Association between Helicobacter pylori infection and metabolic dysfunction-associated steatohepatitis: From an analysis of a population-based study

Abstract

The growing global burden of metabolic dysfunction-associated steatohepatitis (MASH) demands a deeper understanding of its underlying mechanisms and risk factors. Recent studies, such as the large population-based case-control analysis by Abdel-Razeq et al, suggest a significant association between Helicobacter pylori (H. pylori) infection and an increased risk of developing MASH. This study provides compelling data supporting this association, even after adjusting for confounders such as obesity, diabetes, and hyperlipidemia. However, the complexity of this relationship remains unresolved, requiring further investigation into the biological, genetic, and environmental pathways that connect these two conditions. This article critically reviews the study’s findings and identifies its limitations, offering innovative research directions for the future. Key areas of focus include integrating genomic and microbiome analyses, exploring the impact of H. pylori eradication on MASH progression, studying molecular mechanisms at the intersection of infection and liver disease, and developing personalized therapeutic strategies.

Key Words: Helicobacter pylori infection; Metabolic dysfunction-associated steatohepatitis; Metabolic dysfunction-associated steatotic liver disease; Non-alcoholic fatty liver disease; Innovative research directions

Core Tip: The association between Helicobacter pylori (H. pylori) infection and metabolic dysfunction-associated steatohepatitis (MASH) highlights a potentially significant but complex relationship. This article critically reviews recent findings and proposes innovative research directions, including genetic and microbiome studies, longitudinal evaluations of H. pylori eradication effects on MASH, and mechanistic investigations into inflammation and metabolic pathways. Personalized medicine approaches are also suggested to optimize MASH management based on individual risk factors. These strategies aim to uncover the underlying mechanisms linking H. pylori to liver disease, offering new opportunities for targeted diagnostic and therapeutic interventions in metabolic liver disorders.

TO THE EDITOR

The association between Helicobacter pylori (H. pylori) infection and extra-gastric diseases has been an area of growing interest in medical research. While traditionally associated with gastrointestinal conditions such as gastritis, peptic ulcer disease, and gastric cancer, H. pylori is now being linked to systemic disorders beyond the stomach, including hematologic, dermatologic, ophthalmic, metabolic, neurologic, cardiovascular, allergic, pancreatic, and hepatobiliary diseases[1-3]. Among these, the potential association between H. pylori infection and metabolic dysfunction-associated steatohepatitis (MASH) - the more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) - has been increasingly scrutinized. In 2023, a multisociety Delphi consensus statement proposed a nomenclature change from non-alcoholic fatty liver disease (NAFLD) to MASLD[4]. Maiorana et al[5] reported that H. pylori infection might play a role in the progression of liver injury and fibrosis in MASLD patients with specific genetic predispositions.

The recent largest population-based study by Abdel-Razeq et al[6] in the United States further fully confirmed the potential association. Using a validated multicenter database that spans over 23 years, the study demonstrated that individuals with H. pylori infection had a higher risk of developing MASH compared to non-infected individuals[6]. This risk remained significant even after controlling for major metabolic risk factors such as obesity, diabetes mellitus, and hyperlipidemia[6]. While the study provided important insights, it also raised critical questions about the biological mechanisms that underlay this association and the potential implications for therapeutic interventions. This article critically examines contributions and limitations about the study, and proposes innovative directions for future research that could deepen our understanding of the H. pylori-MASH link. These new perspectives include exploring genetic and microbiome interactions, longitudinal studies on the effects of H. pylori eradication, mechanistic investigations into inflammatory and metabolic pathways, and the application of personalized medicine strategies.

Critical analysis of the study

The study by Abdel-Razeq et al[6] presented a robust analysis of the association between H. pylori and MASH using a large, representative population in the United States. The key strength of the study lied in its comprehensive dataset, which included over 69 million individuals, offering a wide demographic and regional diversity. The use of multivariate regression to adjust for potential confounders such as obesity, type 2 diabetes, hypertension, and hyperlipidemia, enhanced the credibility of the findings. The study revealed that H. pylori infection independently increased the odds of developing MASH by more than twofold (odds ratio: 2.51), adding to the growing body of literature suggesting that chronic infections might contribute to the development of metabolic liver diseases. However, despite its advantages of large sample size and sophisticated analytical approach, the study still has several limitations that must be addressed in future research.

Diagnostic variability and standardization: One of the major limitations in the study is the variability in the diagnostic methods used to detect both H. pylori infection and MASH. H. pylori is diagnosed using a range of techniques, including serology, urea breath tests, and histological examination. Similarly, the diagnosis of MASH is based on diverse methods such as ultrasound, Fibroscan, and liver biopsy. While liver biopsy is the gold standard for diagnosing MASH[7,8], it is fraught with challenges including invasiveness, sampling error, high costs, risk of complications, patient reluctance, and variability in pathologist interpretations. The reliance on non-invasive methods such as biomarkers and non-invasive imaging may not detect the full extent of liver inflammation and fibrosis, which can lead to under- or over-diagnosis of MASH[9]. To overcome this limitation, future studies should aim to standardize diagnostic criteria for both H. pylori infection and MASH. Advances in non-invasive diagnostic techniques, such as elastography and advanced imaging modalities, should be integrated into future research to provide more consistent and accurate diagnoses. Additionally, the use of next-generation sequencing techniques to detect H. pylori and characterize its virulence factors (e.g., cagA, vacA-s1/m1) could help identify subtypes of the infection that are more strongly associated with non-invasive markers of liver injury and fibrosis in patients with MASLD[10].

Cross-sectional nature and causal inferences: The cross-sectional design of the study prevents the establishment of a temporal or causal relationship between H. pylori infection and MASH[6]. While the association is statistically significant, it remains unclear whether H. pylori infection directly contributes to the pathogenesis of MASH or whether both conditions share common risk factors that confound the association. To address this limitation, future research should focus on longitudinal cohort studies that follow patients with H. pylori infection over time to track the development of MASH. These studies could also explore whether eradicating H. pylori reduces the risk or progression of MASH. Longitudinal studies would provide a more definitive understanding of the temporal sequence and causal pathways linking H. pylori to liver disease.

Geographic and genetic variability: While the study based on the population in the United States offers insights into the association between H. pylori and MASH in a Western context, the findings may not be directly applicable to populations in other regions with different genetic backgrounds and environmental exposures. A cross-sectional study in central European showed that H. pylori positivity was not associated with the diagnosis of NAFLD[11]. Both studies in China reported that H. pylori infection was not an independent risk factor for NAFLD[12,13]. However, an updated meta-analysis of observational studies showed that H. pylori infection was associated with a mildly increased risk of prevalent and incident MASLD in middle-aged individuals from different countries[14]. These discrepancies highlight the potential influence of genetic and environmental factors in modulating the relationship between H. pylori and liver disease. Future research should aim to replicate the study’s findings in diverse populations, particularly in regions with high H. pylori prevalence, such as parts of Africa, South America, and Asia. Cross-population genetic studies could also investigate whether specific genetic polymorphisms influence susceptibility to MASH in individuals with H. pylori infection. For example, single nucleotide polymorphisms in genes related to inflammation, lipid metabolism, or insulin signaling may mediate the risk of MASH in the context of chronic H. pylori infection.

Innovative research directions

Building on the findings of Abdel-Razeq et al[6], several innovative research directions could help advance our understanding of the relationship between H. pylori and MASH and open new avenues for therapeutic interventions.

Integration of genomic and microbiome analyses: Recent advances in genomics and microbiome research offer promising tools for investigating the complex interplay between H. pylori infection and liver disease. Future studies could utilize genome-wide association studies to identify genetic variants that predispose individuals to MASH in the presence of H. pylori infection. Specific focus should be placed on genes involved in immune regulation, inflammation, and insulin resistance, as these pathways are critical in the pathogenesis of both MASH and chronic infections. Moreover, metagenomic sequencing of the gut microbiome could shed light on how H. pylori infection alters the composition of the gut microbiota and its metabolites, potentially contributing to liver fat accumulation and inflammation. Gut dysbiosis has been implicated in the development of NAFLD and MASH[15], and H. pylori infection may exacerbate this dysbiosis. Identifying microbial signatures associated with H. pylori and MASH could pave the way for novel microbiota-based therapies, such as probiotics or fecal microbiota transplantation, to mitigate the risk of liver disease in infected individuals.

Longitudinal studies on H. pylori eradication and MASH progression: One of the most pressing questions raised by the study is whether eradicating H. pylori can prevent or reverse MASH progression[6]. Longitudinal studies should be designed to follow patients with H. pylori infection before and after eradication therapy, monitoring changes in liver fat, inflammation, and fibrosis over time. These studies could utilize non-invasive imaging techniques, such as magnetic resonance elastography, to assess liver health in response to H. pylori eradication. In addition to clinical outcomes, these studies should examine changes in systemic and hepatic biomarkers of inflammation, insulin resistance, and lipid metabolism. If H. pylori eradication leads to improvements in these markers, it could provide strong evidence for including H. pylori treatment in the management of MASH. Stratifying patients by baseline characteristics, such as the presence of metabolic syndrome or genetic risk factors, could also help identify subgroups that are most likely to benefit from eradication therapy.

Mechanistic studies to elucidate the biological pathways linking H. pylori and MASH: While the study suggests that chronic inflammation and insulin resistance are key mediators of the association between H. pylori and MASH, the precise molecular mechanisms remain unclear[6]. Mechanistic studies using animal models and in vitro cell culture systems could help elucidate the pathways through which H. pylori infection promotes liver disease. Key areas of focus should include: (1) Inflammatory signaling: Investigating how H. pylori infection activates inflammatory pathways in the liver, such as the nuclear factor kappa B and c-Jun N-terminal kinase signaling cascades, which are known to induce hepatic inflammation and fibrosis[16]. The role of cytokines, such as TNF-α, IL-6, and IL-8, in mediating these effects should also be explored; (2) Insulin resistance: Understanding how H. pylori infection affects insulin signaling in the liver, potentially leading to increased lipogenesis and impaired glucose metabolism. Research should focus on identifying key metabolic regulators that are altered by the infection, such as AMP-activated protein kinase and peroxisome proliferator-activated receptors; and (3) Epigenetic modifications: Examining whether H. pylori infection induces epigenetic changes in hepatocytes, such as DNA methylation or histone modifications, which may alter the expression of genes involved in inflammation, lipid metabolism, and fibrosis. Epigenetic studies could provide new targets for therapeutic intervention.

Development of personalized therapeutic strategies for MASH management: The heterogeneity of MASH and its associated risk factors calls for a personalized approach to treatment. Personalized medicine strategies could be developed based on individual risk profiles, taking into account factors such as genetic predisposition, H. pylori strain virulence, gut microbiota composition, and metabolic status. Specific approaches could include: (1) Predictive biomarkers: Identifying biomarkers that predict an individual’s risk of developing MASH in the presence of H. pylori infection, such as specific inflammatory mediators or genetic variants. These biomarkers could be used to stratify patients for targeted interventions; (2) Pharmacogenomics: Studying how genetic variations affect the response to H. pylori eradication therapy and other treatments aimed at reducing liver inflammation and fibrosis. This could help optimize treatment regimens based on patient-specific genetic profiles; and (3) Lifestyle and environmental interventions: Exploring the impact of lifestyle modifications, such as dietary changes and exercise, in conjunction with H. pylori eradication therapy. Tailored lifestyle interventions could be particularly effective in patients with coexisting metabolic disorders.

Conclusion

The study by Abdel-Razeq et al[6] highlights a significant association between H. pylori infection and increased risk of MASH, but many questions remain unanswered. To build on these findings, future research should prioritize longitudinal studies, integrate genetic and microbiome analyses, and conduct mechanistic investigations to clarify the biological pathways involved. The development of personalized therapeutic strategies based on individual risk factors could also revolutionize the management of MASH. As metabolic liver diseases continue to rise worldwide, understanding the role of infections such as H. pylori in their pathogenesis is crucial for developing innovative diagnostic and therapeutic approaches. By embracing multidisciplinary research and novel technologies, we can address the challenges posed by MASH and improve outcomes for affected individuals.