Analysis and disccusion of how Helicobacter Pylori (H.pylori) developed genetically and physically as a bacterium to be effective in affecting host cells. It has successfully affected 50% of host cells within the human population. Retrospective research of genomic advances and interactions of H.pylori migration between old and new world.
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How Helicobacter Pylori can cause gastric ulcerations and how this can lead to cancers of the stomach - Piril Erel
1. How helicobacter Pylori causes gastric
ulcerations and how this can be linked to
cancers of the stomach
By Piril Erel
2. Helicobacter Pylori
• 50% worlds population have
Helicobacter Pylori (H.
pylori) in upper
gastrointestinal track2.
• Most people infected by H.
pylori will show no
symptoms1.
• Infects gut2.
• H. pylori is a gram-negative
spiral shaped bacterium
• Detected in 19834.
3. H.pylori correlates much better
with socio- economic status than
race
Figure 1 : A worldwide geographic demonstration which illustrates the prevalence of
H.pylori around the world
4. H.pylori - The Almighty
• Flagella gives motility and
enables the bacteria to
grow under the mucosal
membrane3.
• Lipopolysaccharides and
membrane proteins adhere
to host cell receptors3.
• Urease enzyme is used to
combat the acidic
environment of the
stomach by producing
ammonia3.
Figure 2: This image shows the virulence factors of H.pylori and how it can
affect and survive in the human host.
5. How does H.pylori interact and
damage the intestinal mucosa?
• Vac A exotoxin causes injury
to the mucosal membrane3.
• Type IV secretion system
that uses a pillus to inject
effectors3.
• cagA causes actin
remodeling and inhibits
apoptosis3.
• Inhibits immune response by
inhibiting T cell activation
and proliferation3.
Figure 3: This image shows the various ways in which Vac A interacts with
epithelial cells and the various different ways it causes disruption
6. Sequelae
Figure 4: Proportions of individuals
with differing disease severity
• Association between H.pylori
infection and gastric cancer8.
• Infection causes H pylori associated
gastritis8.
• Increasing degenerative changes and
evolution towards atrophy8.
• Nine fold risk of developing
precancerous gastric conditions when
H.pylori positive patients were
compared with those without
infection8.
• Strong association with poor
socioeconomic conditions8.
7. Why does H pylori cause
cancer
This is not well understood, some ideas are:
• Chronic inflammatory response to infection pushes cells
in the stomach lining towards oncogenesis 11.
• Damage of the mucosal membrane due to inflammation
increases the carcinogenic effect of risk factors such as
high salt intake and smoking12.
• Recent research suggests CagA may lead to inactivation
tumor suppressor proteins like p5311.
This protein normally leads cells into apoptosis.
9. Signs
& Symptoms
• Indigestion: this can be caused
by an H pylori induced ulcer1.
Can be accompanied by:
• Dull and burning pain worse on
empty stomach, relieved briefly
by antacids, lasts for minutes
to hours and comes and goes
over days and weeks5.
• Weight loss, vomiting, trouble
in swallowing: can be caused
by H.pylori induced cancer1.
Figure 6: How helicobacter Pylori develops into an Gastric Ulcer
10. Diagnosis
• Blood test: antibody test
meaning that it is difficult to
tell whether the infection is
past or current5.
• Breath test: 14C labeled urea
drink, detection of the isotope
in exhaled CO2 will indicate
presence of urease secreted
by H pylori 5
• Biopsy taken during an
endoscopy, tissue sample
examined in the lab for
presence of H.pylori5.
• X ray examination after
barium meal (white chalky
liquid allowing soft tissues to
become visible on x-ray)5.
Figure 7: Carbon-14 Breath Test
11. Genome interactions
• H. pylori has infected humans since they
originated in the African continent6,7
• The bacterium has evolved with us
accumulating DNA changes as we migrated
across the world6,7.
• Where old world met new e.g. as in South
America, when European colonists arrived this
co-evolution was disrupted6,7
• Thus some individuals became infected with H.
pylori variants with differently evolved
ancestry6,7.
• This mismatch means that a harmless infection
can become cancer causing6,7
• The genomic sequence of the hosts compared
to that of the microbes can predict of the risk
of disease much better than when analysed
alone6,7.
• It was shown that people from Tumaco
Colombia find the majority of their DNA
ancestry and most of their H. pylori strains
come from Africa6,7
• The mountain population from Tuquerres is 67%
American/Indian and 31% European. Their H.
pylori are mostly from European which
replaced the native strains6,7.
• If the H. pylori strains have a different origin to
their hosts, they are more likely to cause
cancer6,7.
• Strains originating in Africa are mostly harmless
Africans, but caused cancer in people with a
largely American/Indian background6,7.
12. Treatment
• Double-dose PPI (e.g. 20 mg omeprazole) 10.
decreases the stomach's production of acid allowing damaged
tissue to heal. Examples of proton pump inhibitors include
Lansoprazole, Omeprazole, Pantoprazole and more.
• Plus two antibiotics; this increases treatment success
and antibiotic resistance9.
Omeprazole 20mg, metronidazole 400 mg & clarithromycin
250 mg TDS
Or, Omeprazole 20mg, amoxicillin 1 g and clarithromycin
500mg TDS
13. References
1. Information about Helicobacter Pylori. (2014). 1st ed. [ebook]
London: Core – the digestive disorders foundation, pp.2-5.
Available at:
http://www.nhs.uk/ipgmedia/national/core%20charity/assets/heli
cobacterpylori.pdf
2. Blaser, M. J. (2006). "Who are we? Indigenous microbes and the
ecology of human diseases". EMBO Reports 7 (10): 956–60.
3. Wikimedia, (2014). Helicobacter Pylori Virulence Factors. [image]
Available at:
http://upload.wikimedia.org/wikipedia/commons/9/9a/H_pylori_
virulence_factors_en.png
4. H.pylori & Peptic Ulcers. (2014). 1st ed. [ebook] Bethesda:
Clearinghouse, pp.1-6. Available at:
http://digestive.niddk.nih.gov/ddiseases/pubs/hpylori/hpylori_50
8.pdf
5. Yong, E/ (2014). Human-microbe mismatch boosts risk of
stomach cancer. [online] Available at:
http://www.nature.com/news/human-microbe-mismatch-
boosts-risk-of-stomach-cancer-1.14501 [Accessed 18 May.2014].
6. Kodaman, N., Pazos, A., Schneider, B., Piazuelo, M., Mera, R.,
Sobota, R., Sicinschi, L., Shaffer, C., Romero-Gallo, J., de Sablet,
T. and others, (2014). Human and Helicobacter pylori
coevolution shapes the risk of gastric disease. Proceedings of the
8. Forman, D. (1998). Helicobacter Pylori: the gastric cancer problem.
Gut, 43 (Suppl 1), p.33.
9. Uptodate.com, (2014). Helicobacter pylori infection and treatment.
[online[ Avaliable at: .http://www.uptodate.com/contents/helicobacter-
pylori-infection-and-treatment-beyond-the-basics
10. Patient.co.uk, (2014). Helicobacter Pylori [online] Available at:
http://www.patient.co.uk/doctor/helicobacter-pylori-pro
11. National Cancer Institute, (2014). Helicobacter pylori and cancer.
[online] Avaliable at:
http://www.cancer.gov/cancertopics/factsheet/Risk/h-pylori-cancer
12. J, B. and P,M. (2014). Helicobacter pylori and Gastric Cancer.
Digestive Disease, [online] 32(3). Available at:
http://ncbi.nlm.nih.gov/pubmed/24732191 [Accessed 18 May. 2014].
14. Image References
1. Helico.com. Epidemiology | The Helicobacter Foundation [Internet]. 2014 [23 April 2014].
Available from: http://www.helico.com/?q=Epidemiology
2. Upload.wikimedia.org. [Internet]. 2014 [23 April 2014]. Available from:
http://upload.wikimedia.org/wikipedia/commons/9/9a/H_pylori_virulence_factors_en.png
3. Cover T, Blanke S. Helicobacter pylori VacA, a paradigm for toxin multifunctionality.
Nature Reviews Microbiology. 2005;3(4):320--332.
4. Helico.com. Epidemiology | The Helicobacter Foundation [Internet]. 2014 [23 April 2014].
Available from: http://www.helico.com/?q=Epidemiology
5. Kim E, Hong K, Hong H, Hahm K. Detouring the undesired route of Helicobacter pylori-
induced gastric carcinogenesis. Cancers. 2011;3(3):3018--3028.
6. HealthTap. what is the effests of xycam 20mg on a developing peptic ulcer? [Internet].
2014 [23 April 2014]. Available from: https://www.healthtap.com/user_questions/326787-
what-is-the-effests-of-xycam-20mg-on-a-developing-peptic-ulcer
7. Static.groupon.hk, (2014). [online] Avaliable at:
https://static.groupon.hk/56/20/1328191622056.jpg [Accessed 18th May.2014]
Notas do Editor
Welcome to my presentation, Here I will be discussing how helicobacter pylori causes gastric ulcerations and how this can be linked to cancers of the stomach. I hope you enjoy the following slides
It affects around 50% of the world’s population. It’s one of the most common infections in the U.K. Unless it is treated, the infection will stay for the rest of an individuals life. Now this is due to the fact that H.pylori will not show any symptoms or problems caused by H.pylori and so will not even know that they are affected. However, further complications may indicate the presents of H.pylori in the gut and will then allow individuals to seek medical help.
Helicobacter Pylori is a gram-negative spiral shaped bacterium that grows in mucus layer that coats the inside of the human stomach. Gram-negative refers to the thin layer of peptidoglycan and presents of a outer membrane in the helicobacter cell wallHelicobacter was detected by Robin Warren who was a pathologist and a physician named Barry Marshall in Australia. Although many individuals did not believe Warren & Marshall as H.pylori did not show symptoms. Barry Marshall had decided to do something drastic and drank a solution of H.pylori and within 2 weeks developed acute symptoms which we will discuss later onNext Slide
The prevalence of H.Pylori infected varies widely by geographic area it can be seen that countries such as South America and Africa have the highest prevalence. This is due to the transmission of H.pylori. It is mostly transmitted through contamination of water and food which is much more likely to occur in 3rd world countries and when we compare these percentages with those such as The united states or united kingdom or even Australia, we can see here that the sanitization are much better and therefore the prevalence is much more lower.
Next Slide
There are 4 different steps that helicobacter pylori does in order to affect the human host. 1. Firstly there is the addition of Helicobacter Pylori to the host cell
2. Secondly, and most importantly helicobacter pylori minimizes the content of the acid in the stomach 3. it colonizes 4. and finally the degrades the epithelial cells
1 The addition of helicobacter pylori is enabled by the flagella which allows the bacterium to be motile and also permits the bacteria to propel itself through the gastric fluid, mucus layer and finally adheres itself to the epithelial lipopolysaccharides and membrane proteins, using this it interacts with epithelial cells of stomach
2 The hydrochloric acid keeps the pH of the stomach strongly acidic, between a pH of one and two, H.pylori is able to survive in acidic conditions but as the stomach pH is a little too acidic for the bacteria it uses an enzyme to raise the pH around the bacteria to a more survivable level. Urease enzyme is used where it will breakdown urea and water to produce carbon dioxide and ammonia. As we know that ammonia is a base and HCl is an acid this allows a neutralizing reaction making the pH of the stomach increase.
3This creates a microenvironment for the bacterium to survive this allows the colonization of more and more H.Pylori to thrive in this environmentNext Slide
Now the degradation of the epithelial cells occurs in many different ways:
The Vac A exotoxin causes injury to the mucosal membrane by inducing alterations in mitochondrial membrane permeability and apoptosis, it also stimulates pro-inflammatory signaling and increases the permeability of the plasma membrane.
Type IV secretion system uses a pillus to inject effectors such as Cytotoxin-associated gene A - cagA is a needle-like appendage that injects a toxin which remodels actin the cytoskeleton of the cell thereby disrupting the epithelial barrier and facilitating the passage of Vac A, it is also found to inhibit apoptosis.
These responses altogether inhibits immune response by T cell activation and proliferation so the body cannot produce an immune response against Helicobacter pylori and this is the development of gastric ulcerations
Next Slide
So this image shows the proportions of individuals with differing disease severity The 50% of the worlds population who has helicobacter pylori is more susceptible in developing duodenal ulcers about 90% compared to the unaffected population. The development of gastritis is more likely when affected with the bacterium. There is a nine fold risk of developing precancerous gastric conditions when compared with individuals with and without the bacterium. Also almost all cases of gastric lymphoma is linked to helicobacter pylori being present in the human host. As discussed before the prevalence of helicobacter pylori in individuals and country is strongly associated with poor socioeconomic conditions.
Next slide
How helicobacter pylori leads to gastric cancer is not well understood but some ideas are put forward by scientist, it is unclear whether it is one specific cause or a collection of all of these effects of helicobacter pylori which increases the chance of gastric cancer. Long-term exposure to cagA toxin causes chronic inflammation and can induce oncogenesis, this inflammation leads to a damaged mucosal membrane and can increase the carcinogenic effect of risk factors leading to gastric cancer such as high salt intake and smoking. Recent research suggest that cagA may lead to inactivation and alteration of tumor suppressor proteins such as p53 which normally leads to apoptosis and therefore inactivation can promote the development and progression of gastric cancerNext Slide
80% of individuals who suffer with helicobacter pylori will experience chronic gastritis which is characterized by chronic inflammation of the stomach mucosa which is caused by injury to the gastric mucosa resulting from reflux of bile and pancreatic secretions into the stomach after adhesion of helicobacter pylori.15-20% of theses individuals will further develop chronic atrophic gastritis known as Type A or B gastritis is a process of chronic inflammation of the stomach mucosa leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. A duodenal ulcer can also develop due to the corrosive HCl in the stomach causing inflammation and ulcers to area of epithelial cells that are infected with helicobacter pylori. Furthermore 1% of these individuals can finally be presented with gastric carcinoma Next Slide
Indigestion is the main symptom of helicobacter pylori due to a induced ulcer however this symptom is common among many types of disorders, so can be difficult to link to helicobacter induced disorder. Indigestion can further be accompanied by dull and burning pain which is worse on an empty stomach and can be relieved by antacids very briefly. This burning pain can last for minutes to hours and comes and goes over days an weeks. Gastric carcinoma can present itself as weight loss, vomiting, dysphagia and anemia.Next Slide
Blood tests are used to measure antibodies to Helicobacter pylori. Antibodies are proteins made by the body’s immune system when it detects harmful substances such as bacteria. Blood tests for Helicobacter pylori can only tell if your body has Helicobacter pylori antibodies. It cannot however tell if you have a current infection or how long you have had it, this is because the test can be positive for years even if the infection is cured. As a result blood tests cannot be used to see if the infection has been cured after treatment. During breath tests the patient is asked to swallow a special substance that has urea labeled with carbon 14. Urea is a waste product the body produces as it breaks down protein. The urea used in the test has been made harmlessly radioactive. If Helicobacter pylori is present, the bacteria convert the urea into CO2, which is detected and recorded in your exhaled breath after 10 minutes. This test can identify almost all people who have Helicobacter pylori. A biopsy may also be taken from the stomach lining which is the most accurate way to tell if an individual has Helicobacter pylori.. To remove the tissue sample the patient undergoes an endoscopy. Common complications of helicobacter pylori infection are gastritis and ulcers. To check for ulcers, you may have a special stomach x-ray examination after a barium meal which becomes visible on x-rays.Next Slide
I found it interesting when doing my research about helicobacter pylori the origins and geographic distribution worldwide affecting 50% of the worlds population and genomic interactions universally. Helicobacter pylori was first originated in the African content and mutated across the world and has undergone genetic mutations along this spread. Where the old world met the new world the co-evolution was disrupted and helicobacter pylori was not dependent on infecting host cells in the African content. Individuals started to become infection with helicobacter pylori. Helicobacter pylori encountered new genetic material and evolved differently than compared to its origin. If an individual did not contain the resistant genomic sequence to helicobacter pylori it could become cancerous. Scientists in Tumaco Colombia had found the majority of their DNA ancestry and helicobacter pylori strains come from Africa. The mountain population from Tuquerres is 67% American/Indian and 31% European. Their helicobacter pylori are mostly from European which replaced the native strains. If the H.pylori strains have a different origin to their hosts, they are more likely to cause cancer. Strains originating in Africa are mostly harmless to Africans, but caused cancer in people with a largely American/Indian background
Next Slide
Helicobacter pylori is treated with a double-dose Proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole which decreases the stomach’s production of acid allowing damaged tissue to heal, this is accompanied with 2 antibiotics which increases treatment success and antibiotic resistance. These two antibiotics can either be metronidazole, clarithromycin and amoxicillinNext Slide