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Vitamin C: A Preventative, Therapeutic
Agent Against Helicobacter pylori
Azhar Hussain , Elsa Tabrez , Jagannadha Rao Peela , Prasanna Honnavar , Shams S.M.
Tabrez
1. Medicine, Davenport University, College of Health Professionals, Grand Rapids, USA 2. Medicine, St.
Matthew’s University School of Medicine, George Town, CYM 3. Faculty of Medicine, Professor of Medical
Genetics and Biochemistry, St. Matthew's University School of Medicine, George Town, CYM 4. Faculty of
Medicine, Chair of Infection and Immunity System, Department of Microbiology and Immunology.,
Xavier University School of Medicine, Oranjestad, ABW 5. Board Certified Gastroenterologist and
Hepatologist, University of Central Florida, College of Medicine, Orlando, USA
Corresponding author: Azhar Hussain, azharhu786@gmail.com
Disclosures can be found in Additional Information at the end of the article
Abstract
The treatment of Helicobacter pylori (H. pylori) induced infections using antibiotic therapies is
clinically well accepted; however, using a noninvasive approach with the implementation of
therapeutic agents such as vitamin C is not well investigated. Vitamin C has certain
characteristics, which allow for it to be considered as a potential treatment option for patients
with H. pylori infections. Vitamin C’s hostility and mechanism of action towards H. pylori
infection in peptic ulcer disease can be classified into two categories: as a preventative agent
and alternatively as a therapeutic agent. Preventatively vitamin C acts as a biological
antioxidant as well as an immune boosting agent, while therapeutically it acts as an inhibitor of
urease, a potential collagen synthesizing agent, and a stimulant in prostaglandin synthesis. As
a result, the dosage of vitamin C should be highly regulated. Furthermore, numerous studies
have shown that vitamin C supplementation if taken with antibiotics can increase the
efficiency of the treatment leading to an increased possibility of eradication of H. pylori in
infected individuals. This paper will investigate the recent studies that show different
mechanisms through which vitamin C can be used as a preventative or a therapeutic agent for
the treatment of H. pylori related infections.
Categories: Internal Medicine, Gastroenterology, Infectious Disease
Keywords: peptic ulcer disease, vitamin c supplementation, urease, vitamin c, helicobacter pylori
infection
Introduction And Background
Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic, spiral-shaped bacterium that
colonizes on the mucosal lining of the stomach [1]. H. pylori is one of the primary causes of
upper gastrointestinal diseases, including dyspepsia, peptic ulcer diseases, heartburn, and
gastroesophageal reflux disease. Chronic disease due to H. pylori has been associated with the
advancement of gastric adenocarcinoma and lymphoma involving mucosa-associated lymphoid
tissue (MALT) [2]. Some 95% of the patients with H. pylori infection develop duodenal ulcers,
80% of the patients develop gastric ulcers, and 10%-15% of the patients develop peptic ulcers.
The bacteria transmit via oro-oral, oro-fecal, or oro-gastric route. Recent studies showed that
over 50% of the global population is infected by H. pylori infection in which 1%-3% develop
gastric cancer. As a result, the World Health Organization classified H. pylori as a group 1
carcinogen [1].
1 2 3 4
5
Open Access Review
Article DOI: 10.7759/cureus.3062
How to cite this article
Hussain A, Tabrez E, Peela J, et al. (July 30, 2018) Vitamin C: A Preventative, Therapeutic Agent Against
Helicobacter pylori. Cureus 10(7): e3062. DOI 10.7759/cureus.3062
The proton pump inhibitor (PPI) (e.g., omeprazole 20 mg BID, lansoprazole 30 mg BID, or
pantoprazole 40 mg QID) with two antibiotics treatment (such as amoxicillin 1000 mg BID and
clarithromycin 500 mg BID) is considered as a standard triple therapy and as a first-line
treatment option for H. pylori infection [3]. The optimal duration of a standard triple therapy is
14 days achieving a H. pylori eradication rate of 81.9%, as compared to 7 days triple therapy
which attains an eradication rate of only 72.9% [4]. The standard triple therapy is followed by a
second-line treatment, which is a quadruple therapy that consists of a PPI or H2 receptor
antagonist (e.g., lansoprazole 30 mg BID or ranitidine 150 mg BID) plus bismuth subsalicylate
525 mg QID, metronidazole 250 mg QID, and tetracycline 500 mg QID for additional 10-14 days
for 90.4% eradication [3], but the eradication rate of infection is minimal due to antibiotic
resistance and compliance. However, several nonantibiotic treatments have been investigated
as potential adjuvants for the treatment of H. pylori; these include phytomedicines, probiotics,
and antioxidants [5]. The vitamin C content in gastric juice has recently pulled in numerous
researchers, suggesting that vitamin C might be a protective agent against the H.
pylori infection especially against the development of gastric cancer [6]. N-nitroso compounds
(NOCs) are strong carcinogens and are closely related to food and nutrition [7]. It has been
demonstrated that vitamin C is anticarcinogenic because it inhibits the development of N-
nitroso mixes (NOCs) in gastric juice [8].
There have been several clinical studies which demonstrated that high H. pylori infection rate is
related to low vitamin C (ascorbic acid) level in the gastric juice as well as in the serum [9-10].
Nevertheless, many studies demonstrated that a high dose of vitamin C would inhibit the
growth and colonization of H. pylori and even eradicate them [11-12]. Understanding the
mechanism would help to design more clinical studies in more reasonable ways to formulate
appropriate anti-H. pylori agents.
Review
Survival of H. pylori at low gastric pH
Helicobacter pylori is not an acidophile, but the main reason for its ability to overcome the
acidic gastric environment is due to its ability to synthesize a large amount of urease enzyme
that catalyzes the hydrolysis of urea to yield ammonia and carbonic acid [13]. The activation of
the urease is a key factor in the successful colonization of bacteria into the gastric mucosa
because it can allow the bacteria to survive at a very low acidic pH of 2.5 [1]. However, in the
absence of the enzyme urease, the bacteria can only survive at a pH of 4.0-8.0 [13]. Autolysis of
the H. pylori colony results in the release of cystolic urease into the gastric mucosa, which
attaches to the surface of the H. pylori bacteria [5, 14]. In the gastric mucosa, the deprotonated
carbonic acid and protonated ammonia are in equilibrium [15]. The effect of this reaction is an
increase in pH and formation of a basic ammonium cloud around the bacteria allowing H.
pylori to survive and to colonize on the gastric epithelium [15]. On successful colonization, H.
pylori resides below the gastric mucus which has a higher pH than the gastric lumen [16].
The motility of the H. pylori plays an important role in the pathogenesis and successful
colonization into gastric mucosa. For this purpose, H. pylori has two to six polar sheathed
flagellae, which allow the movement of the bacterium into the highly viscous mucus layer of
the gastric epithelium. These flagellae are composed of three main structures: the basal body,
which serves as a cell anchor and contains the proteins required for rotation and chemotaxis, a
curved hook, and the helically shaped flagellar filament [17]. The lining of the stomach is a
spongy gel-like state because of the acid content which the bacterium is unable to penetrate.
However, by using its flagella, H. pylori releases an adhesion molecule, which allows the
bacterium to bind to the host cell [18]. The bacterium then releases a high amount of urease
enzyme, which can neutralize the acid by converting urea into carbon dioxide, and ammonia,
and drills in the mucoid lining of the gastric epithelium [16].
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Discussion: mechanisms of action of vitamin C against H.
pylori
Vitamin C can be used as a preventative agent as summarized in Table 1 and as a therapeutic
agent as summarized in Table 2. This review focuses on the mechanism through which vitamin
C can be preventative: as beneficially used to prevent H. pylori infection as well as therapeutic:
as to control the infection and eradicate the bacteria.
I. Vitamin C as a Preventative Agent
Preventative agent
Role Function
Biological antioxidant Ascorbic acid scavenges and eliminates free radicals
Immune booster 100-fold increase of vitamin C inside immune cells and decrease of plasma vitamin C
TABLE 1: Role of vitamin C as a preventative agent.
Biological Antioxidant
Vitamin C is a nonessential, potent, water-soluble micronutrient that can neutralize a wide
range of pro-oxidants, due to its low redox potential [19-20]. Vitamin C functions as a
biological antioxidant, an oxidative stress reducer, a factor in immune function and in enzyme
activation as shown in Table 1 [19]. Vitamin C also acts as a cofactor in the biosynthesis of
collagen, catecholamines, and peptide hormones [21]. Vitamin C exists in two major forms:
reduced form as ascorbic acid, as well as its oxidized form as dehydroascorbic acid, which may
be interconvertible [20], by a dehydroascorbic acid reductase, glutaredoxins or other thiols
acting as an electron donor [5]. The reduced form as ascorbic acid has scavenger properties and
may be beneficial to eliminate free radicals under the formation of semidehydroascorbic acid,
which is a nonreactive radical [22]. The dehydroascorbic acid may spontaneously hydrolyze and
dehydrate; however, the ascorbic acid is more stable and does not show the same tendency to
irreversibly hydrolyze particularly at pH > 4 [5]. This mechanism is essential for the inhibition of
the growth of H. pylori [16, 18, 23].
Immune Boosting Agent
The immune system within the human body acts as a protective agent against pathogens that
cause infections and diseases. These immune responses are divided into two categories; an
innate system is the first nonspecific immune response, while the adaptive immune response is
pathogen-specific and develops over time subsequent to the introduction of that particular
pathogen [23-24]. The innate immune response is particularly very important in children
because it exists at birth and offers initial protection against foreign pathogens. Adaptive
immune responses are different in that they are dependent upon prior exposure to the antigens.
The adaptive immune response, therefore, has mature plasma B cells and antibodies, which are
capable of recognizing specific previously encountered antigens. Each successful immune
response concludes with phagocytic engulfing of pathogens by macrophages [24].
One of the most important functions of vitamin C is that it helps in the activation of the
immune system of the body. Within the plasma membrane of the immune cells, there are active
2018 Hussain et al. Cureus 10(7): e3062. DOI 10.7759/cureus.3062 3 of 11
transporters of vitamin C that bind to it and actively transport the vitamin C into the cell [25].
For example, during inflammation due to infection, these transporters increase the influx of
vitamin C up to 100-fold compared to the amount of vitamin C present in the plasma [26]. As a
result, plasma vitamin C concentration can be depleted during infection. Studies show that the
aging of the immune system can be reversed by the supplementation of vitamin C [27]. This
study shows significant results in geriatric patients whose overall immune function is in a
process of degradation.
II. Vitamin C as a Therapeutic Agent
Therapeutic agent
Function Mechanism of action
Urease maturation (potent
virulence factor required for
survival of
H. pylori
in acidic
environments)
Increase in vitamin C leads to the reduction of nickel of urease enzyme
Collagen synthesis
Vitamin C acts as a cofactor for synthesizing collagen type IV required for
synthesis of lamina propria in the stomach lining. The absence of vitamin C
allows easy penetration of
H. pylori
Prostaglandin synthesis
Phospholipid molecule converts to arachidonic acid via the enzyme
phospholipase A2. Arachidonic acid is then converted to prostaglandin via the
enzymes cyclooxygenase 1 (COX1) and cyclooxygenase 2 (COX2)
TABLE 2: Role of vitamin C as a therapeutic agent.
Inactivation of Urease
Urease is an important enzyme that constitutes approximately 5%-6% of the total protein of H.
pylori and it is linked to its pathogenicity as shown in Table 2 [28], due to its ability to colonize
on the gastric mucosa at a low pH [23]. The structure of urease enzyme is composed of two half
subunits held together by a noncovalent bond [5], each subunit containing a specific active site.
These active sites contain two nickel ions that are bound by a carbamylated lysine and an
oxygen donor [29]. In addition to the binding, the first nickel ion is held by two histidine amino
acids and a water molecule and the second nickel ion which is similar in composition to the
first nickel ion, also contains the amino acid aspartate as shown in Figure 1 [5, 14, 28-29]. The
ability of vitamin C to inhibit urease action plays an important role in understanding the
mechanism of H. pylori infection and bacterial eradication [30]. Studies show that the high
concentration of vitamin C favors reduction of the nickel center in the urease enzyme [5],
which in turn inhibits the activity of the enzyme and may reduce the H. pylori manifestations.
2018 Hussain et al. Cureus 10(7): e3062. DOI 10.7759/cureus.3062 4 of 11
FIGURE 1: The structure of urease and the role of vitamin C as
an inhibitor.
Vitamin C, which is a relatively strong acid (pKa = 4.1) further lowers the pH of the gastric
lumen [28]. Vitamin C, a reducing agent of urease, when added to the gastric lumen results in
urease becoming structurally unstable, therefore, irreversibly losing its enzyme activity [30].
Therefore, vitamin C can be beneficial in inhibiting the growth, colonization, and endurance
of H. pylori at an earlier period of the infection and may be helpful in the eradication of the
bacteria [23].
Collagen Synthesizing Agent
The stomach inner lining itself is a layered structure containing four sublayers which are the
mucosa, the submucosa, the muscular, and the serosa. The mucosa layer of the inner stomach
lining is composed of epithelial cells specific to the stomach including parietal cells, chief cells,
and gastric enteroendocrine cells. Below this layer of epithelial cells in the mucosa is the
lamina propria. Under the mucosa layer is the submucosa which entirely contains blood
vessels. H. pylori can bind to the extracellular matrix (ECM) proteins on the surface of the
epithelial cells and infiltrate the cells by releasing toxins as shown in Figure 2 [31]. Once H.
pylori infiltrates the cells, it can further penetrate the deeper layers of the stomach lining and
travel through the bloodstream. Presuming that H. pylori can only penetrate farther into tissues
if it passes through the lamina propria, a durable lamina propria has the potential to prevent
penetration. The lamina propria is composed predominantly of collagen fibers, specifically
collagen type IV which provides structure and support for the epithelial cells located within the
gastric mucosa [32]. Vitamin C is a known cofactor in the synthesis and strengthening of
collagen [33]. Vitamin C's collagen strengthening abilities could potentially be a significant
reason as to why patients with an increased serum and plasma vitamin C experience very little
to no infestation of H. pylori [34]. Stronger collagen in the lamina propria under the epithelium
could attribute to a more difficult infiltration mechanism of H. pylori into the tissues and
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bloodstream, therefore, resulting in decreased penetration and decreased overall prevalence
of H. pylori linked diseases [33].
FIGURE 2: Role of vitamin C in collagen synthesis.
Vitamin C is specifically required for hydroxylation in collagen synthesis, a post-translational
modification [35]. Once pre-procollagen is translated from mRNA, it enters the rough
endoplasmic reticulum for elongation, hydroxylation, and glycosylation prior to its maturation.
Hydroxylation of pre-procollagen allows for further glycosylation of the molecule and
subsequent triple helix formation. Both enzymes, lysyl hydroxylase and prolyl hydroxylase are
necessary for hydroxylation and require vitamin C as a cofactor amongst other elements such as
O2, ferrous (Fe2+), and alpha-ketoglutarate [34]. Without vitamin C, the enzymes are not able to
function and additional modification of pre-procollagen does not take place, in which case the
molecule does not mature to collagen [35]. An increase of vitamin C in the plasma of an
individual could account for an increase in collagen synthesis, therefore, resulting in a tougher
collagen-saturated lamina propria [32]. This relationship has the potential for being a possible
correlating factor between the high vitamin C serum and plasma concentrations and low
occurrence of H. pylori penetrance in certain individuals.
Prostaglandin Synthesis
Prostaglandins (PG) are lipid-derived compounds, subdivided into PGA, PGB, PGE, and
PGF [36], which have inflammatory responses and hormone-like effects on various reactions
within the body [37]. The effect of specific prostaglandins is dependent on its location of the
action. Prostaglandin E2 (PGE2) is found in high concentrations within the gastric juice and
mucosa, and thus has forceful protective effects on the gastric mucosa layer of the inner
stomach lining [38]. PGE2s are protective in the sense that they stimulate mucosal blood flow as
well as mucus and bicarbonate secretion within the lumen of the stomach. The release and
activation of PGE2s are contingent upon injury to the mucosal layer [39]. Subsequent to H.
pylori penetration of the epithelial cells within the mucosa [37], PGE2s are released to secrete
mucus and act as defensive agents [39]. A high degree of prostaglandin synthesis is most likely
related to a high defense against bacterial agents like H. pylori [38].
Certain studies have identified a correlation between vitamin C and the synthesis of
prostaglandin E2 specifically [40]. A study was conducted using inbred mice to assess the
influence of vitamin C on prostaglandin E2 synthesis. A 90%-100% increase in PGE2 output
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Author Publication
date Patients Treatment Results
Sezikli et
al. [47] April 2012
30 patients with
severe gastritis
(
H. pylori
related
infection)
Vitamin C 500 mg BID and vitamin E 200
IU BID for four weeks orally
Increase of eradication of
H.
pylori
was noted upon the introduction of vitamin C [41]. Prostaglandin synthesis begins with the
conversion of a phospholipid molecule to arachidonic acid in the presence of the enzyme
phospholipase A2. Arachidonic acid undergoes a cyclooxygenase reaction and a peroxidase
reaction in the presence of enzymes COX-1 and COX-2, to produce prostaglandin which
becomes tissue-specific depending upon location [42]. El Attar et al. showed that vitamin C has
dose-dependent effects on the release of arachidonic acid which leads to further PGE2
synthesis. In addition to that, vitamin C acts as a stimulant of PGE2 synthesis by inducing the
release of exogenous arachidonic acid in fibroblast cells [40]. Similar findings observed by
Siegel et al. show an abundance of mucous production upon abrasion of the mucosal layer
from H. pylori [41].
Dose regulation of vitamin C
Vitamin C is a water-soluble vitamin and an essential nutrient that must be taken from the diet.
The optimum dietary vitamin C intake of 200 mg per day is essential to increase vitamin C’s
health benefits with the least risk of adverse effects in the majority of the adult population [43].
Normally an excess dose of a water-soluble vitamin simply passes through the body without
causing any toxic effects; however, if vitamin C consumption is more than 2000 mg per day, it
can cause kidney stones as well as osmotic diarrhea due to limited absorption [44].
Recently there have been numerous studies that discuss the dosage of vitamin C in the
treatment of H. pylori. Zojaji et al. conducted a study in which two groups were given
amoxicillin 1 g with metronidazole 500 mg BID and bismuth 240 mg BID with omeprazole 40
mg QID in two divided doses. The second group was given an additional 500 mg of vitamin C.
Experimental results showed that 78% of individuals of group two with the additional vitamin
C were able to eradicate H. pylori as compared to 48.8% of individuals from group one [45].
Similar results were shown byJarosz et al. in which two groups of patients with H.
pylori infection were treated without the administration of any antibiotics. The control group
was treated with antacids for four weeks whereas the second group was treated with the same
antacids for four weeks with an additional dose of 5 g of vitamin C daily for a span of four
weeks. Plasma and gastric juice total vitamin C levels were measured at baseline, at the end of
four weeks’ treatment, and again four weeks after treatment cessation. In the control group, H.
pylori infection remained unchanged in all the patients; however, the patients with vitamin C
treatment were able to eradicate the H. pylori (p = 0.01) [46]. These studies do show promising
results; however, more research must be conducted to determine the best treatment options
accompanied by vitamin C dosages for the treatment of H. pylori.
Additional clinical trials
Table 3 shows the clinical trials that have been previously conducted to assess the effectiveness
of vitamin C with or without the use of antibiotics. These clinical trials further suggest that
vitamin C may be beneficial for decreasing the incidence rate for H. pylori related infections.
2018 Hussain et al. Cureus 10(7): e3062. DOI 10.7759/cureus.3062 7 of 11
Zojaji et al.
[45]
September
2009
312 patients
with
H.
pylori
infection
Group A:162 patients received
amoxicillin 1 g, metronidazole 500 mg
BID, bismuth 240 mg BID, and
omeprazole 40 QID in two doses Group
B: 150 patients received the same
regimen plus 500 mg vitamin C
48.8% of the patients in
Group A and 78% in Group
B responded to eradication
therapy
Sasazuki et
al. [48] April 2003
635 patients
diagnosed with
chronic gastritis
(
H. pylori
related
infection), but
only 244
finished the
treatment
120 patients given low-dose vitamin C
(50 mg) and 124 patients given high-
dose vitamin C (500 mg) completing
five-year supplementation
H. pylori
titer was
significantly reduced by
both low-dose and high-
dose vitamin C
Jarosz et
al. [46]
December
1998
60 patients with
dyspeptic
symptoms and
proven chronic
gastritis, and
H.
pylori
infection
Group 1: 28
patients Group
2: 32 patients
Group 1 was treated with antacid for
four weeks whereas Group B was
treated with antacids for four weeks
with an addition of 5 g of vitamin C for
four weeks, but no antibiotic treatment
in both groups
In the Group A,
H.
pylori
infection remained
unchanged in all patients.
In Group B, the eradication
of
H. pylori
was 30%.
Chuang et
al. [49]
October
2002
104 patients
with
H.
pylori
infection
Group 1 was treated with lansoprazole,
amoxicillin, and metronidazole BID for a
week. Group 2 was treated with
lansoprazole, amoxicillin, and
metronidazole plus vitamin C (250 mg)
and vitamin E (200 mg) BID for a week,
followed by vitamin C and vitamin E QD
for six consecutive weeks
Vitamin C and vitamin E in
combination with triple
therapy is not effective and
showed no
H. pylori
eradication
Chuang et
al. [50]
January–
February
2007
171
H. pylori
i
nfected
patients
Group 1: 55 patients received 20 mg
omeprazole, 1 g amoxicillin, and 250 mg
clarithromycin BID Group 2: 61 patients
received 20 mg omeprazole, 1 g
amoxicillin, and 250 mg clarithromycin
with additional 500 mg vitamin C BID
Group 3: 55 patients 20 mg
omeprazole, 1 g amoxicillin, and 500 mg
clarithromycin
Group 2 had a higher
eradication rate than Group
1 but had an equivalent rate
to Group 3. Results indicate
that an addition of vitamin
C to one week triple therapy
can allow for a reduction of
the dosage of
clarithromycin
TABLE 3: Clinical trial data analysis.
However, there are certain studies, as shown in Table 3, that show that vitamin C, if added with
the triple therapy regimen, may not improve the H. pylori eradication rate. The studies’ inability
to elicit a positive correlation between vitamin C and H. pylori eradication could be attributed
to a particularly low dose [49], a short duration time of the therapy, or the patients’
2018 Hussain et al. Cureus 10(7): e3062. DOI 10.7759/cureus.3062 8 of 11
noncompliance to vitamin C treatment protocols. Further research investigation is needed for
the proper protocol through which vitamin C can be added to the triple therapy regimen to
increase the eradication of the H. pylori infection. These studies must focus on determining the
optimum vitamin C dosage and treatment duration required for H. pylori eradication.
Conclusions
When assessing treatment mechanisms with regard to H. pylori infections, vitamin C’s role as a
potential preventative and therapeutic agent is distinctive. High serum vitamin C levels are
associated with a low incidence rate of H. pylori infection upon exposure. Vitamin C properties
such as biological antioxidant and immune regulator act as a preventative agent against H.
pylori related infections. Vitamin C also acts as a therapeutic agent by functioning as an
inhibitor of urease, a synthesizing agent for collagen, and a stimulant in prostaglandin
synthesis. Therefore, while vitamin C’s preventative and therapeutic capacity is significantly
under-investigated, current studies have established a distinct positive correlation between
vitamin C levels and the body’s ability to combat H. pylori infections.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors
declare the following: Payment/services info: All authors have declared that no financial
support was received from any organization for the submitted work. Financial relationships:
All authors have declared that they have no financial relationships at present or within the
previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or
activities that could appear to have influenced the submitted work.
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