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”Advanced microbiology seminar”
Helicobacter pylori
Done by:
Tala Alsaket
Ruba Al-mgableh
Salam Hiasat
Lujain Arabiat
Background:
Helicobacter pylori is a spiral-shaped Gram-negative bacterium that colonizes the human
stomach and can establish a long-term infection of the gastric mucosa, a condition that affects
the relative risk of developing various clinical disorders of the upper gastrointestinal tract, such
as chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma,
and gastric adenocarcinoma. H. pylori present a high-level of genetic diversity, which can be an
important factor in its adaptation to the host stomach and also for the clinical outcome of
infection. There are important H. pylori virulence factors that, along with host characteristics
and the external environment, have been associated with the different occurrences of diseases.
H.pylori is one of the most important and prevalent pathogen contributes in many
gastrointestinal diseases including: peptic ulcers, gastric carcinoma and others. This infection is
more common in developing countries than in developed countries.
Aim:
To review the recent studies about H.pylori infection, symptoms, causes and treatment
References:
PubMed literature research.
Introduction
Helicobacter pylori consider one of the most important factors causes peptic ulcers, chronic
gastritis and gastric neoplasms. The international agency of cancer first classified it as a group1
carcinogen.
Studies have been shown that ingestion of contaminated food increases the risk of h.pylori
infection. Person-person transmission by oral-oral or fecal-fecal consider the most likely route of
transmission, Also mammals and insects consider reservoirs and can transmit this infection. On
the other hand; many studies prove that good hygiene habits play a good role in preventing or
at least decreasing the risk of h.pylori infection and complications.
This infection occurs worldwide, but there are a certain countries or regions with higher
prevalence of h.pylori infection. Many studies shown that a poor socioeconomic state
contribute in increasing the risk of h.pylori infection.
With increased risk of h.pylori infection in many countries there is also an increase in the
antibiotic resistance which is alarming sign.[1,5,8,10,11]
Virulence factors, General H.pylori structure and internal organization
Urease[8,9,11,12]
Urease activity and association with gastric mucosal cells are important virulence factors of H.
pylori. Urease activity is perhaps the best characterized of these factors. Urease activity creates
a cloud of ammonia around the bacterium, thus neutralizing the lethal effects of gastric acid.
The process, which we term "altruistic autolysis," involves release of urease by genetically
programmed autolysis with adsorption of the released urease onto the surface of neighboring
intact bacteria.
Cag-PAI [8,9, 11,13]
Is a 40 kb region of chromosomal DNA encoding approximately 31 genes that forms a type IV
secretion system and can be divided into two regions, cag I and cag II. This secretion system
forms a pilus that delivers CagA.
The presence of cagA gene has been associated with higher grades of inflammation, which may
lead to the development of the most severe gastrointestinal diseases, it has been reported that
individuals infected with cagA-positive strains of H. pylori are at a higher risk of peptic ulcer
disease than those infected with cagA-negative strains. However, in East Asia, most strains of H.
pylori have the cagA gene irrespective of the disease.
The EPIYA-C segment variably multiplies (mostly one to three times) in tandem among different
Western CagA species. There is an important relationship between strains vacA s1m1 and CagA
positive has also been reported. Although located in different genomic regions, the cagA gene is
strongly associated with the cytotoxic activity of VacAand strains expressing the combination of
these alleles and cagA are considered the most virulent causing more severe epithelial damage,
which can be associated with the development of the most severe gastric diseases.
VacuolatingCytotoxin Gene (vacA)[8,9,11,13]
VacA is a cytotoxin secreted from bacteria as a large 140-kDa polypeptide and latter trimmed at
both ends to finally deliver it in an active form to host cells, where it exerts its activity.
The gene encoding VacA is present in all H. pylori strains and displays allelic diversity in three
main regions, the s (signal), the i (intermediate), and the m (middle) regions, and consequently,
the cytotoxic activity of the toxin varies between strains. Different combinations of two major
alleles of each region (s1, s2, i1, i2, m1, m2) may exist, which results in VacA toxins with distinct
capability of inducing vacuolation in epithelial cells. While vacA s1/m1 strains are consistently
vacuolating and vacA s2/m2 strains are non-vacuolating.
In Western countries, including Latin America, the Middle East, and Africa, there have been
many reports that individuals infected with s1 or m1 H. pylori strains have an increased risk of
peptic ulcer compared with individuals infected with s2 or m2 strains
Blood group antigen-binding adhesion (BabA)[8,11,12,13]
BabA is the best-characterized adhesion .Some researchers have demonstrated that there is an
association between babA2-positive genotypes and occurrence of peptic ulcer disease, although
it remains controversial. The study performed by Zambon showed that babA2 and cagA, and
vacA s1 and m1 coexpressed by the same H. pylori strain work synergistically in worsening
inflammation and may be a potential risk of intestinal metaplasia. A recent study with Iranian
patients reported that babA2 prevalence was significantly higher in GC patients (95%) when
compared with DU patients (18.1%) and non-ulcer dyspepsia subjects (26.1%).
Symptoms and causes of infection
Causes:
It’s still not known exactly how H. pylori infections spread. The bacteria have coexisted with
humans for many thousands of years. The infections are thought to spread from one person’s
mouth to another. They may also be transferred from feces to the mouth. This can happen
when a person does not wash their hands thoroughly after using the bathroom. H. pylori can
also spread through contact with contaminated water or food.
The bacteria are believed to cause stomach problems when they penetrate the stomach’s
mucous lining and generate substances that neutralize stomach acids. This makes the stomach
cells more vulnerable to the harsh acids. Stomach acid and H. pylori together irritate the
stomach lining and may cause sores or peptic ulcers in your stomach or duodenum, which is the
first part of your small intestine.[1,6,8]
Symptoms:
H.pylori is bacterium that causes chronic inflammation in stomach and duodenum, and is a
common contagious cause of ulcers worldwide.
H.pylori causes chronic inflammation (gastritis) by invading the lining of the stomach and
producing cytotoxins termed vaculating toxin A (vac-A), and thus can lead to ulcer formation.
Typical symptoms of h.pylori infection are similar to those of gastritis or peptic ulcers and they
may include gnawing or burning sensation. Many infected individuals may have no symptoms;
other infected people may experience some: belching, bloating, nausea and vomiting as well as
abdominal discomfort.Sometimes serious infection may cause nausea and vomiting including
vomiting blood. Also chronic infection may suppress natural body defenses.[1,2,6,9]
People at risk of h.pylori infection
Children are more likely to develop an H. pylori infection. Their risk is higher mostly due to lack
of proper hygiene. Your risk for the infection partly depends on your environment and living
conditions. Your risk is higher if you:




live in a developing country
share housing with others who are infected with H. pylori
live in overcrowded housing
have no access to hot water, which can help to keep areas clean and free from bacteria
It’s now understood that peptic ulcers are not caused by stress or eating foods high in acid, but
they’re actually caused by this type of bacteria. About 10 percent of people infected with H.
pylori develop a peptic ulcer. Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs)
also increases your risk of getting a peptic ulcer[1,8]
Diagnosis of H.pylori
Histology: was golden standard in detection of h.pylori, but no more because of many issues
associated with this approach include: site, number and size of infection, methods of staining
and level of experience that pathologist has.[1,6,7]
Advantages: excellent sensitivity and specificity.
Ability to evaluate pathologic changes associated with h.pylori.
Disadvantages: require trained, well skilled person.
Require multiple-applications for accurate measurements.
Plus it’s expensive.
Rapid Urease Test: Utilizes the ability of H. pylori to produce large quantities of urea as the basis
for diagnosing infection. Biopsies obtained during endoscopy are placed in a agar media contain
urea and a pH indicator. If H.pylori present then it will produce large quantities of urea so this
will increase PH and changes the color of PH sensitive indicator. we can obtain results within 24
hours.[1,6]
Medications such as: PPI's, bismuth and antibiotics decrease the sensitivity of this test.
Blood antibody test: it’s qualitative and quantitative approach with excellent specificity and
sensitivity and allows the determination of anti-biotic sensitivity. It's a blood test checks to see
whether your body has made antibodies to H. pylori bacteria or not. If you have antibodies to H.
pylori in your blood, it means you either are currently infected or have been infected in the past.
Disadvantages: methodology is not standardized across labs and not widely available. [1,6,7]
Treatment: pharmacologic and non-pharmacologic
Treatment of h.pylori has been shown great benefits in fighting the underlying disease, such as:
Duodenal and gastric ulcers: Ford ET. Meta-analysis including 52 trials shown that h.pylori
eradication in patients yield a superior healing rates in duodenal ulcers compared with short
treatment courses of ulcer healing with H2-blockers or PPI's .Also h.pylori eradication was
superior to no treatment. [6,7]
Gastric bleeding: H.pylori treatment decreases recurrent bleeding by (17%) compared to healing
treatment alone. [6,7]
Gastric MALT lymphoma: h.pylori treatment achieves tumor regression in 60-90% of patients.
Relapse rates were 0% for high grade MALT lymphoma after medium follow up more than 5
years.[6,7]
GERD: h.pylori eradication could be associated with worsening, no change nor improvement of
GERD.[6,7]
-NON-pharmacological treatment:[3,6]
(CRANBERRY)
Cranberry juice consider successful in preventing the adhesion of bacteria to the lining of
the GI or any site of infection, scientists opinions:
-A recent study illustrated that when cranberry juice was fed to mice infected with H.
pylori, 80% were cured 24 h following treatment, with an eradication rate of 20%, and 4
weak post treatment.
-Zhang ET in 90 trial of cranberry juice compared to placebo in 189 patients, exhibited
an increase in eradication rates of H. pylori.[3]
(GARLIC)
-In Cañizares ET study of allium sativum extracts; the authors used garlic. By using the
solvents ethanol and acetone in a stirred tank, it was shown that garlic extracts inhibit H.
pylori comparable to commercial materials.
-Allicin, associated with Allium sativum is believed accountable for garlic’s bacteriostatic
properties. The existence or lack of allicin is critical in inhibiting in-vitro growth of H.
pylori.
- Salih et reported that in a Turkish population, consumption of garlic for long periods of
time did not affect the occurrence of H. pylori infection.[3]
(Curcumin)
Curcumin is the most active component in turmeric. Have a distinct yellow color and
used as spice. it have anti inflammatory, antimutagen and anti-oxidant properties.
- Han et confirmed that the growth inhibitory activity of curcumin via H. pylori infection is
a result of inhibition of the shikimate pathway essential for the production of aromatic
amino acids in bacteria, but not in humans.
- Patients who received OAM treatment found that the eradication rate was significantly
higher in these patients than those who ingested curcumin (78.9%vs 5.9%).[3]
-pharmacologic treatment:
Primary treatment of h.pylori include: PPI, calrithromycin and amoxicillin or metronidazole
(calrithromycin, based-triple therapy) for 14 days. PPI, H2-recepter blocker, bismuth,
metronidazole and tetracycline for 10-14 days.
Sequential therapy include: PPI and amoxicillin for 5 days followed by PPI, clarithromycin and
trinidazole for other 5 days. [1,2,6 and 7]
-Resistance:
Antibiotic resistance is regionally variable, Also H.pylori eradication rates declining globally.
Clarithromycin resistance has been increased in many countries over the past decade because of
the treatment failure and patient compliance. Also metronidazole resistance increased in many
countries, 20-40% in Europe and USA with exception of north Italy (14.5%), with higher
resistance rates in developing countries (50-80%).
Tetracycline resistance is as low as (0.7%) in Spain, (0.5%) in Hong Kong or even absent in most
countries.
Floroquinones resistance determined in very limited countries, in china and Italy it was (34.5%)
and (22.1%) respectively.
Amoxicillin resistance was almost negligible (0-2%) in Europe, 6% in Alaska and (38%) in Asia and
South America but fortunately resistance of amoxicillin doesn’t affect treatment efficacy. [1,2,4
and 5]
amoxicillin resistance:
The main mechanisms leading to amoxicillin resistance of H. pylori are alterations in penicillinbinding proteins, decreased membrane permeability of antibiotics into the bacterial cell. Also,
Expression of active efflux pumps that excrete drugs and point mutations in the pbp1A gene
may contribute to the mechanisms of resistance to beta-lactams. [1,4 and 5]
Clarithromycin resistance:
Generally caused by point mutations in the 23S rRNA gene, the most frequent is A2143G
followed by A2142G and A2142CThese mutations prevent the macrolide from binding. [1,2,4
and 5]
Metronidazole resistance:
Null mutations in the rdxA gene, this gene codes for an oxygen-insensitive
NADPH nitro-reductase (RdxA), whose expression is necessary for intracellular activation of the
drug, and the mutations causes inactivation of these nitro-reductases. [1,4 and 5]
Rifabutin resistance:
Resistance to rifabutin is generally caused by point mutation in codons 524–545 or codon 585 of
the rpoB gene, cross resistance between rifabutin and rifampin has been reported. [1,4 and 5]
Tetracycline resistance:
Tetracycline resistance occurs because of enhancing efflux mechanisms which leads to decrease
the concentrations of tetracycline inside the bacterial cells. Also, protection proteins increase
tetracycline resistance either by decreasing the affinity of ribosomes for tetracycline or by
releasing the bound antibiotic from the ribosome. [1,4 and 5]
Levofloxacin resistance:
Point mutations of gyrA, which codes for DNA gyrase, have been identified in the quinoloneresistant determination region with the major mutations being found at position in the codons
coding for amino acid 87, 88, 91 or 97. [1,4 and 5]
References:
1] I. Thung, H. Aramin, V. Vavinskaya, S. Gupta, J.Y. Park, S. E. Crowe & M. A. Valasek. The
global emergence of Helicobacter pylori antibiotic resistance, 2015.
2]Klein PD, Stratton CW, Drnec J, Prokocimer P, seipman N. Clarithromycin aas monotherapy for
eradication of Helicobacter pylori, 1993.
3]Haim shmuely, Noam Dominz, Jacob Yahav. Non-pharmacological treatment of Helicobacter
pylori, 2016.
4]Vincenzo De Francesco, Angelo Zulla, Cesare Hassan, Floriana Giorgio, Rosa Rosania and Enzo
Ierardi. Mechanisms of H.pylori antibiotic resistance: An updates appraisal, 2011.
5]F Me´graud. H PYLORI ANTIBIOTIC RESISTANCE: PREVALENCE, IMPORTANCE, AND ADVANCES
IN TESTING, 2003.
6] William D. Chey, M.D., F.A.C.G., A.G.A.F., F.A.C.P., Benjamin C.Y. Wong, M.D., Ph.D., F.A.C.G.,
F.A.C.P., American College of Gastroenterology Guideline on the Management of Helicobacter
pylori Infection,2007.
7]Maliheh Safavi, Reyhaneh Sabourian, Alireza Foroumadi. Treatment of Helicobacter pylori
infection: Current and future insights, 2016.
8] Kodaman N., Sobota R. S., Mera R., Schneider B. G., Williams S. M. Disrupted humanpathogen co-evolution: a model for disease. Frontiers in Genetics,2014.
9] Yamaoka, Yoshio. Helicobacter pylori: Molecular Genetics and Cellular Biology,2008.
10] Marshall BJ, Warren JRLancet. Unidentified curved bacilli in the stomach of patients with
gastritis and peptic ulceration.
11] Kathryn P. Haley and Jennifer A. Gaddy .Nutrition and Helicobacter pylori: Host Diet and
Nutritional Immunity Influence Bacterial Virulence and Disease Outcome.
12] Bruna M. Roesler, Elizabeth M.A. Rabelo-Gonçalves,José M.R. Zeitune. Virulence Factors of
Helicobacter pylori.
13] Bruce E. Dunn and Suhas H. Phadnis. Structure, function and localization of Helicobacter
pylori urease.