Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome
1. H.
Helicobacter pylori is a Gram-negative member of the Epsilonproteobacteria class.
Over 50% of the global human population is colonized with H. pylori, which inhabits the gastric niche of human hosts and is commonly acquired early in life. Furthermore, evidence indicates that H. pylori has colonized human hosts and coevolved for at least a thousand centuries [1–4]. The human stomach provides numerous nutritional opportunities and challenges for an invading prokaryote. To colonize the stomach successfully, H. pylori must survive the acidic pH in the lumen of the stomach, move through the mucus lining of the gastric tissue via chemotactic flagellar-mediated motility, attach to gastric epithelial cells using a repertoire of adhesins, and deploy cytotoxins to alter the gastric environment and create a hospitable niche for bacterial proliferation [3]. These bacterial toxins promote necrosis, autophagy, and proinflammatory signaling cascades [4, 5]. However, H. pylori persists in the stomach despite a robust inflammatory response, indicating that
2. H. pylori Infection and Disease Outcomes
Virtually all hosts infected with H. pylori experience gastritis while a smaller subset of these patients develop more serious outcomes such as peptic or duodenal ulcer, MALT lymphoma, or gastric adenocarcinoma. Nearly 75% of all gastric cancer and 5.5% of all malignancies worldwide can be attributed to H. pylori [4]. H. pylori infection is the strongest risk factor for developing gastric cancer [5]. It is proposed that the profound proinflammatory signaling initiated by H. pylori infection leads to atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric cancer [6]. This process, termed the “Correa pathway” is predicated on the chronic inflammation of the gastric mucosa which fosters a cascade of genotypic perturbations that ultimately lead to carcinogenesis [6–9]. It is increasingly appreciated that carcinogenesis is established due to a constellation of factors including host genetics, environment, and bacterial strain differences [6–10]. A better understanding of how these factors intersect to promote disease progression could yield novel preventative or therapeutic strategies to ameliorate the global disease burden, which costs hundreds of thousands of human lives each year [10]. In this review we consider how nutrition, or the process by which an organism derives cofactors and metabolic precursors, impacts the progression of H. pylori-associated disease outcomes and gastric
homeostasis. Furthermore, we discuss how host micronutrients can alter bacterial growth and virulence and ultimately influence pathogenesis.
H. pylori has an ancient association with human beings [1]. Although H. pylori strains exhibit remarkable genetic diversity, phylogenetic analyses have revealed that strains can be classified into distinct phylogeographic clades indicative of their origin [2, 3]. These results indicate that H. pyloristrains have coevolved with their hosts, observations which are supported by results indicating that H. pylori has undergone reductive evolution during its association with man [11]. However, prolonged coevolution is commonly associated with commensal adaptation and concurrent loss of virulence [12, 13]. Because H. pylori exhibits strain-specific virulence and potential to cause disease, this supports a model in which the coevolution of H. pylori and its cognate human host has been perturbed [2, 3].
In some geographical settings, such as Asia, H. pylori infection and gastric cancer rates are correlative. However, in other areas, such as Africa, Malaysia, India, and Costa Rica, infection rates are high and gastric cancer rates are low [14–17]. These are collectively referred to as “enigmas” because the protective mechanisms in these populations are obscure. It is proposed that H. pylori potentially coevolves with its host to dampen pathogenic effects and promote immunological tolerance which facilitates protection against numerous autoimmune diseases including allergic airway disease [18, 19]. However, the role of geography, nutrition, and
Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome
Kathryn P. Haley and Jennifer A. Gaddy
Abstract
Helicobacter pylori colonizes the stomachs of greater than 50% of the world's human population making it arguably one of the most successful bacterial pathogens. Chronic H. pylori colonization results in gastritis in nearly all patients; however in a subset of people, persistent infection with H. pylori is associated with an increased risk for more severe disease outcomes including B-cell lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma) and invasive adenocarcinoma. Research aimed at elucidating determinants that mediate disease progression has revealed genetic differences in both humans and H. pylori which increase the risk for developing gastric cancer. Furthermore, host diet and nutrition status have been shown to influence H. pylori-associated disease outcomes. In this review we will discuss how H. pylori is able to create a replicative niche within the hostile host environment by subverting and modifying the host-generated immune response as well as successfully competing for limited nutrients such as transition metals by deploying an arsenal of metal acquisition proteins and virulence factors. Lastly, we will discuss how micronutrient availability or alterations in the gastric microbiome may exacerbate negative disease outcomes associated with H. pyloricolonization.
1. H. pylori Infects the Human Stomach
Helicobacter pylori is a Gram-negative member of the Epsilonproteobacteria class. Over 50% of the global human population is colonized with H. pylori, which inhabits the gastric niche of human hosts and is commonly acquired early in life. Furthermore, evidence indicates that H. pylori has colonized human hosts and coevolved for at least a thousand centuries [1–4]the human stomach provides numerous nutritional opportunities and challenges for an invading prokaryote. To colonize the stomach successfully, H. pylori must survive the acidic pH in the lumen of the , move through the mucus lining of the gastric tissue via chemotactic flagellar-mediated motility, attach to gastric epithelial cells using a repertoire of adhesins, and deploy cytotoxins to alter the gastric environment and create a hospitable niche for proliferation These bacterial toxins promote necrosis, autophagy, and proinflammatory signaling cascades However, H. pylori persists in the stomach despite a robust inflammatory response, indicating that this organism has evolved elaborate mechanisms circumnavigatethe onslaught of host immunity].
2. H. pylori Infection and Disease Outcomes
Virtually all hosts infected with H. pylori experience gastritis while a smaller subset of these patients develop more serious outcomes such as peptic or duodenal ulcer, MALT lymphoma, or gastric adenocarcinoma. Nearly 75% of all gastric cancer and 5.5% of all malignancies worldwide can be attributed to H. pylori H. pylori infection is the strongest risk factor for developing gastric cancer It is proposed that the profound proinflammatory signaling initiated by H. pylori infection leads to atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric cancer [6]. This process, termed the “Correa pathway” is predicated on the chronic inflammation of the gastric mucosa which fosters a cascade of genotypic perturbations that ultimately lead to carcinogenesis [6–9]. It is increasingly appreciated that carcinogenesis is established due to a constellation of factors including host genetics, environment, and bacterial strain differences [6–10]. A better understanding of how these factors intersect to promote disease progression could yield novel preventative or therapeutic strategies to ameliorate the global disease burden, which costs hundreds of thousands of human lives each year [10]. In this review we consider how nutrition, or the process by which an organism derives cofactors and metabolic precursors, impacts the progression of H. pylori-associated disease outcomes and gastric homeostasis. Furthermore, we discuss how host micronutrients can alter bacterial growth and virulence and ultimately influence pathogenesis.
H. pylori has an ancient association with human beings [1]. Although H. pylori strains exhibit remarkable genetic diversity, phylogenetic analyses have revealed that strains can be classified into distinct phylogeographic clades indicative of their origin [2, 3]. These results indicate that H. pyloristrains have coevolved with their hosts, observations which are supported by results indicating that H. pylori has undergone reductive evolution during its association with man [11]. However, prolonged coevolution is commonly associated with commensal adaptation and concurrent loss of virulence [12, 13]. Because H. pylori exhibits strain-specific virulence and potential to cause disease, this supports a model in which the coevolution of H. pylori and its cognate human host has been perturbed [2, 3].
In some geographical settings, such as Asia, H. pylori infection and gastric cancer rates are correlative. However, in other areas, such as Africa, Malaysia, India, and Costa Rica, infection rates are high and gastric cancer rates are low [14–17]. These are collectively referred to as “enigmas” because the protective mechanisms in these populations are obscure.
It is proposed that H. pylori potentially coevolves with its host to dampen pathogenic effects and promote immunological tolerance which facilitates protection against numerous autoimmune diseases including allergic airway disease [18, 19]. However, the role of geography, nutrition, and host genetics remains ill-defined in this model. Furthermore, regions within a single country, such as Colombia, experience differential disease outcomes [20]. Recent assessments of genetic variations in both host andH. pylori strain by multilocus sequence typing analyses (MLST) were performed to ascertain how the coevolutionary relationships between hosts and pathogens were shaping development of gastric cancer [2]. This work demonstrated that low-risk coastal Colombians exhibit phylogenetic variations consistent with an admixture of Amerindian, European, and African populations. Similarly, H. pylori strains recovered from these individuals primarily represented an African lineage of H. pylori that was concordant with the host genetic background [2, 3]. Conversely, mountain-dwelling Colombians exhibit phylogenetic variations consistent with Amerindian heritage and their H. pylori strains predominantly were associated with a European phylogenetic clade [2, 3]. The authors conclude that infection with a strain of H. pylori that is discordant with host phylogenetic background is predictive for increased risk of gastric cancer [2].
3. H. pylori Virulence Factors
Besides phylogenetic differences between host and pathogen, there are specific strain differences that have been associated with increased risk of gastric disease. H. pylori strains that harbor a 40 kb genomic island termed the “cag-pathogenicity island” (cag-PAI) have been associated with increased risk of gastric disease outcome [21]. The cag-
PAI encodes a type
Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome
Helicobacter pylori colonizes the stomachs of greater than 50% of the world's human population making it arguably of the most successful bacterial pathogens. Chronic H. pylori colonization results in gastritis in nearly all patients; however in a subset of people, persistent infection with H. pylori is associated with an increased risk for more severe disease outcomes including B-cell lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma) and invasive adenocarcinoma. Research aimed at elucidating determinants that mediate disease progression has revealed genetic differences in both humans and H. pylori which increase the risk for developing gastric cancer. Furthermore, host diet and nutrition status have been shown to influence H. pylori-associated disease outcomes. In this review we will discuss how H. pylori is able to create a replicative niche within the hostile host environment by subverting and modifying the host-generated immune response as well as successfully competing for limited nutrients such as transition metals by deploying an arsenal of metal acquisition proteins and virulence factors. Lastly, we will discuss how micronutrient availability or alterations in the gastric microbiome may exacerbate negative disease outcomes associated with H. pyloricolonization.
1. H. pylori Infects the Human Stomach
Helicobacter pylori is a Gram-negative member of the Epsilonproteobacteria class. Over 50% of the global human population is colonized with H. pylori, which inhabits the gastric niche of human hosts and is commonly acquired early in life. Furthermore, evidence indicates that H. pylori has colonized human hosts and coevolved for at least a thousand centuries [1–4]. The human stomach provides numerous nutritional opportunities and challenges for an invading prokaryote. To colonize the stomach successfully, H. pylori must survive the acidic pH in the lumen of the stomach, move through the mucus lining of the gastric tissue via chemotactic flagellar-mediated motility, attach to gastric epithelial cells using a repertoire of adhesins, and deploy cytotoxins to alter the gastric environment and create a hospitable niche for bacterial proliferation [3]. These bacterial toxins promote necrosis, autophagy, and proinflammatory signaling cascades [4, 5]. However, H. pylori persists in the stomach despite a robust inflammatory response, indicating that this organism has evolved elaborate mechanisms to circumnavigate the onslaught of host immunity [4–6].
2. H. pylori Infection and Disease Outcomes
Virtually all hosts infected with H. pylori experience gastritis while a smaller subset of these patients develop more serious outcomes such as peptic or duodenal ulcer, MALT lymphoma, or gastric adenocarcinoma. Nearly 75% of all gastric cancer and 5.5% of all malignancies worldwide can be attributed to H. pylori [4]. H. pylori infection is the strongest risk factor for developing gastric cancer [5]. It is proposed that the profound proinflammatory signaling initiated by H. pylori infection leads to atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric cancer [6]. This process, termed the “Correa pathway” is predicated on the chronic inflammation of the gastric mucosa which fosters a cascade of genotypic perturbations that ultimately lead to carcinogenesis [6–9]. It is increasingly appreciated that carcinogenesis is established due to a constellation of factors including host genetics, environment, and bacterial strain differences [6–10]. A better understanding of how these factors intersect to promote disease progression could yield novel preventative or therapeutic strategies to ameliorate the global disease burden, which costs hundreds of thousands of human lives each year [10]. In this review we consider how nutrition, or the process by which an organism derives cofactors and metabolic precursors, impacts the progression of H. pylori-associated disease outcomes and gastric homeostasis. Furthermore, we discuss how host micronutrients can alter bacterial growth and virulence and ultimately influence pathogenesis.
H. pylori has an ancient association with human beings [1]. Although H. pylori strains exhibit remarkable genetic diversity, phylogenetic analyses have revealed that strains can be classified into distinct phylogeographic clades indicative of their origin [2, 3]. These results indicate that H. pyloristrains have coevolved with their hosts, observations which are supported by results indicating that H. pylori has undergone reductive evolution during its association with man [11]. However, prolonged coevolution is commonly associated with commensal adaptation and concurrent loss of virulence [12, 13]. Because H. pylori exhibits strain-specific virulence and potential to cause disease, this supports a model in which the coevolution of H. pylori and its cognate human host has been perturbed [2, 3].
In some geographical settings, such as Asia, H. pylori infection and gastric cancer rates are correlative. However, in other areas, such as Africa, Malaysia, India, and Costa Rica, infection rates are high and gastric cancer rates are low [14–17]. These are collectively referred to as “enigmas” because the protective mechanisms in these populations are obscure. It is proposed that H. pylori potentially coevolves with its host to dampen pathogenic effects and promote immunological tolerance which facilitates protection against numerous autoimmune diseases including allergic airway disease [18, 19]. However, the role of geography, nutrition, and host genetics remains ill-defined in this model. Furthermore, regions within a single country, such as Colombia, experience differential disease outcomes [20]. Recent assessments of genetic variations in both host andH. pylori strain by multilocus sequence typing analyses (MLST) were performed to ascertain how the coevolutionary relationships between hosts and pathogens were shaping development of gastric cancer [2]. This work demonstrated that low-risk coastal Colombians exhibit phylogenetic variations consistent with an admixture of Amerindian, European, and African populations. Similarly, H. pylori strains recovered from these individuals primarily represented an African lineage of H. pylori that was concordant with the host genetic background [2, 3]. Conversely, mountain-dwelling Colombians exhibit phylogenetic variations consistent with Amerindian heritage and their H. pylori strains predominantly were associated with a European phylogenetic clade [2, 3]. The authors conclude that infection with a strain of H. pylori that is discordant with host phylogenetic background is predictive for increased risk of gastric cancer [2].
3. H. pylori Virulence Factors
Besides phylogenetic differences between host and pathogen, there are specific strain differences that have been associated with increased risk of gastric disease. H. pylori strains that harbor a 40 kb genomic island termed the “cag-pathogenicity island” (cag-PAI) have been associated with increased risk of gastric disease outcome [21]. The cag-PAI encodes a type IV secretion system (cag-T4SS) which is a macromolecular nanomachine that spans both the inner and outer membrane of H. pylori. The cag-T4SS functions to transport substrates, such as peptidoglycan, and effector molecules, such as the oncogenic cytotoxin CagA, from the bacterial cytoplasm into the host epithelial cell. The activity of the T4SS has multiple effects on the host including nuclear factor κB activation, IL-8 chemokine secretion, host cytoskeletal rearrangement, and recruitment of innate immune cells to the site of infection [22–25]. In addition to the cag-T4SS cytotoxin secretion, H. pylori also secretes a pore-forming cytotoxin, VacA [26]. VacA is an 88-kDa protein that is secreted through type V, or autotransporter secretion pathway [27]. It causes a variety of alterations in target cells including vacuolation, depolarization of membrane potential, permeabilization, disruption of endosomal and lysosomal trafficking, autophagy, programmed necrosis, and immune modulation including inhibition of T cell activation and proliferation. Interestingly, VacA and CagA appear to have antagonistic properties: CagA is highly proinflammatory, while VacA is immunosuppressive, and VacA induces CagA degradation via autophagic pathways [22, 27, 28]. Interestingly, both VacA and CagA are often coregulated in response to nutritional signals, indicating that H. pylori has evolved to utilize both of these toxins in concert under certain nutritional stresses [29]. Together, these two cytotoxins promote H. pylori-dependent pathogenesis.
Additionally, H. pylori utilizes a repertoire of outer membrane proteins to facilitate host-pathogen interactions. The adhesin BabA binds mucosal
Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome
.
4. H. pylori and Nutrition
In addition to host or strain genetic differences, environmental factors, such as host diet, are emerging as important components of the ecology within the gastric environment. It is likely that the gastric environment is highly influenced by host nutrient intake. Epidemiological
studies have
revealed that dietary habits such as high intake of green tea, fruits, or vegetables are protective against gastric cancer risk [37–39]. Conversely, case-controlled and cohort studies reveal that high intake of red meat and/or processed meat (which are high in transition metals) and preserved foods (pickled, dried, smoked, or salted) which are often high in salt is associated with increased risk of noncardia gastric cancer [40, 41]. Furthermore, the advent of refrigeration has radically changed the manner in which food is prepared for storage. Case-controlled population studies have demonstrated that access to refrigeration is protective against gastric cancer [42]. This is attributed to the fact that refrigeration leads to prolonged access to fresh foods such as fruits and vegetables, which would otherwise be unavailable. It is hypothesized that carotenoids, folate, vitamin C, and phytochemicals from fruits and vegetables have a protective role against carcinogenesis. Conversely, salt and the availability of some transition metals can alter H. pylori virulence and accelerate carcinogenesis [43, 44]. The contribution of these individual micronutrients to H. pylori-dependent diseases will be reviewed in detail below.
4.1. Salt
Gastric cancer is the third leading cause of death from cancer worldwide. While large geographic and ethnic differences in gastric cancer incidence exist, a common risk factor for gastric cancer development is high levels of dietary salt intake. A meta-analysis of studies analysing the association
2. H. pylori Infection and Disease Outcomes
Virtually all hosts infected with H. pylori experience gastritis while a smaller subset of these patients develop more serious outcomes such as peptic or duodenal ulcer, MALT lymphoma, or gastric adenocarcinoma. Nearly 75% of all gastric cancer and 5.5% of all malignancies worldwide can be attributed to H. pylori [4]. H. pylori infection is the strongest risk factor for developing gastric cancer [5]. It is proposed that the profound proinflammatory signaling initiated by H. pylori infection leads to atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric cancer [6]. This process, termed the “Correa pathway” is predicated on the chronic inflammation of the gastric mucosa which fosters a cascade of genotypic perturbations that ultimately lead to carcinogenesis [6–9]. It is increasingly appreciated that carcinogenesis is established due to a constellation of factors including host genetics, environment, and bacterial strain differences [6–10]. A better understanding of how these factors intersect to promote disease progression could yield novel preventative or therapeutic strategies to ameliorate the global disease burden, which costs hundreds of thousands of human lives each year [10]. In this review we consider how nutrition, or the process by which an organism derives cofactors and metabolic precursors, impacts the progression of H. pylori-associated disease outcomes and gastric homeostasis. Furthermore, we discuss how host micronutrients can alter bacterial growth and virulence and ultimately influence pathogenesis.
H. pylori has an ancient association with human beings [1]. Although H. pylori strains exhibit remarkable genetic diversity, phylogenetic analyses have revealed that strains can be classified into distinct phylogeographic clades indicative of their origin [2, 3]. These results indicate that H. pyloristrains have coevolved with their hosts, observations which are supported by results indicating that H. pylori has undergone reductive evolution during its association with man [11]. However, prolonged coevolution is commonly associated with commensal adaptation and concurrent loss of virulence [12, 13]. Because H. pylori exhibits strain-specific virulence and potential to cause disease, this supports a model in which the coevolution of H. pylori and its cognate human host has been perturbed [2, 3].
In some geographical settings, such as Asia, H. pylori infection and gastric cancer rates are correlative. However, in other areas, such as Africa, Malaysia, India, and Costa Rica, infection rates are high and gastric cancer rates are low [14–17]. These are collectively referred to as “enigmas” because the protective mechanisms in these populations are obscure. It is proposed that H. pylori potentially coevolves with its host to dampen pathogenic effects and promote immunological tolerance which facilitates protection against numerous autoimmune diseases including allergic airway disease [18, 19]. However, the role of geography, nutrition, and host genetics remains ill-defined in this model. Furthermore, regions within a single country, such as Colombia, experience differential disease outcomes [20]. Recent assessments of genetic variations in both host andH. pylori strain by multilocus sequence typing analyses (MLST) were performed to ascertain how the coevolutionary relationships between hosts and pathogens were shaping development of gastric cancer [2]. This work demonstrated that low-risk coastal Colombians exhibit phylogenetic variations consistent with an admixture of Amerindian, European, and African populations. Similarly, H. pylori strains recovered from these individuals primarily represented an African lineage of H. pylori that was concordant with the host genetic background [2, 3]. Conversely, mountain-dwelling Colombians exhibit phylogenetic variations consistent with Amerindian heritage and their H. pylori strains predominantly were associated with a European phylogenetic clade [2, 3]. The authors conclude that infection with a strain of H. pylori that is discordant with host phylogenetic background is predictive for increased risk of gastric cancer [2].
3. H. pylori Virulence Factors
Besides phylogenetic differences between host and pathogen, there are specific strain differences that have been associated with increased risk of gastric disease. H. pylori strains that harbor a 40 kb genomic island termed the “cag-pathogenicity island” (cag-PAI) have been associated with increased risk of gastric disease outcome [21]. The cag-PAI encodes a type IV secretion system (cag-T4SS) which is a macromolecular nanomachine that spans both the inner and outer membrane of H. pylori. The cag-T4SS functions to transport substrates, such as peptidoglycan, and effector molecules, such as the oncogenic cytotoxin CagA, from the bacterial cytoplasm into the host epithelial cell. The activity of the T4SS has multiple effects on the host including nuclear factor κB activation, IL-8 chemokine secretion, host cytoskeletal rearrangement, and recruitment of innate immune cells to the site of infection [22–25]. In addition to the cag-T4SS cytotoxin secretion, H. pylori also secretes a pore-forming cytotoxin, VacA [26]. VacA is an 88-kDa protein that is secreted through type V, or autotransporter secretion pathway [27]. It causes a variety of alterations in target cells including vacuolation, depolarization of membrane potential, permeabilization, disruption of endosomal and lysosomal trafficking, autophagy, programmed necrosis, and immune modulation including inhibition of T cell activation and proliferation. Interestingly, VacA and CagA appear to have antagonistic properties: CagA is highly proinflammatory, while VacA is immunosuppressive, and VacA induces CagA degradation via autophagic pathways [22, 27, 28]. Interestingly, both VacA and CagA are often coregulated in response to nutritional signals, indicating that H. pylori has evolved to utilize both of these toxins in concert under certain nutritional stresses [29]. Together, these two cytotoxins promote H. pylori-dependent pathogenesis.
Additionally, H. pylori utilizes a repertoire of outer membrane proteins to facilitate host-pathogen interactions. The adhesin BabA binds mucosal ABO/Lewis-B blood group carbohydrates and consequently facilitates adhesion to gastric surfaces. Adherence to the gastric mucosa and/or epithelial surface is a critical first step in colonization and ultimately aids bacterial virulence by promoting the interaction of the cag-T4SS with host cells [30, 31]. Another adhesin, SabA, binds to laminin and sialyl-dimaric-Lewis × glycosphingolipid receptor and is a member of the BabA protein family [32]. Upon binding to the receptor, SabA promotes hemagglutination via sialyl-Lex binding, a process that is critical for survival within the hostile gastric environment [33]. Additionally, H. pylori outer membrane protein and Hop-family proteins such as outer membrane inflammatory protein A (OipA, encoded by hopH) or HopZ protein are both required for gastric epithelial cell binding [33]. Although the host receptors for these proteins have not yet been identified, both proteins have been implicated in inflammation and/or carcinogenesis [34, 35]. Interestingly, there is a high degree of variation in the sequence of CagA, VacA, BabA, SabA, OipA, and HopZ, indicating that H. pylori adapts to its host by modifying the repertoire of virulence factors to accommodate niche-specific challenges [36].
4. H. pylori and Nutrition
In addition to host or strain genetic differences, environmental factors, such as host diet, are emerging as important components of the ecology within the gastric environment. It is likely that the gastric environment is highly influenced by host nutrient intake. Epidemiological studies have revealed that dietary habits such as high intake of green tea, fruits, or vegetables are protective against gastric cancer risk [37–39]. Conversely, case-controlled and cohort studies reveal that high intake of red meat and/or processed meat (which are high in transition metals) and preserved foods (pickled, dried, smoked, or salted) which are often high in salt is associated with increased risk of noncardia gastric cancer [40, 41]. Furthermore, the advent of refrigeration has radically changed the manner in which food is prepared for storage. Case-controlled population studies have demonstrated that access to refrigeration is protective against gastric cancer [42]. This is attributed to the fact that refrigeration leads to prolonged access to fresh foods such as fruits and vegetables, which would otherwise be unavailable. It is hypothesized that carotenoids, folate, vitamin C, and phytochemicals from fruits and vegetables have a protective role against carcinogenesis. Conversely, salt and the availability of some transition metals can alter H. pylori virulence and accelerate carcinogenesis [43, 44]. The contribution of these individual micronutrients to H. pylori-dependent diseases will be reviewed in detail below.
4.1. Salt
Gastric cancer is the third leading cause of death from cancer worldwide. While large geographic and ethnic differences in gastric cancer incidence exist, a common risk factor for gastric cancer development is high levels of dietary salt intake. A meta-analysis of studies analysing the association between diets rich in salt and gastric cancer risk concluded that salt consumption is directly associated with the risk of gastric cancer [45]. Furthermore, the risk of developing cancer increases with increased salt ingestion in a dose-dependent manner [46]. Studies included in this meta-analysis looked at the association between high salt diets and gastric cancer across a spectrum of countries and ethnicities. For example, the meta-analysis included studies which found a correlation between consumption of salty foods, such as miso soup, pickled vegetables, and salted fish within Japanese people, and a study conducted in Norway evaluating the risk of total salt intake and gastric carcinoma. Also included in this meta-analysis are studies which show no correlation between excessively salted foods and cancer; however the strain of H. pylori endemic to these regions lacks cagA and is associated with a decreased risk of gastric cancer as compared to strains harboring cagA. Additional studies indicated that the association between salt consumption and gastric cancer risk was highest amongst individuals who were habitual consumers of high salt foods [45]. The rationale for this association between heavy salt intake and gastric cancer is multifaceted and includes that salt perturbs the integrity and viscosity of gastric mucosa and promotes colonization by H. pylori both of which ultimately contribute to increased inflammation and subsequent gastric cell proliferation and endogenous DNA mutations [47–49]. One such study compared gastric tissue morphology of mice maintained on a standard diet compared to mice sustained on a high salt diet and found that 4.2. Iron
Iron is an essential nutrient for nearly every living organism including H. pylori [53]. Iron is frequently used as an enzymatic cofactor and plays a critical role in respiration and electron transport [54]. To prevent bacterial growth, the human body exploits this need for iron by limiting bacterial access to this vital metal and sequestering iron intracellularly in a process referred to as nutritional immunity [55]. The majority of iron within the human body is localized within erythrocytes in the form of heme, a tetrapyrrole ring with a coordinated iron center. Heme is then further complexed within hemoglobin [56]. Any extracellular iron is rapidly removed by high-affinity iron binding proteins such as lactoferrin and transferrin [57]. Nutritional immunity is a dynamic process capable
