBD treatment[83]. However, the impact of combining PPIs with biologics on the efficacy of IBD treatment has not yet been clearly elucidated.

A meta-analysis of randomized controlled studies by Lu et al[84] showed that a combination of PPIs and IFX was significantly less effective in achieving remission at week 30 compared to the IFX treatment alone, according to multivariable analysis (OR = 0.45, P < 0.001). When the data for UC and CD were analyzed separately, a statistically significant difference was noted among CD patients using IFX and PPIs (OR = 0.39, P < 0.001); however, the findings did not reach significance in UC patients (OR = 0.57, P = 0.092). Furthermore, at week 54, a statistically significant difference was observed in the remission rate between patients using PPIs and those who did not (40% vs 62%, P < 0.001). Additionally, patients using PPIs were more likely to be hospitalized (15% vs 8%, P = 0.007). These results suggest that IBD patients using PPIs may have a lower likelihood of achieving remission while on IFX therapy. This association remained significant even after adjusting for confounders through multivariable analysis and propensity score-matched analysis. Further prospective research is needed to explore potential mechanisms.

The latest nationwide multicenter cohort study from Hungary showed that the co-administration of PPIs may negatively affect the outcome in patients with IBD on vedolizumab (VDZ)[85]. In this study, PPI use was identified in 108 of the 240 IBD patients with VDZ treatment[85]. Patients on concomitant corticosteroid treatment without PPIs were more likely to have a clinical response at week 14 than the patients on concomitant PPIs (95% vs 67%, P = 0.005). Compared to smokers, non-smokers receiving VDZ treatment were more likely to show a clinical response at week 14, particularly those not receiving PPI compared to patients on co-administered PPI therapy (81% vs 53%, P = 0.041, and 92% vs 74%, P = 0.029, respectively). The authors conducted a post-hoc analysis and showed that in patients receiving VDZ treatment, PPI use may impair the achievement of response in certain subgroups. Therefore, any inappropriate use of PPIs in IBD patients must be avoided, especially in patients without gastrointestinal risk factors who were taking corticosteroids alone.

SUGGESTIONS FOR THE USE OF PPIS IN PATIENTS WITH IBD

It is widely recognized that PPIs are comparatively safe. They are commonly prescribed in clinical practice for patients with IBD. The use of PPIs in IBD patients has been increasing of late for several reasons. Firstly, CD can affect the entire gastrointestinal tract, including the esophagus and stomach. Patients with erosion and ulcers in the upper gastrointestinal tract may experience symptoms, such as upper abdominal pain[86]. Moreover, IBD can result in impaired motility of the small intestine, leading to delayed gastric emptying and an increased likelihood of gastroesophageal reflux[47]. Therefore, PPIs are prescribed to control ulcers or reflux in the upper gastrointestinal tract caused by IBD. Secondly, PPIs are often used to inhibit acid production and protect the stomach in IBD patients receiving corticosteroid therapy to reduce inflammation. Corticosteroids can increase the levels of gastric acid and pepsin, which can induce and worsen gastrointestinal ulcers, leading to symptoms, such as upper abdominal pain[87]. Patients are often prescribed PPIs, sometimes at high doses, throughout the course of corticosteroid therapy. Thirdly, PPIs are frequently prescribed for IBD-related symptoms, regardless of whether the patients have actually been diagnosed with gastric acid digestive disease, leading to their overuse. Even though PPIs are not currently included in the guidelines for IBD treatment, many patients continue to use them routinely.

The relationship between PPI use and IBD has attracted significant attention from scholars[19,20]. The current research suggests that long-term use of PPIs may increase the risk of developing IBD, affect the severity of the disease, and even impact the effectiveness of treatment drugs. It is important to regulate the use of PPIs and minimize their impact on IBD patients. Firstly, a time limit should be defined for the long-term use of PPIs in IBD patients. A meta-analysis showed that the duration of long-term PPI use ranged from 2 to 7 years, with the most common definition being ≥ 6 months[88]. However, the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends that elderly patients should avoid using PPIs for more than 8 wk[89]. IBD patients who require PPIs should use them for as short a period as possible to avoid potential long-term effects. Secondly, the indications for PPI use in IBD patients should be clearly defined. PPIs are primarily used to treat gastrointestinal disorders related to acid secretion[90]. Therefore, before prescribing PPIs, it is important to determine whether IBD patients have upper gastrointestinal symptoms caused by increased gastric acid secretion. Lee et al[91] found that, compared to the general population, IBD patients have more severe abdominal pain, gas/bloating, diarrhea, and bowel incontinence, but less severe gastroesophageal reflux and swallowing difficulties. Therefore, most IBD patients may have more involvement in the lower digestive tract. The indications for PPI use should be carefully reviewed before prescribing PPIs. Lastly, the dosage and frequency of PPIs for IBD patients should be tailored to each individual. Typically, PPIs are prescribed at a standard dose, once or twice a day, depending on the condition. For patients with gastroesophageal reflux disease, the dosage or frequency of PPI use may be relatively high[92]. To prevent stomach symptoms caused by corticosteroids, a standard daily dose of PPIs is usually prescribed. When IBD patients require PPI treatment, the prescription should be personalized based on their specific condition. It is still not clear how long-term use of PPIs impacts IBD, such as the exact mechanism by which PPIs affect IBD and variations in effects among different types of PPIs. Further research is needed on the use of PPIs in IBD to enable their standardized and rational application.

CONCLUSION

PPIs are extensively utilized worldwide for treating patients with IBD. However, excessive or inappropriate use of PPIs in the management of IBD has created many problems. Although PPIs are generally considered safe, numerous studies have demonstrated their potential adverse effects on patients. The present study reviewed the potential impact of PPIs on the risk, severity, and pharmacotherapy of IBD. Additionally, we summarized the possible mechanisms through which PPIs may affect IBD. Based on our results, we suggest that physicians should exercise caution when prescribing PPIs to patients with IBD. Research on the effects of PPIs on IBD is still in its preliminary stages. Large-scale, multicenter, prospective studies are needed to clarify the relationship between PPIs and IBD. Further research is also necessary to elucidate the underlying mechanisms. Therefore, it is crucial to continue monitoring the effects of PPIs on IBD to ensure their safe and appropriate use.

ACKNOWLEDGEMENTS

The authors thank all members of the Department of Gastroenterology and Department of Pharmacy for assistance in various aspects of this work.