The Controversies of the Relationship Between Helicobacter Pylori Infection and Inflammatory Bowel Disease: A Review

1. Introduction

Helicobacter pylori (H. pylori) has co-evolved with humans for over 60,000 years [1] and was first successfully isolated from a gastric biopsy in 1983 by Marshall and Warren [2]. This spiral-shaped, microaerophilic, Gram-negative bacterium infects more than 50% of the global population [3]. Its prevalence is positively correlated with advancing age and lower socioeconomic status, although substantial geographic and demographic variations exist due to environmental and population-specific factors [4]. Early-life conditions, particularly poor hygiene and overcrowded living environments during childhood, have been identified as key risk factors for acquisition of the infection [5,6].

H. pylori is primarily transmitted via oral-oral and fecal-oral routes, with contaminated water sources also recognized as a potential vehicle for transmission [7]. Infection typically occurs during childhood and, in the absence of treatment, tends to persist throughout the host’s lifetime [8].

Clinically, H. pylori is associated with a wide spectrum of gastrointestinal and extra-gastrointestinal diseases. These include peptic ulcer disease, autoimmune gastritis, and gastric malignancies including mucosa-associated lymphoid tissue (MALT) lymphoma and adenocarcinoma, as well as conditions such as iron deficiency anemia, vitamin B12 deficiency, and idiopathic thrombocytopenic purpura [9,10]. Also, increasing evidence has suggested a potential association between H. pylori infection and several autoimmune diseases. It has been reported a higher prevalence of H. pylori infection among patients with autoimmune conditions compared to the general population [11]. One of the most thoroughly investigated associations is with idiopathic thrombocytopenic purpura (ITP), where several clinical studies have shown that eradication of H. pylori can lead to a significant increase in platelet counts in a subset of patients. A similar trend has been observed in autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves' disease, where H. pylori infection appears more frequently in affected individuals than in healthy controls. Elevated rates of infection have also been reported in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis, and primary Sjögren’s syndrome [11].

Interestingly, some studies have demonstrated an inverse association between H. pylori colonization and the incidence of certain autoimmune diseases, particularly inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. In these cases, H. pylori infection was significantly less common in affected individuals compared to control populations, leading to hypotheses regarding a possible protective role [12].

While the exact nature of the relationship remains unclear, current literature supports a statistically significant association between H. pylori infection and various autoimmune conditions. These findings highlight the need for further research to clarify potential causality and to evaluate the clinical relevance of screening or treating H. pylori infection in patients with autoimmune diseases.

Inflammatory bowel disease (IBD) is a chronic, relapsing-remitting inflammatory disorder of the gastrointestinal tract, encompassing Crohn’s disease (CD), ulcerative colitis (UC), and other related entities [13]. The hallmark feature of IBD is mucosal inflammation of the intestinal tract, manifesting clinically with abdominal pain, diarrhea, rectal bleeding (hematochezia), weight loss, and histologically with infiltration of neutrophils and macrophages. These immune cells release pro-inflammatory cytokines, proteolytic enzymes, and reactive oxygen species, contributing to tissue injury, ulceration, and progressive mucosal damage [13,14].

IBD typically presents early in life, affects both sexes, and persists throughout the patient's lifetime. Its pathogenesis is multifactorial, involving a complex interplay of genetic susceptibility, environmental influences, and immune system dysregulation. A positive family history is a strong risk factor, indicating a significant genetic contribution. Environmental triggers-such as Westernized diet, smoking, and antibiotic exposure—are believed to disturb the composition of the gut microbiota (dysbiosis), thereby promoting chronic inflammation. Immune dysregulation plays a central role, wherein an aberrant immune response mistakenly targets the intestinal epithelium. The systemic nature of IBD is evidenced by its common extraintestinal manifestations, including arthritis, dermatologic conditions, and hepatobiliary disorders [15].

Since the mid-20th century, the global incidence and prevalence of IBD have increased substantially, making it one of the most common chronic gastrointestinal diseases in the 21st century. Although the incidence in Western countries has plateaued or slightly declined since the 1990s, newly industrialized regions in Asia, Africa, and South America are experiencing a rapid rise in IBD cases [16,17,18]. For instance, the highest prevalence rates have been documented in Europe, with ulcerative colitis reaching 505 per 100,000 individuals in southeastern Norway and Crohn’s disease 322 per 100,000 in Hesse, Germany. Similarly, in North America, ulcerative colitis and Crohn’s disease were reported at 286.3 and 318.5 per 100,000 individuals, respectively, in Olmsted County (USA) and Nova Scotia (Canada) [18]. Despite a decline in the age-standardized incidence rate, the global burden of IBD among the elderly is projected to rise significantly by 2051, necessitating strategic planning for healthcare systems worldwide [19].

Crohn’s disease most frequently involves the terminal ileum, cecum, perianal region, and colon, but it may affect any segment of the gastrointestinal tract in a discontinuous (skip lesion) pattern [15,20,21]. In contrast, ulcerative colitis is characterized by continuous mucosal inflammation beginning in the rectum and extending proximally to varying lengths of the colon [15,20,21]. Histopathological features further distinguish the two conditions: CD demonstrates transmural inflammation, submucosal thickening, fissuring ulcers, and granuloma formation, while UC is confined to the mucosa and submucosa, typically presenting with cryptitis, crypt abscesses, and architectural distortion [15,21,22].

As chronic, immune-mediated disorders, IBDs necessitate lifelong management strategies aimed at achieving and maintaining clinical remission, minimizing flares, and preventing complications. Immunosuppressive and biologic therapies are the cornerstone of treatment, targeting the inflammatory cascade to modulate disease activity.

The coexistence of H. pylori infection and IBD raises important clinical questions. Epidemiological studies consistently report a lower prevalence of H. pylori infection among IBD patients compared to the general population [23]. This observation has been attributed to factors such as frequent antibiotic use in IBD management, immune dysregulation that may impair bacterial colonization, and the altered gut microbiota environment in IBD patients. However, the implications of H. pylori eradication therapy in this population remain unclear, with conflicting evidence regarding its impact on IBD disease activity, symptomatology, and long-term outcomes.

The impact of Helicobacter pylori eradication on inflammatory bowel disease (IBD) activity remains controversial. While some evidence suggests a potential increase in disease relapse following antibiotic therapy, findings are inconsistent. A recent meta-analysis reported a 1.41-fold increased risk of IBD relapse after H. pylori eradication [23]. In contrast, a study by Rosania et al. found no significant recurrence among over 100 IBD patients [24]. Similarly, a large retrospective cohort study in Japan involving more than 400 IBD patients revealed no significant exacerbation of disease activity at two and six months post-eradication therapy compared to controls [25]. Additionally, studies such as that by Lahat et al., which excluded patients with active IBD at baseline, reported no statistically significant changes in clinical indices or inflammatory markers up to eight weeks post-therapy [26]. However, the small sample size in that study limits the generalizability of its conclusions. Collectively, current evidence remains inconclusive, underscoring the need for larger, prospective studies to clarify the relationship between H. pylori eradication and IBD activity.

Despite ongoing research, the implications of Helicobacter pylori eradication for inflammatory bowel disease remain uncertain, especially in the context of disease activity and potential exacerbations. Moreover, eradication of Helicobacter pylori has been considered a potential environmental factor in the development of inflammatory bowel disease, particularly among individuals with underlying genetic susceptibility. This possibility warrants a cautious approach when contemplating eradication therapy in IBD patients and emphasizes the importance of further prospective, controlled investigations into its long-term impact.

This article explores the complexities associated with diagnosing and treating H. pylori infection in IBD patients, with a focus on potential complications, therapeutic strategies, and areas for future research.

2. Materials and Methods

2.1. Information Source and Search Strategies

The aim of this review was to determine: 1) the association between H. pylori infection and inflammatory bowel diseases; 2) the prevalence of H. pylori infection in patients with inflammatory bowel diseases (ulcerative colitis and Crohn's disease), and 3) the impact of H. pylori eradication on the new occurrence of IBD or exacerbation of pre-existing inflammatory bowel disease; 4) and the general cause-and-effect relationship between these two chronic infections of the gastrointestinal tract.

A comprehensive literature search was conducted in PubMed electonic database from inception to 25th May 2025. The MeSH terms used in the search were “Helicobacter pylori”, “inflammatory bowel disease”, “eradication”, “association”. Using the simultaneous combination of these MeSH terms with "AND" as a boolean operator did not get the required research results, so we used a combination of terms “Helicobacter pylori” AND “inflammatory bowel disease” AND “eradication”, and combination of these MeSH terms “Helicobacter pylori” AND “inflammatory bowel disease”, AND “association”.

Only publications in the English language were included. Inclusion criteria encompassed diverse study designs, including Clinical Study, Clinical Trial, Controlled Clinical Trial, Meta-Analysis, Multicenter Study, Observational Study, Randomized Controlled Trial, Review, Systematic Review, to ensure thorough evidence coverage.

The reference lists of the relevant articles were manually searched for additional studies.Only publications in the English language were included and free-full texts manuscripts. There was no restriction on the year of publication for the documents. All included publications were critically reviewed.The summary tables of articles used in this paper are available in the section Results.

2.2. Eligibilty Criteria

Specific inclusion criteria involved human studies with adult and pediatric study populations and animal studies, too. Clinical study, clinical trial, controlled clinical trial, meta-analysis, multicenter study, observational study, randomized controlled trial, review and systematic review written in English with free full text availability are included in our review.

Exclusion criteria for this review were delineated as follows: (1) studies with primary endpoints not aligned with the scope of this review, (2) books and documents, letter, commentaries, preprint, case reports, and case series, (3) in vitro studies, (4) studies published in languages other than English, (5) articles without full-text availability.

3. Results

Using MeSH terms “Helicobacter pylori” AND “inflammatory bowel disease” AND “eradication” the article search identified twenty-six relevant full-text articles from the PubMed electronic database, of witch sixteen articles met the full inclusion criteria [12,23,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. By searching electonic database PubMed using MeSH terms “Helicobacter pylori” AND “inflammatory bowel disease” AND “association” we have identified seventy six full text articles. After elimination of duplicate articles with the first search and identification of additional manuscripts, twenty-four studies that met the full inclusion criteria for this article were retrieved and fully reviewed [11,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65].

Summarizing all forty selected articles for this article, 18 review articles, 9 meta-analyses, 4 systematic reviews, 1 umbrella review of meta-analyses, 2 bibliometric analysis, 3 multicenter studies, and 3 observational studies were included in this review.

See the results in the Table 1.

Research into the relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) began to take shape around 2009 and has gained momentum over the years. Since then, interest in this topic has grown steadily, with a marked increase in studies exploring possible protective, immunological, and microbial mechanisms. Importantly, many of these studies are based on high levels of evidence, including numerous systematic reviews and meta-analyses. These consistently show a lower prevalence of H. pylori infection in IBD patients across various populations and settings. The fact that such findings are replicated across different study designs and regions strengthens the validity of this association. Together, the accumulated evidence points to a meaningful biological link that warrants further investigation.

4. Discussion

The coexistence of Helicobacter pylori infection and Inflammatory Bowel Disease (IBD) presents a unique set of challenges that complicate both diagnosis and management. While H. pylori is a recognized pathogen implicated in significant gastric morbidity, its relationship with IBD remains controversial. The lower prevalence of H. pylori in IBD patients, consistently reported across multiple studies, raises questions about potential protective roles or interactions between the bacterium and host immunity [11,12,23,31,33,34,35,37,38,39,43,44,46,47,48,49,50,51,52,55,56,57,58,59,60,61,62,63]. This phenomenon has been attributed to several factors, including extensive antibiotic use in IBD management, immune modulation associated with chronic inflammation, and dysbiosis of the gut microbiota. The frequent use of antibiotics, particularly broad-spectrum agents during IBD flares or for perioperative prophylaxis in Crohn’s disease, likely contributes to the observed lower colonization rates. However, this reduced prevalence may not uniformly translate into clinical benefit, as it introduces unique diagnostic and therapeutic challenges.

From a diagnostic perspective, the accuracy of non-invasive tests for H. pylori, such as the urea breath test (UBT) and stool antigen test, is diminished in IBD patients due to confounding factors such as active intestinal inflammation and the use of proton pump inhibitors (PPIs). These medications, commonly prescribed for upper GI symptoms in IBD patients, suppress bacterial load and gastric acidity, leading to false-negative test results. Endoscopic biopsy remains the gold standard for diagnosis, offering the opportunity for histological examination and culture, but the invasive nature of this procedure poses risks for IBD patients, particularly during active disease. Moreover, in patients with Crohn’s disease involving the upper GI tract, the differentiation between H. pylori-related gastritis and Crohn’s-associated gastroduodenitis adds an additional layer of complexity.

Therapeutically, H. pylori eradication in IBD patients necessitates a nuanced approach, balancing the benefits of eradication against the potential risks of exacerbating IBD symptoms. Therapy consisting of a PPI, clarithromycin, and amoxicillin, achieves eradication rates of approximately 70–80% in the general population. However, rising rates of antibiotic resistance, particularly to clarithromycin and metronidazole, reduce the efficacy of these regimens in IBD patients, many of whom have been exposed to antibiotics for disease management [64]. Bismuth-containing quadruple therapy or regimens tailored based on antibiotic susceptibility testing may be required in these cases.

A critical concern in IBD patients undergoing H. pylori eradication therapy is the potential for antibiotic-induced gut microbiota disruption. Dysbiosis, a hallmark of IBD, may be exacerbated by the broad-spectrum antibiotics used in eradication therapy, leading to disease flares or worsening symptoms. Oral supplementation with a narrow spectrum of Gram-positive bacteria has shown clinical improvement in H. pylori-related symptoms, yet microbiota alterations may predispose individuals to intestinal or systemic diseases later in life. Emerging evidence suggests that using multi-strain probiotics or paraprobiotics, rather than single-strain formulations, may help reduce the incidence of metabolic disturbances associated with dysbiosis [65].

Considering the diverse effects of different bacterial strains, high-throughput sequencing technologies are essential for characterizing microbiota changes at the strain level and personalizing probiotic interventions. Furthermore, next-generation probiotics and genetically modified microorganisms are being explored to enhance clinical outcomes, either by restoring disease-specific bacterial taxa or by producing therapeutic compounds such as antimicrobial peptides. Innovations such as microencapsulation and nanotechnology are also being developed to optimize probiotic delivery and minimize adverse metabolic effects. These advances may offer promising adjuncts in managing H. pylori eradication in the context of IBD [66]. Additionally, PPIs-an essential component of H. pylori therapy-may interact with immunosuppressive agents such as azathioprine, methotrexate, or biologics, potentially altering their pharmacokinetics and efficacy. The impact of H. pylori eradication on IBD activity remains debated. Some articles suggest that H. pylori colonization may exert an immunomodulatory effect by reducing pro-inflammatory cytokine production and promoting regulatory T-cell activity [67,68]. Consequently, eradication might remove this protective mechanism and exacerbate IBD symptoms. Conversely, H. pylori may aggravate upper GI symptoms in IBD patients, including dyspepsia or gastric ulceration, thereby impairing quality of life and complicating disease management.

In light of these complexities, a tailored approach to managing H. pylori infection in IBD patients is essential. Routine screening may not be justified in asymptomatic individuals, but targeted testing should be performed in patients with upper GI symptoms, a history of peptic ulcer disease, or those requiring long-term PPI use. Whenever possible, eradication therapy should be timed during IBD remission to minimize the risk of flares. A multidisciplinary approach involving gastroenterologists, microbiologists, and clinical pharmacologists is recommended to optimize outcomes and mitigate risks.

Future research should focus on the long-term impact of H. pylori eradication on IBD progression, microbiota composition, and patient quality of life. Large-scale studies using germ-free mice colonized with human microbiota, as well as clinical trials combining broad-spectrum antibiotic regimens with targeted probiotic interventions, are needed to better understand the role of microbiome modulation in this population. The integration of novel diagnostic tools and personalized medicine strategies holds the potential to transform the management of H. pylori in the context of IBD and improve clinical outcomes for this unique patient group.

5. Conclusions

While Helicobacter pylori eradication offers clear oncological benefits-most notably in the primary and secondary prevention of gastric cancer-it presents a distinct set of challenges in patients with inflammatory bowel disease (IBD). Among the most pressing concerns is the possibility of triggering de novo IBD or exacerbating existing disease following eradication therapy. Although an association has been reported in several observational studies, the causal relationship and underlying mechanisms remain poorly defined. Notably, current international guidelines do not offer specific recommendations regarding H. pylori management in patients with IBD (10). This omission highlights a significant gap in clinical guidance and underscores the importance of further research in this area, particularly given the increasing global burden of IBD and the widespread implementation of H. pylori screening and treatment programs. An important, yet often overlooked, aspect is the disease stage at the time of eradication. Patients in clinical or endoscopic remission may respond differently to microbiota-altering antibiotic regimens compared to those with active inflammation. The degree of mucosal integrity, immune activation, and underlying dysbiosis likely modifies the host response to such perturbations. In clinical practice, this makes timing a critical variable that should be factored into therapeutic decision-making. The patient’s current IBD treatment regimen also warrants close attention. Use of corticosteroids, immunomodulators, or biologic agents could influence not only the immune response to eradication therapy but also the risk of opportunistic infections such as Clostridioides difficile (27). Furthermore, these treatments might dampen typical clinical signs of infection or inflammation, complicating post-eradication monitoring. Another important consideration is the history of prior H. pylori eradication attempts. Whether the current therapy is first-line or a salvage regimen will influence the selection of antibiotics, resistance profiles, and the expected degree of microbiota disruption. These variables are not trivial; they may significantly affect IBD stability, symptom recurrence, or the risk of treatment-related adverse events. From a clinical and research standpoint, it is essential to move beyond population-level data and adopt a more individualized approach. Future studies should stratify patients based on IBD phenotype, disease activity, current immunosuppression, and eradication history. Rigorous prospective trials using validated clinical, endoscopic, and biochemical endpoints are urgently needed to elucidate risk profiles and optimize treatment strategies. In countries where H. pylori screening is employed as a public health measure to reduce gastric cancer incidence, clinical guidelines must be adapted for patients with IBD. These should incorporate stratification models that account not only for cancer risk but also for potential immunological and microbiome-mediated effects unique to this population. Clinicians also need practical tools to differentiate between genuine IBD flares and predictable adverse effects of eradication therapy. Conversely, decisions to withhold H. pylori treatment due to concerns about disease destabilization or C. difficile infection must be supported by robust, patient-specific risk–benefit assessments. Ultimately, the management of H. pylori in the context of IBD sits at the intersection of gastroenterology, microbiology, and immunology. It demands a nuanced approach, informed by both high-quality evidence and careful clinical judgment. This evolving field offers significant opportunities-not only to improve outcomes for a vulnerable subgroup of patients, but also to deepen our understanding of host–microbiome interactions in immune-mediated disease.

6. Future Directions

Future research should aim to clarify the causal mechanisms underlying the inverse association between Helicobacter pylori infection and inflammatory bowel disease (IBD), with particular focus on the immunological and microbiome-related pathways involved. It remains important to determine whether the observed relationship reflects a true biological interaction or is influenced by confounding factors such as antibiotic use, disease severity, or treatment history. Further investigation into the role of specific H. pylori strains, host genetics, and environmental exposures could provide deeper insight into the variability seen among patients. Additionally, studies assessing the impact of H. pylori eradication on IBD activity, therapeutic response, and gut microbial balance will be essential for informed clinical management. Incorporating microbiome analysis, immune profiling, and precision medicine strategies may help identify patient subgroups that could benefit from personalized approaches. A clearer understanding of this complex interplay could ultimately refine both diagnostic and therapeutic practices in IBD care.