Helicobacter pylori and diabetic complications: Stronger evidence for the interlink

Abstract

An association between Helicobacter pylori (H. pylori) infection and various systemic diseases, including diabetes mellitus (DM), has been well known for several years. H. pylori infection can result in metabolic dysregulation through the contribution to the development of insulin resistance, β-cell dysfunction, systemic inflammation, and hormonal signalling with alterations in glucose and lipid homeostasis. This can result in metabolic syndrome and type 2 DM. An association between H. pylori and immune-mediated diseases such as autoimmune thyroiditis and type 1 DM has been identified. Emerging evidence also points to a strong bidirectional relationship between type 2 DM and H. pylori infection, leading to worsening of either disease and/or its complications. Therefore, DM patients with H. pylori infection are likely to have more aggressive disease with the development of various end-organ complications of diabetes early in their disease course, mandating rigorous monitoring. A recent basic study investigating the interlink between H. pylori infection and DM provides strong evidence of worse damage to the stomach, liver, and kidneys in diabetic mouse models. In this article, we outline our current understanding of the association between H. pylori disease and diabetic complications.

Key Words: Autoimmune disorders; Helicobacter pylori; Metabolic dysregulation; Type 1 diabetes mellitus; Type 2 diabetes mellitus

Core Tip: Helicobacter pylori (H. pylori) infection is increasingly recognized as a systemic disease with important metabolic consequences. Growing evidence supports a bidirectional relationship between H. pylori infection and diabetes mellitus (DM), particularly type 2 DM, in which chronic inflammation, insulin resistance, and immune dysregulation play central roles. Patients with DM and concomitant H. pylori infection appear to have a higher risk of gastrointestinal, hepatic, and renal complications. Recent experimental data further strengthen this association by demonstrating aggravated organ damage in diabetic models with H. pylori infection. Recognition of this interlink has important implications for screening, monitoring, and therapeutic strategies in patients with diabetes.

INTRODUCTION

Helicobacter pylori (H. pylori) is a flagellated and helical gram-negative bacterium that colonizes the gastric mucosa and can cause chronic gastritis in a proportion of affected individuals. The prevalence figures of H. pylori disease vary widely depending on the geographical region involved (more common in developing nations). 35%-45% of the world population is estimated to harbour this pathogen currently, making this one of the most common human infections globally[1]. Although a majority of people infected with H. pylori remain asymptomatic, H. pylori infection can result in peptic ulcers, chronic gastritis and gastric cancer[1,2].

Though H. pylori infection is known to be linked to serious upper gastrointestinal illnesses, as mentioned above, over the past few decades, its association with various systemic disorders was unknown until recently. Emerging evidence suggests that chronic infection with H. pylori can be associated with the risk of development of a verity of systemic diseases such as iron deficiency anaemia, immune thrombocytopenic purpura, atherosclerotic cardiovascular disease (coronary artery disease and stroke), hypertension, autoimmune disorders (rheumatoid arthritis, systemic lupus, type 1 diabetes mellitus (T1DM) and Sjogren’s syndrome), neurodegenerative diseases, dermatological disorders (rosacea, psoriasis and urticaria), and metabolic diseases [type 2 diabetes mellitus (T2DM), metabolic-dysfunction associate fatty liver disease (MAFLD) and insulin resistance (IR)][3-5]. A strong bidirectional interlink between H. pylori infection and diabetes mellitus has been recently observed, with perpetuation of either disease in patients[6]. A study by Yang et al[7] published recently investigating the interlink between H. pylori infection and diabetes mellitus provides us stronger evidence for the devastating complications of this disease combo in the stomach, liver and kidneys in diabetic mouse models. In this opinion review, we update the evidence base for H. pylori and systemic diseases with a special focus on metabolic disorders like T2DM, IR, and MAFLD.

H. PYLORI INFECTION AND GASTROINTESTINAL DISEASE: MECHANISMS

H. pylori initiates gastrointestinal disease through a multifaceted interaction with the gastric mucosa that begins with successful colonization and persistence in the harsh acidic environment of the stomach. The bacterium uses flagellar motility and specific outer membrane adhesins (e.g., BabA, SabA) to penetrate the mucous layer and firmly attach to epithelial cells, a critical step for establishing persistent infection[8]. Once adherent, H. pylori deploys a repertoire of virulence factors, most notably the cytotoxin-associated gene A (CagA) and the vacuolating cytotoxin A (VacA), which manipulate host cell signaling and immune responses[9]. CagA is delivered into gastric epithelial cells via a type IV secretion system, where it disrupts tight junctions, deregulates cell proliferation pathways, and triggers pro-inflammatory cascades, contributing to mucosal damage and carcinogenic processes[8,9]. VacA, present in virtually all strains, forms pores in host cell membranes, induces mitochondrial dysfunction, and interferes with immune cell function, promoting bacterial persistence and tissue injury[10]. These interactions collectively lead to chronic inflammation, epithelial cell damage, and alterations in gastric acid secretion, which underlie clinical manifestations such as chronic gastritis, peptic ulcer disease, and increased risk of gastric carcinoma[8,10].

The chronic inflammatory response to H. pylori infection is orchestrated through activation of host pattern recognition receptors, including toll-like receptors (TLR), which initiate downstream signaling via nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways, resulting in the sustained release of pro-inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, IL-8, and tumour necrosis factor-alpha (TNF-α). IL-8, in particular, acts as a potent chemoattractant for neutrophils, perpetuating mucosal inflammation and facilitating a cycle of tissue damage and immune cell infiltration[8,10]. The resulting oxidative stress, driven by reactive oxygen and nitrogen species released from activated immune cells, further contributes to DNA damage and a pro-carcinogenic environment[8,11]. Strain-specific variation in virulence factor expression (e.g., CagA and VacA genotypes) is associated with the severity of histopathological changes, with CagA-positive strains linked to more intense inflammation and greater risk of atrophic gastritis and gastric cancer. These mechanistic insights underscore the critical role of H. pylori in not only initiating but also driving the progression of gastrointestinal pathology through direct disruption of epithelial integrity and sustained mucosal immune activation[8-11].

THE LINK BETWEEN H. PYLORI AND SYSTEMIC DISEASES

Recent evidence underscores that H. pylori infection, beyond its established role in gastritis and peptic ulcer disease, has significant links with systemic diseases via chronic inflammation, immune response modulation, metabolic dysregulation, and possibly direct pathogen-associated molecular mechanisms (Figure 1).

Figure 1 Putative mechanisms involved in developing cardiovascular disease and metabolic dysfunction-associated fatty liver disease in patients with Helicobacter pylori infection. H. pylori: Helicobacter pylori; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; ICAM: Intercellular adhesion molecule; VCAM-1: Vascular cell adhesion molecule-1; NF-κB: Nuclear factor kappa B; JNK: C-Jun N-terminal kinase; TGF-β: Transforming growth factor beta; AMPK: Adenosine monophosphate phosphate-activated protein kinase; SREBP1: Sterol regulatory element-binding protein 1; PPARα: Peroxisome proliferator-activated receptor alpha; MASH: Metabolic dysfunction-associated steatohepatitis; LPS: Lipopolysacharide; IgA: Immunoglobulin A; IgG2: Immunoglobulin G2; TXA2: Thromboxane A2; PGE2: Prostaglandin E2; TC: Total cholesterol; LDL: Low density lipoprotein; TG: Triglyceride; HDL: High density lipoprotein; hs-CRP: Highly sensitive C-reactive protein; HOMA-IR: Homeostatic model assessment for estimating insulin resistance; ROS: Reactive oxygen species; LPL: Lipoprotein lipase; ER: Endoplasmic reticulum; MAFLD: Metabolic-dysfunction associate fatty liver disease.

H. pylori and cardiovascular diseases

Studies now extend the H. pylori associations to include cardiovascular conditions such as atherosclerosis, hypertension, and abdominal aortic aneurysm, where persistent H. pylori infection can foster chronic vascular inflammation and endothelial dysfunction that contribute to plaque formation and vascular damage[5]. A Mendelian randomization study directly supports a causal association between H. pylori and atherosclerosis, implicating bacterial factors like CagA in systemic vascular pathology[12]. Moreover, systematic reviews report that chronic H. pylori infection is linked to increased prevalence of cardiovascular abnormalities and may play a role in conditions including myocardial infarction and stroke, potentially mediated by oxidative stress and pro-inflammatory signaling[13].

The rise in inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), fibrinogen, thrombin, intercellular adhesion molecule 1 and vascular cell adhesion molecule-1 mediated by chronic H. pylori infection results in activation of T lymphocytes and macrophages[14-16]. Eventually, this would lead to proliferation of vascular smooth muscle cells and extracellular matrix, endothelial cell dysfunction and atherosclerosis[17]. Additional mechanism for endothelial dysfunction is the H. pylori mediated B12 and folate malabsorption and resultant raised homocysteine levels[18].

The binding of the lipopolysaccharide (LPS), the polysaccharide antigen from the cell wall of the H. pylori, to the TLRs on the phagocytes and B lymphocytes leads to the secretion of TNF-α, dendritic cell and CD4⁺ T cell activation, and immunoglobulin (IgG) 2 production[19]. IgG positivity to H. pylori is observed in those with coronary artery disease than in those without, and IgG positivity to multiple pathogens, including H. pylori, is an independent risk for endothelial dysfunction and severe coronary artery disease[20,21].

LPS-binding protein presents LPS to TLRs resulting in activation of kinases (MAPK, c-Jun N-terminal kinase), and NF-kB signalling pathways, enhances expression of cycloxygenae-2 genes and increased thromboxane A2 levels, a potent vasoconstrictor and platelet aggregator[22,23]. The cross-reactive immune response from structural similarity between H. pylori heat shock protein (bacterial KSP60) and that present on the endothelial cells (human HSP60) promotes endothelial inflammation and atherosclerosis[24].

H. pylori infected individuals exhibit a rise in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels and a drop in high-density lipoprotein levels, with the latter two resulting from chronic inflammation mediated inhibition of lipoprotein lipase activity[25]. Reactive oxygen species from H. pylori infection results in generation of oxidized-LDL, which, rather than binding to the LDL receptors, bind to the scavenger receptors on the macrophage surface thereby forming the foam cells and atherosclerosis[26]. The raised homocysteine levels result in reduced nitric oxide availability/endothelial stress, oxidative stress, endoplasmic reticulum stress, and altered lipid metabolism[27].

In metabolic and endocrine domains, accumulating data highlight a relationship between H. pylori infection and T2DM, metabolic syndrome, and hepatic steatosis[28]. Additionally, experimental transcriptomic research in murine models reveals that H. pylori infection can exacerbate MAFLD through lipid metabolic perturbations, linking gastric infection to hepatic metabolic outcomes[29].

Beyond cardiometabolic effects, H. pylori infection has been associated with other systemic conditions, including osteoporosis, autoimmune haematological disorders, and potentially neurological diseases via mechanisms involving molecular mimicry, systemic inflammation, and altered microbiota interactions[30]. While causality remains to be fully delineated in many contexts, these emerging findings collectively frame H. pylori as a multisystem pathogen with implications for chronic disease beyond the gastrointestinal tract, meriting further longitudinal and interventional research to clarify causal pathways and therapeutic consequences.

H. pylori and metabolic syndrome

Emerging research increasingly implicates H. pylori infection in metabolic dysregulation and related disorders, where systemic inflammation and immune modulation play central roles in disrupting metabolic homeostasis. A recent large cross-sectional study found that H. pylori infection correlates with unfavorable metabolic profiles, including higher fasting glucose, increased body mass index, and elevated blood pressure, the features commonly linked with MAFLD and metabolic syndrome[31]. Meta-analytic evidence further supports that H. pylori infection is associated with a mildly increased risk of incident MAFLD, suggesting that chronic infection may contribute to hepatic lipid accumulation and metabolic liver disease progression via inflammatory and IR pathways[32]. Mechanistically, H. pylori infection is thought to exacerbate metabolic disturbances through chronic systemic inflammation, oxidative stress, gut microbiota alterations and altered gastric hormones, which in turn impair glucose and lipid metabolism - central drivers of metabolic disorders[31].

In addition to liver disease, IR and T2DM have been linked with H. pylori infection in both epidemiological and experimental studies. A systematic review and meta-analysis demonstrated that individuals with H. pylori have higher odds of metabolic syndrome and IR, highlighting a potential relationship between gastric infection and systemic metabolic dysfunction[33]. Recent experimental work in animal models reveals that H. pylori infection can impair glucose homeostasis by altering gut microbiota composition and reducing beneficial short-chain fatty acids, which are important for maintaining the gut barrier integrity[5]. The drop in integrity of the gut mucosal barrier results in LPS translocation, metabolic endotoxemia, inflammation, and insulin resistance. Furthermore, observational studies indicate that H. pylori infection in people with diabetes may exacerbate complications such as nephropathy and increased visceral fat, indicating that the infection may worsen metabolic outcomes in susceptible populations[34].

H. pylori and T2DM

Accumulating epidemiological evidence suggests that H. pylori infection is associated with an increased risk of developing T2DM. A recent large meta-analysis of 45 case-control studies found that individuals with H. pylori infection had a significantly higher odds of having diabetes overall, with particularly strong associations for T2DM. Subgroup analyses showed stronger associations with non-invasive H. pylori detection methods [odds ratio (OR) = 1.99], in the 40-60 age group (OR = 2.00), and for T2DM (OR = 2.25)[35]. Retrospective cohort data further support this relationship, showing that H. pylori-positive participants had a higher incidence of T2DM than those without infection, even after adjusting for confounders such as age, sex, and baseline metabolic parameters (adjusted hazard ratio is approximately 1.59)[36]. These findings highlight that chronic H. pylori infection may contribute to the global burden of T2DM, although the magnitude of the association varies by population and diagnostic methods[35,36].

Several biologically plausible mechanisms have been proposed to explain how H. pylori infection might influence glucose metabolism and diabetes risk. CagA-positive H. pylori infection results in NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation to induce systemic low-grade inflammation, characterized by elevated pro-inflammatory cytokines such as IL-1β, IL-18, IL-6, IL-8, TNF-α, transforming growth factor (TGF)-β, C-reactive protein, which can impair insulin signaling and promote IR - central drivers in the pathogenesis of T2DM[37,38]. Additionally, H. pylori-related inflammation may alter gastric and metabolic hormone profiles, including leptin, ghrelin, and somatostatin, which in turn affect appetite regulation, insulin secretion, and metabolic homeostasis[23]. The secretion of ghrelin is low and that of leptin is high[39,40], both culminating in a raised IR and T2DM[41,42]. Although a drop in the secretion of ghrelin and somatostatin is expected to enhance the insulin secretion, their primary effects, in reality, are to enhance IR[43,44].

Gut microbiota dysbiosis resulting from H. pylori infection impairs insulin sensitivity and glucose homeostasis[45]. The intestinal inflammation and pro-inflammatory cytokines increase IR and T2DM[46]. Finally, signalling through MAPK and epidermal growth factor receptor results in apoptosis of the pancreatic beta cells[22].

For T2DM, multiple pathways, including NLRP3 inflammasome activation, hormonal imbalances (e.g., ghrelin, leptin), and immune-genetic interactions involving TLR4 and suppressor of cytokine signaling 3, suggest a role for H. pylori in metabolic dysregulation and impaired glycemic control[47]. These multifactorial pathways collectively provide a biological basis for the observed epidemiological associations[48].

Beyond its potential role in the onset of T2DM, H. pylori infection may influence the complications and metabolic control in T2DM patients. A recent retrospective study of nearly 1000 T2DM patients found that H. pylori positivity was significantly associated with diabetic nephropathy, particularly among patients with hypertension, poor glycemic control [glycated haemoglobin or (HbA1c) ≥ 8%], or long disease duration, suggesting that infection may exacerbate certain chronic complications[49]. Preliminary evidence from interventional studies suggests that eradication of H. pylori might improve glycemic control, although larger randomized controlled trials are needed to establish causality and clinical benefit.

H. pylori and MAFLD

Several observational and meta-analytic studies indicate that H. pylori infection is linked with a higher prevalence and incidence of MAFLD. A comprehensive meta-analysis of data from longitudinal studies showed that H. pylori infection was significantly associated with an increased risk of developing incident MAFLD over a mean 5-year follow-up [n = 4 studies; random-effects OR = 1.20, 95% confidence interval (CI): 1.08-1.33; I² = 44%][50]. A large cross-sectional study of over 28000 Chinese adults demonstrates that H. pylori infection is independently associated with unfavorable metabolic profiles - particularly higher body mass index, glucose levels, and diastolic blood pressure - and with the presence and metabolic severity of MAFLD, while high-density lipoprotein cholesterol appears protective[51]. The large cross-sectional study of Hispanic/Latino adults found a modest but significant association between H. pylori seropositivity and MAFLD, particularly when defined by the Hepatic Steatosis Index, as well as with obesity. The association varied by Hispanic/Latino heritage and was most evident among individuals of Puerto Rican and Mexican backgrounds. While supportive of a link between H. pylori infection and metabolic liver disease, the findings are exploratory and do not establish causality, highlighting the need for further mechanistic and longitudinal studies[52-54]. These patterns align with metabolic syndrome components frequently co-occurring in MAFLD, including IR, obesity, and dyslipidemia, all of which are thought to both contribute to and be exacerbated by chronic inflammatory states associated with H. pylori infection.

Experimental research provides biological plausibility for these clinical associations. In murine models, H. pylori infection - especially with virulent CagA-positive strains - aggravated high-fat diet-induced hepatic steatosis and altered lipid metabolic pathways in the liver, with transcriptomic analyses highlighting disruptions in fatty acid degradation and peroxisome proliferator-activated receptor alpha signaling[29]. These transcriptomic findings suggest that bacterial virulence factors - for example, H. pylori CagA - may influence hepatic lipid uptake, storage, and oxidative metabolism, thereby exacerbating steatotic changes and inflammation. Emerging clinical evidence suggests that eradication of H. pylori may have favourable effects on MAFLD-related outcomes. These findings support the hypothesis that H. pylori contributes to MAFLD not simply as a coincident infection but potentially as a modifiable risk factor influencing metabolic and hepatic pathology[55,56].

The chronic low grade inflammation results in an increased IR mediated through enhanced NLRP3 inflammasome secretion, pro-inflammatory cytokines, and increased secretion of fetuin A from the liver, one of the hepatokines[57]. MAFLD pathogenesis is mediated by an enhanced activity of SREBP1 (increasing lipogenesis) and a suppressed activity of peroxisome proliferator-activated receptor alpha (decreasing the fatty acid beta-oxidation)[58]. TGF-β acts on hepatic stellate cells through the suppressor of mothers against decapentaplegic pathway, resulting in progression of MAFLD to metabolic dysfunction associated steatohepatitis and liver fibrosis[59]. The decreased adiponectin and increased leptin levels associated with chronic low-grade inflammation have a similar effect on MAFLD pathogenesis by increasing lipogenesis and decreasing the fatty acid beta-oxidation[60]. Figure 1 shows the putative mechanisms involved in developing cardiovascular disease and MAFLD in patients with H. pylori infection.

H. pylori and T1DM

Emerging evidence on the relationship between H. pylori infection and T1DM suggests a potential association, although findings are heterogeneous and mechanistic links remain incompletely understood. The meta-analysis, including thirty-seven case-control studies and 2 cohort studies, showed H. pylori was associated with increased risks of T1DM and T2DM, separately (OR = 1.99, 95%CI: 1.52-2.60, and OR = 2.15, 95%CI: 1.81-2.55, respectively), but also with diabetic nephropathy risk (OR = 1.60, 95%CI: 1.10-2.33)[61]. A significant association was observed between H. pylori infection and T1DM (OR = 1.77, 95%CI: 1.47-2.12, P < 0.0001), and subgroup analysis showed that H. pylori infection was significantly associated with a longer duration of T1DM and higher HbA1c levels (P < 0.001 for both) but not with age at T1DM diagnosis (P = 0.306)[62]. This suggests that H. pylori infection may not only be more prevalent in T1DM but could also correlate with markers of disease severity, potentially through chronic immune stimulation and inflammatory responses that overlap with autoimmune processes in T1DM.

Additional case-control research indicates that children and adolescents with T1DM have a higher prevalence of H. pylori antibodies and evidence of concomitant autoimmune thyroiditis compared with healthy peers, implying a broader interplay between H. pylori and autoimmune conditions[63]. The bacterium has been implicated in systemic immune activation that could influence autoimmune risk and progression, although it remains unclear whether H. pylori directly contributes to T1DM pathogenesis or reflects shared environmental and immunological risk factors[64]. Overall, while some studies support an association between H. pylori and T1DM, causality has not been definitively established, and further large, prospective studies are needed to clarify the nature and directionality of this relationship. Figure 2 outlines the potential links between T2DM and T1DM with H. pylori infection. H. pylori infection with Cag-A positive strain mediated a Th1-immune response, which is a key driver in the pathogenesis of organ-specific autoimmune diseases[65]. Other mechanisms include pro-inflammatory cytokines induced nitric oxide and reactive oxygen species production, pancreatic beta-cell mitochondrial dysfunction and decreased insulin secretion[65]. Owing to the structural similarity between microbial and host proteins, anti-Cag-A antibodies could react against pancreatic antigens, forming anti-glutamic acid decarboxylase and anti-insulinoma antigen 2 antibodies, thereby causing β-cell destruction[66]. Gut microbiome dysbiosis and metabolic endotoxemia results in autoreactive T cells against pancreatic islets, causing direct damage and T1DM[67].

Figure 2 Potential links between type 2 diabetes mellitus and type 1 diabetes mellitus with Helicobacter pylori. H. pylori: Helicobacter pylori; Cag A: Cytotoxin-associated gene A; IL-1β: Interleukin; TNF-α: Tumour necrosis factor-alpha; NF-κB: Nuclear factor kappa B; TGF-β: Transforming growth factor beta; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; IFNγ: Interferon γ; STAT1: Signal transducer and activator of transcription 1; NO: Nitric oxide; GAD: Glutamic acid decarboxylase; IA2: Insulinoma antigen 2; LPS: Lipopolysacharide; JNK: C-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; EGFR: Epidermal growth factor receptor.

A recently published study by Yang et al[7] is an important contribution to the evolving understanding of the bidirectional relationship between H. pylori infection and diabetes, particularly in the context of diabetic complications. A major strength of this work lies in its mechanistic experimental design, using well-controlled diabetic mouse models to demonstrate that H. pylori infection aggravates tissue injury in multiple organs, including the stomach, liver, and kidneys. By integrating histopathological assessment with inflammatory and metabolic readouts, the study provides biological plausibility to epidemiological observations linking H. pylori infection with worse metabolic control and accelerated end-organ damage in diabetes. Importantly, the work moves beyond associative human data and offers causal insight, strengthening the argument that H. pylori may actively contribute to the progression and severity of diabetic complications rather than acting as a coincidental comorbidity.

However, several limitations should be acknowledged when interpreting the findings. The study is based on animal models, which, while valuable for mechanistic insight, may not fully recapitulate the complexity of human diabetes, particularly regarding disease duration, environmental exposures, and host immune heterogeneity. Additionally, the experimental design does not fully address the reversibility of observed organ damage following H. pylori eradication, limiting direct translational implications for clinical management. The absence of detailed exploration of bacterial virulence factors (such as CagA status), gut microbiome alterations, and host genetic susceptibility further constrains mechanistic generalizability. Nevertheless, despite these limitations, Yang et al’s study[7] represents a significant advance by providing experimental evidence that supports a pathogenic role of H. pylori in diabetic complications and underscores the need for future translational and interventional studies in human populations.

AREAS OF UNCERTAINTY AND FUTURE RESEARCH

Despite growing evidence linking H. pylori to T2DM and its complications, the relationship remains complex and partly inconsistent. Differences in study design, diagnostic criteria for infection and diabetes, population characteristics, and confounding lifestyle factors contribute to heterogeneity among studies[33]. Additionally, while associations are robust across many observational datasets, definitive causality requires well-controlled prospective interventional studies that assess whether H. pylori eradication can reduce diabetes risk or improve metabolic outcomes. Future human studies examining the relationship between H. pylori infection and diabetes complications should prioritize clinically relevant primary endpoints beyond HbA1c, such as reductions in albuminuria among patients with diabetic nephropathy. The role of virulence factors (e.g., CagA status), host genetics, and gut microbiome interactions should also be clarified in shaping the interplay between H. pylori infection and T2DM.

Moreover, residual confounding by unmeasured factors such as diet quality, socioeconomic status, medication use, and coexisting infections cannot be fully excluded and may partially explain the observed associations between H. pylori infection and T2DM. Future studies should prioritize large, multiethnic prospective cohorts and randomized eradication trials integrating metabolic phenotyping, microbial profiling, and host genetic data to better define causality and identify patient subgroups most likely to benefit from targeted H. pylori treatment.

CONCLUSION

This article synthesizes growing evidence that H. pylori infection is not merely a localized gastric pathogen but a systemic disease with important metabolic and endocrine consequences, particularly in the context of T2DM. It highlights robust epidemiological, mechanistic, and experimental data linking H. pylori to IR, metabolic syndrome, T2DM, and MAFLD, while also addressing its potential role in diabetic complications affecting the stomach, liver, and kidneys. The paper emphasizes chronic inflammation, immune dysregulation, oxidative stress, hormonal disturbances, and gut microbiota alterations as shared pathogenic pathways through which H. pylori may worsen metabolic control and accelerate end-organ damage in diabetic patients.

By integrating clinical observations with recent experimental findings, the editorial underscores the clinical relevance of recognizing this bidirectional relationship. It argues for heightened vigilance in screening and monitoring H. pylori infection in patients with DM and related metabolic disorders, as no major international or national guidelines currently recommend routine H. pylori screening in these populations. Overall, this paper positions H. pylori as a potentially modifiable factor in metabolic disease progression and diabetic complications and calls for well-designed prospective and interventional studies to inform future clinical practice.