Dietary factors in Helicobacter pylori-negative early gastric cancer: Risk, protection, and mechanistic insights

Abstract

Helicobacter pylori (H. pylori)-negative early gastric cancer (GC) is an emerging clinical and epidemiological challenge that cannot be explained by the classical H. pylori-driven carcinogenic pathway. Growing evidence indicates that dietary factors play a critical role in modulating gastric mucosal integrity, inflammation, and carcinogenic progression in the absence of H. pylori infection. High salt intake and processed foods, particularly those rich in nitrates and nitrites, are associated with mucosal injury, oxidative stress, and endogenous N-nitroso compound formation, thereby increasing early GC risk. In contrast, diets rich in fruits, vegetables, antioxidants, and dietary fiber exert protective effects by reducing oxidative DNA damage, attenuating chronic inflammation, and supporting a favorable gastric microenvironment. Mediterranean and prudent dietary patterns, characterized by plant-based foods, polyphenols, and unsaturated fatty acids, show inverse associations with GC risk independent of H. pylori status. While vitamins C and E demonstrate consistent protective trends, evidence regarding vitamin D remains inconclusive due to population heterogeneity. Emerging studies using the dietary inflammatory index further suggest that pro-inflammatory diets may promote H. pylori-negative gastric carcinogenesis. This minireview summarizes current evidence and highlights key mechanistic gaps to inform targeted prevention strategies in high-risk populations.

Key Words: Helicobacter pylori-negative; Early gastric cancer; Dietary risk factors; Dietary patterns; Dietary inflammatory index

Core Tip: Diet plays a critical role in the development of Helicobacter pylori (H. pylori)-negative early gastric cancer. High salt intake and processed foods increase carcinogenic risk, while fruits, vegetables, antioxidants, dietary fiber, and Mediterranean-style dietary patterns provide protective effects independent of H. pylori status. Understanding these dietary influences is essential for improving prevention strategies and refining risk assessment in H. pylori-negative populations.

INTRODUCTION

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide, despite significant decreases in incidence, particularly in high-income countries. However, in low- and middle-income countries, GC continues to represent a growing challenge, often linked to dietary habits, environmental exposures, and other lifestyle factors. Importantly, dietary habits in these settings are heterogeneous, and risk-promoting and protective dietary patterns may coexist within the same region or population. Helicobacter pylori (H. pylori) infection, a well-established risk factor for GC, has historically been central to the study of gastric carcinogenesis. Yet, the increasing recognition of H. pylori-negative early GC (EGC) has shifted the focus toward understanding additional factors contributing to GC development, particularly the role of dietary components. While H. pylori infection remains a key player in the pathogenesis of GC, a growing body of evidence has begun to explore how diet, particularly in individuals without H. pylori infection, modulates cancer risk. This minireview examines the critical dietary factors involved in H. pylori-negative EGC, synthesizing research findings related to the role of nutrients, dietary patterns, and specific food components (Figure 1; Table 1).

Figure 1  Dietary factors and their impact on Helicobacter pylori-negative early gastric cancer.

Table 1 Dietary factors and their association with Helicobacter pylori-negative early gastric cancer.

Dietary component	Effect on gastric cancer risk
High salt intake	Increases risk; associated with mucosal damage and carcinogen promotion
Processed meats	Increases risk; linked to carcinogen formation
Fruits and vegetables	Protective effect; rich in antioxidants and micronutrients
Dietary fiber	Protective effect; aids in carcinogen excretion and gut health
Mediterranean diet	Protective effect; rich in anti-inflammatory foods
Western diet	Increases risk; high in processed foods, red meats, and fats
Vitamin C	Protective effect; reduces oxidative DNA damage
Vitamin D	Mixed evidence; some studies suggest protective effect

HIGH-SALT DIET AND PROCESSED FOODS AS RISK FACTORS

One of the most consistently reported dietary risk factors for GC, including H. pylori-negative EGC, is high salt intake. Numerous studies have demonstrated a positive association between high dietary sodium and increased GC risk, regardless of H. pylori infection status[1,2]. Salt, particularly in preserved foods such as pickled vegetables, salted fish, and processed meats, has been linked to mucosal damage and the promotion of carcinogenic compounds such as N-nitroso compounds, with similar associations observed across different populations and dietary settings. Excessive salt exposure may directly impair gastric epithelial integrity and increase endogenous formation of N-nitroso compounds, thereby enhancing susceptibility to DNA damage and early malignant transformation. These compounds are produced during the preservation process and are thought to contribute to DNA damage in the gastric mucosa, which can lead to carcinogenesis[2,3].

In a large cohort study, Peleteiro et al[2] found that high salt intake was significantly associated with an increased risk of GC, even after adjusting for H. pylori infection status. Similarly, Takasu et al[1] identified salt as a prominent risk factor for GC, further highlighting its role in both H. pylori-positive and H. pylori-negative cases. This evidence underscores the importance of reducing salt intake as part of broader dietary interventions for GC prevention.

PROTECTIVE EFFECTS OF FRUITS, VEGETABLES, AND DIETARY FIBER

Conversely, diets rich in fruits and vegetables have consistently been associated with a reduced risk of GC, including H. pylori-negative EGC[4,5]. These foods are rich in antioxidants, fiber, and micronutrients, which have protective effects against oxidative stress and inflammation, two key contributors to gastric carcinogenesis. Antioxidant-rich diets may mitigate oxidative DNA damage and limit inflammation-driven epithelial injury, thereby reducing carcinogenic progression. This inverse association has been reported in diverse study populations, supporting a broadly protective role of plant-based dietary components. Beyond these general effects, such dietary components may also contribute to the maintenance of gastric mucosal barrier integrity and attenuation of chronic inflammatory signaling, thereby reducing vulnerability to malignant transformation.

Antioxidants such as vitamin C, vitamin E, and carotenoids (e.g., beta-carotene and lycopene) have shown inverse associations with GC risk, potentially through their ability to neutralize free radicals and prevent oxidative DNA damage[5,6]. However, reported effect sizes vary across studies, which may reflect differences in baseline nutritional status, dietary assessment methods, and population characteristics, rather than uniform biological effects. Moreover, dietary fiber, found abundantly in fruits, vegetables, and whole grains, has been shown to reduce the risk of GC by improving gut health and reducing exposure to carcinogens, with comparable trends observed across different geographic regions and study designs[4,5]. Fiber intake may further influence the gastric and intestinal microenvironment through modulation of microbial metabolites and local immune responses, although direct mechanistic evidence specific to H. pylori-negative EGC remains limited[5]. A meta-analysis by Collatuzzo et al[4] demonstrated that high dietary fiber intake is inversely associated with GC risk, with stronger effects observed in studies focusing on high-risk populations. These findings suggest that dietary modifications that emphasize fruits, vegetables, and fiber-rich foods could play a significant role in reducing the incidence of GC, especially in H. pylori-negative individuals.

DIETARY PATTERNS: MEDITERRANEAN VS WESTERN DIETS

Dietary patterns, rather than isolated nutrients, have also been studied in relation to GC risk. The Mediterranean diet, characterized by high consumption of fruits, vegetables, legumes, whole grains, olive oil, and fish, has been consistently associated with a lower risk of GC, including in H. pylori-negative cases[7,8]. Although such dietary patterns are not universally adopted in low- and middle-income countries, they provide a useful reference framework for understanding how plant-based and anti-inflammatory dietary characteristics may confer protection against gastric carcinogenesis. This association appears to be relatively stable across populations with varying baseline dietary habits, suggesting that the protective effect is not confined to Mediterranean regions alone[9,10].

In contrast, Western dietary patterns, which are characterized by high consumption of red meat, processed foods, refined grains, and saturated fats, are associated with increased GC risk. The Western diet’s pro-inflammatory effects and high content of harmful fats and preservatives contribute to gastric carcinogenesis, both in H. pylori-positive and H. pylori-negative populations[1,11]. The association between Mediterranean dietary patterns and reduced GC risk was also supported by Castelló et al[10], who found that high adherence to Mediterranean and prudent diets, which share similarities in their focus on plant-based foods, was inversely related to GC risk. These findings emphasize the role of overall diet quality in modulating GC risk, independent of H. pylori status.

THE ROLE OF VITAMIN D AND OTHER MICRONUTRIENTS

The potential role of micronutrients, including vitamin D, in GC prevention remains a topic of ongoing research. While vitamin D is known for its role in bone health, emerging evidence suggests it may also influence cancer-related pathways, including cell proliferation and immune regulation. These proposed mechanisms provide biological plausibility; however, inconsistent epidemiological findings indicate that such effects may be context-dependent rather than universal. Some studies have indicated that low vitamin D levels are associated with an increased risk of GC, particularly in regions with insufficient sunlight exposure[1,12].

However, the evidence on vitamin D’s protective effects against GC remains mixed. Several studies have reported null or inconsistent associations, suggesting that observed discrepancies may be driven by heterogeneity in study design, vitamin D exposure assessment, genetic background, sunlight availability, and residual confounding, rather than true biological contradiction. Consequently, current evidence does not allow a definitive conclusion regarding the role of vitamin D in H. pylori-negative gastric carcinogenesis.

EMERGING EVIDENCE ON DIETARY INFLAMMATORY INDEX

Recent studies have explored the role of dietary inflammation in GC development. The Dietary Inflammatory Index (DII) is a tool used to assess the inflammatory potential of a diet based on the intake of specific nutrients and food groups. A higher DII score indicates a more pro-inflammatory diet, which has been linked to increased cancer risk, including GC[8,13]. Such pro-inflammatory dietary profiles may promote gastric carcinogenesis through sustained immune activation, oxidative stress, and disruption of epithelial homeostasis, even in the absence of H. pylori infection. This relationship has been observed across multiple populations, supporting the relevance of diet-induced inflammation beyond specific regional contexts. From a mechanistic perspective, pro-inflammatory dietary patterns may promote gastric carcinogenesis through sustained immune activation, oxidative stress, and disruption of epithelial homeostasis, even in the absence of H. pylori infection. Conversely, diets with lower DII scores tend to emphasize anti-inflammatory components that may counterbalance these processes[8].

METHODOLOGICAL CONSIDERATIONS AND GAPS IN RESEARCH

While substantial evidence supports the role of diet in modulating GC risk, especially in H. pylori-negative populations, several methodological challenges remain. Differences in population characteristics, dietary assessment tools, and cultural eating patterns may partially account for variability in reported associations, highlighting the need for cautious interpretation of effect sizes. A major limitation in the current literature is the reliance on observational studies, which, despite their ability to identify associations, are prone to confounding and bias. In addition, overlapping dietary exposures and interrelated nutritional components complicate efforts to isolate individual effects, contributing to apparent inconsistencies across studies. These limitations underscore the importance of integrative analytical approaches that link dietary patterns with mechanistic biomarkers and stratified analyses, particularly in H. pylori-negative EGC[14,15].

Moreover, while dietary patterns such as the Mediterranean diet show promise in reducing GC risk, there is still considerable variability in how these patterns are defined and assessed. Standardized methodologies for evaluating dietary patterns are needed to improve comparability across studies and provide more robust evidence for dietary interventions. Finally, future research should focus on large-scale, longitudinal studies that explicitly stratify H. pylori-negative populations to better understand the long-term effects of dietary factors on GC development. Additionally, mechanistic studies are needed to explore the biological pathways through which specific nutrients and dietary patterns influence gastric carcinogenesis.

CONCLUSION

Dietary factors play a crucial role in the development of H. pylori-negative EGC. High salt intake, processed foods, and low consumption of fruits and vegetables have been consistently identified as risk factors, while diets rich in antioxidants, dietary fiber, and specific micronutrients offer protective effects. Mediterranean and other prudent dietary patterns have shown an inverse association with GC risk, independent of H. pylori infection. Despite these findings, significant gaps remain in understanding the precise mechanisms by which diet influences gastric carcinogenesis in H. pylori-negative populations. Future research should focus on clarifying these mechanisms and developing targeted dietary interventions to reduce GC risk in high-risk individuals.