TO THE EDITOR
We are delighted to read the high-quality article ‘Prevalence and risk factors associated with metabolic dysfunction-associated steatohepatitis in patients with Helicobacter pylori infection: A population-based study’ by Abdel-Razeq et al[1], which will be published in the World Journal of Hepatology. Helicobacter pylori (H. pylori) is a common gastrointestinal pathogen classified as a Group 1 carcinogen by the International Agency for Research on Cancer and is widely recognized as a major factor leading to gastritis, gastric ulcers, and gastric cancer. Additionally, studies have indicated its role in promoting the development of colorectal cancer[2-4]. However, as research has progressed, the impact of H. pylori infection has not been limited to gastrointestinal effects, and its association with metabolic diseases has gradually become a research hotspot[2,5,6]. In recent years, metabolic dysfunction-associated steatohepatitis (MASH), a liver disease closely related to metabolic syndrome, has drawn increasing attention. MASH syndrome is characterized by liver cell steatosis, inflammation, and fibrosis, with metabolic syndrome as the central driver[7]. Unlike nonalcoholic steatohepatitis (NASH), which primarily focuses on nonalcoholic factors as the cause of liver damage, MASH explicitly highlights metabolic dysfunction as the primary pathogenesis[8]. Moreover, H. pylori has been implicated in both MASH and NASH through mechanisms involving chronic inflammation, oxidative stress, gut-liver axis disruption, and metabolic dysregulation, further linking metabolic and liver diseases[9]. The pathogenesis of MASH is still not fully understood[10]. This study systematically evaluated the potential association between H. pylori infection and MASH via a large-scale multicenter database and proposed that H. pylori might be involved in the development of MASH through complex inflammatory and metabolic mechanisms, providing a new perspective for further exploration of the role of H. pylori in metabolic liver diseases.
Large-scale multicenter study: Revealing a new link between H. pylori and MASH
This study analyzed data from a multicenter database of more than 69.23 million patients, setting a precedent in the relevant field with its unprecedented scale. Compared with previous small-scale, regional studies, this study overcomes issues related to small sample sizes and limited conclusions, significantly enhancing the reliability of the statistical results. The study revealed that H. pylori infection is an independent risk factor for MASH development, with high statistical significance (OR: 2.51, 95%CI: 2.31-2.73). Even after controlling for known metabolic syndrome risk factors, such as obesity, diabetes, hypertension, and hyperlipidemia, H. pylori infection remained an important independent factor influencing MASH, revealing its potential pathogenic effect on the liver. This discovery provides a rationale for considering H. pylori as a potential therapeutic target for MASH.
H. pylori and metabolic dysfunction: Potential mechanisms from the gastrointestinal tract to liver pathology
The mechanisms by which H. pylori leads to or exacerbates MASH are not yet clear, but this study provides new perspectives for exploring potential pathophysiological mechanisms. While the exact mechanism by which H. pylori affects liver metabolism remains to be further studied, combining the literature and new evidence provided by this paper suggests that H. pylori infection may promote MASH development and progression by impairing liver function, disturbing glucose and lipid metabolism, triggering inflammatory responses, and exacerbating metabolic syndrome[11]. The OR values for H. pylori infection in MASH patients range from 1.13 to 1.38[10,12].
H. pylori infection exacerbates high-fat diet-induced MASH by disrupting gastric epithelial regeneration, leading to chronic inflammation and immune activation. These events trigger elevated production of reactive oxygen species (ROS), which increases epithelial and endothelial permeability, facilitating the systemic entry of bacterial components[13]. The resulting oxidative stress and lipid peroxidation cause endothelial lipid deposition, impaired apoptosis, and cell lysis. These changes increase low-density lipoprotein and triglyceride levels while reducing high-density lipoprotein levels, promoting liver steatosis, fibrosis, inflammation, and systemic complications such as obesity and atherosclerosis[13,14]. Additionally, H. pylori, through virulence factors such as CagA and VacA, may trigger inflammatory responses not only in the stomach but also via the gut-liver axis, affecting liver function. These virulence factors can damage the intestinal mucosal barrier, allowing bacterial metabolites such as endotoxins to enter the liver and induce local inflammation and fat degeneration, thereby exacerbating MASH[2,9]. Second, higher H. pylori infection rates in diabetic patients reveal a link between H. pylori infection and insulin resistance. The underlying mechanism involves the activation of proinflammatory mediators such as C-reactive protein (CRP) and tumor necrosis factor-alpha by H. pylori infection, alongside the production of ROS, ghrelin, and leptin, as well as the release of lipopolysaccharides[11]. Conversely, virulent strains of H. pylori (cag+) induce the production of inflammatory factors, including interleukin-6 and CRP, and chronic inflammation. This inflammatory cascade disrupts the regulation of gastroduodenal hormones mediated by insulin, impairing insulin signaling pathways. Collectively, these changes contribute to the development of insulin resistance, which predisposes individuals to obesity and type 2 diabetes[15,16]. Hyperglycemia and insulin resistance are key pathological mechanisms of MASH[17]. H. pylori may exacerbate insulin resistance and disrupt lipid metabolism by inducing chronic systemic low-grade inflammation, thus promoting liver steatosis and inflammatory responses[18]. This study provides new directions for further exploration of the role of H. pylori in liver metabolic dysfunction. Future studies should further clarify H. pylori’s specific pathogenic pathways in liver inflammation, steatosis, and fibrosis, particularly in chronic liver disease patients. The mechanisms are shown in Figure 1.
Figure 1 Mechanisms of Helicobacter pylori infection-induced oxidative stress and its role in liver and metabolic dysregulation.
H. pylori: Helicobacter pylori.
Genetic perspectives: Genetic susceptibility to H. pylori infection and MASH
Although this paper does not perform a genetic analysis, it proposes new genetic hypotheses for future research, particularly with respect to genetic susceptibility. For example, the relationship between H. pylori infection and MASH may be influenced by specific single-nucleotide polymorphisms (SNPs) or gene mutations, particularly in genes involved in inflammation and lipid metabolism pathways. These genetic variations may increase the influence of H. pylori on metabolic liver disease in specific populations. Recent studies suggest a potential genetic interaction between H. pylori infection and MASH. Specifically, the PNPLA3 gene SNP rs738409 is considered to increase the risk of metabolic liver disease[19,20]. This variation impacts lipid metabolism and may exacerbate liver damage in the context of chronic inflammation (e.g., H. pylori-induced inflammation).
Potential therapeutic strategies: From H. pylori eradication to new approaches for mash management
The results of this study not only reveal the association between H. pylori and MASH but also offer new clinical treatment perspectives. Traditional MASH treatments focus primarily on lifestyle interventions and managing metabolic syndrome-related diseases[21]. This study suggests that H. pylori could become a new therapeutic target for MASH. Clinical studies have shown that H. pylori eradication can improve several metabolic abnormalities, including insulin sensitivity and lipid levels[17,22,23]. Future clinical trials should further explore the actual therapeutic effects of H. pylori eradication in MASH patients, especially in high-risk populations with concomitant metabolic syndrome.
By integrating H. pylori eradication into treatment, MASH management may evolve into a more comprehensive approach, combining metabolic syndrome management, anti-inflammatory therapy, and H. pylori infection control. This multidimensional treatment strategy holds promise for improving the long-term prognosis of MASH patients.
Limitation and future directions
Although the study suggested that H. pylori eradication may improve metabolic dysfunction, clinical trial data to support its efficacy in MASH and NASH patients are lacking. Future randomized controlled trials are needed to evaluate the therapeutic benefits of H. pylori eradication in patients with metabolic liver diseases. Future studies should focus on the following: Exploring the specific molecular mechanisms by which H. pylori infection leads to liver metabolic dysfunction, especially in terms of inflammation, insulin resistance, and the gut-liver axis; designing prospective clinical trials to verify the therapeutic effects of H. pylori eradication in MASH patients; and conducting genomic studies to explore the potential genetic susceptibility between H. pylori infection and MASH development. By further investigating the role of H. pylori in metabolic liver diseases, we can not only better understand the pathogenesis of MASH but also develop new, multidimensional therapeutic approaches to promote personalized medicine.
