What is H. pylori?
Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonizes the stomach .
This bacterium is the second most commonly studied pathogen (after E. coli) . Marshall and Warren were awarded the 2005 Nobel Prize in Medicine for linking the presence of H. pylori to inflammation of the stomach (gastritis) and peptic ulcer disease .
Infection with H. pylori is most often acquired in early childhood and persists for life .
In spite of the immune response, H. pylori is frequently not cleared from the body completely because the bacterium is equipped with an array of mechanisms that allow it to evade or inhibit host responses .
This bacterium is one of the most prevalent human pathogens, infecting more than 50% of the human population . H. pylori is present in approximately 70 – 80% of the population in developing countries and 13% – 50% of the population in developed countries .
In recent years, there has been a decrease in the prevalence of H. pylori infection in developed countries. In the United States, less than 6% of the children are infected by H. pylori. A similar trend is becoming apparent in other parts of the developed world .
Research indicates that H. pylori has been around at least since human migration out of Africa about 60,000 years ago .
Symptoms of Infection
The majority of patients infected with H. pylori (around 80%) do not develop symptoms . However, in almost all infected people, the infection causes progressive damage to the lining of the stomach .
Approximately 20% of those with an H. pylori infection will experience an H. pylori-related disease . These diseases include gastritis and gastric or duodenal ulcers in 15 – 20% of patients.
- iron-deficiency anemia
- idiopathic thrombocytopenic purpura (easy bruising)
- vitamin B12 deficiency
These issues are likely due to a decreased ability to metabolize certain vitamins in the stomach during infection.
H. pylori has also been implicated as a risk factor in non-gastrointestinal disorders, like atherosclerosis (hardening of the arteries), ischemic heart disease (reduced blood supply to the heart) and stroke . More information is needed to determine the significance and cause of these associations .
Infection in Children
H. pylori infection is acquired primarily in early childhood and is predominantly transmitted within families. Infected mother and siblings are the most common familial source of H. pylori .
Most of the infected children do not develop any complications . Childhood H. pylori infection causes less stomach inflammation and ulceration than in adults . However, some children can develop symptoms such as a burning sensation in the stomach, nausea, vomiting, and loss of appetite .
In children, H. pylori infection has been associated with malnutrition, iron deficiency anemia, diarrhea, and impairment of growth, weight, and cognitive functions, especially when food intake is poor [14, 16].
H. pylori Interferes with the Host’s Metabolism
H. pylori and Nutrient Availability
The concentration of β-carotene and vitamin E in the stomach is also decreased .
H. pylori Affects Hormones that Regulate Appetite
Since leptin decreases appetite, and ghrelin stimulates the release of growth hormone, H. pylori infection could result in decreased growth, especially in children who are already at risk for malnutrition [16, 17].
In some studies of infected children, the eradication of H. pylori increased ghrelin levels and resulted in growth increases in both weight and height .
The research on the links between H. pylori and leptin are ghrelin levels are conflicting in some cases, however. The majority of studies found lower levels of circulating ghrelin in H. pylori-positive subjects in Asia and Europe but not in the United States.
Conflicting results were also obtained when the effect of H. pylori eradication on ghrelin levels was evaluated [17, 19]. In a study of infected veterans, ghrelin levels were nearly six-fold higher than pre-eradication, but leptin levels also increased significantly seven months following eradication .
H. pylori and the Gut Microbiota
H. pylori alters the stomach bacterial community, increasing bacteria in the Proteobacteria, Spirochete, and Acidobacteria species and decreasing bacteria in the Actinobacteria, Bacteroidetes and Firmicutes species [20, 18].
How to Treat H. pylori
Testing for H. pylori
The H. pylori bacterium can be detected in most biological fluids. This includes the saliva, breath, blood, feces, and urine, in addition to the bacterium’s primary site of residence in the stomach lining .
Urease is an enzyme produced by H. pylori which can be used to detect its presence . Common assessments include gastric biopsies for rapid urease detection (rapid urease test (RUT)), the 13C-urea breath test (13C-UBT) or fecal antigen determination (fecal antigen test (FAT)) . The noninvasive 13C-UBT and FAT are of comparable diagnostic accuracy with biopsy-based tests and are the methods of choice in the test-and-treat setting and for controlling the effect of eradication treatments .
|Urease (breath) test||67%||100%|
|Serology (blood) test for H. pylori antibodies||84%||60%|
|Stomach biopsy – histopathology (examining tissues under the microscope)||83%||100%|
|Stomach biopsy – H. pylori culture||64%||100%|
|Stool antigen test||86-97% (depending on antigen tested)||93-97%|
Higher sensitivity (true positive rate) demonstrates that the test is better at detecting H. pylori in the true presence of H. pylori. Lower specificity (true negative rate) indicates that the test may those without H. pylori as having H. pylori. This means that the stomach biopsy and blood test, for example, may not detect H. pylori in about 20 – 30% of people with H. pylori infections.
H. pylori serology test may detect antibodies against H. pylori either in individuals with active infections or even after infections have been eradicated. Therefore, the serology test is not a good test to follow up after H. pylori treatment .
Standard H. pylori Eradication Treatment
Eradication of virulent H. pylori is necessary for people with the negative symptoms of infection, such as stomach ulcers. However, there are conflicting opinions whether asymptomatic H. pylori-positive children and adults should be treated because the antibiotic treatments have strong side effects [24, 25].
The usual treatment, called the standard triple therapy, consists of a short course of two antibiotics (mostly clarithromycin and amoxicillin) along with proton pump inhibitors (stomach acid-reducing drugs, e.g. omeprazole or lansoprazole) [20, 26]. 14-day triple therapy is proven to be superior to the equivalent 7- or 10-day triple therapy .
Because H. pylori is adapted to surviving in an acidic environment, reducing stomach acid with proton pump inhibitor drugs inhibit H. pylori growth and is beneficial during the short-term standard triple therapy . However, long-term treatment with PPI therapy can result in atrophy (wasting) of the stomach lining .
Standard treatment for H. pylori infection can alter healthy gut microbiota, leading bloating, diarrhea, and nausea . These side effects are estimated to affect over 50% of patients and are associated with decreased compliance and treatment failure . Resistance to antibiotics or reinfection from remaining H. pylori bacteria can also cause the failure of the treatment to clear H. pylori.
The effectiveness of the standard triple therapy ranges between 60% and 80% .
Factors that Affect the Effectiveness of H. pylori Treatments
Cytochrome P450 2C19 (CYP2C19) Mutation Affects Drug Effectiveness
Another cause of eradication failure is a mutation in cytochrome P450 2C19 (CYP2C19). CYP2C19 is the principal enzyme involved in the metabolism of proton pump inhibitors (omeprazole or lansoprazole). When CYP2C19 works more effectively than usual, the drugs get degraded faster and have lower efficacy .
H. pylori Reservoir in the Mouth May Lead to Reinfection
Dental plaque can act as a reservoir of H. pylori, making proper oral hygiene maintenance is essential to prevent re-infection .
Several studies suggest that untreated periodontal disease increases the risk of becoming re-infected after H. pylori eradication. Reducing the number of oral H. pylori using an antiseptic mouthwash and/or periodontal treatment improves the eradication rate following antibiotic therapy .
For example, in one study, the treatment of an oral infection increased the success rate of H. pylori eradication from the stomach from 61% to 82% .
Antibiotic Resistance Decreases the Effectiveness of H. pylori Treatment
Increased resistance to the antibiotic clarithromycin has accounted for a dramatic decline in the efficacy of standard triple therapies across the world . Alternative antibiotic regimens have been shown to overcome clarithromycin resistance and are now preferred treatments achieving improved eradication rates (>90%) .
Negative Health Effects of H. pylori
Although H. pylori infects the stomach, it has health impacts both in and outside of the digestive system.
Diseases of the Digestive System
1) Can Cause Gastritis and Indigestion
Although the majority of patients infected with H. pylori do not develop symptoms, the infection still causes progressive damage to the lining of the stomach that may be irreversible . H. pylori infection is the predominant cause of chronic gastritis (the inflammation or the irritation of the lining of the stomach) .
Indigestion, also known as dyspepsia, is a group of symptoms related to the upper gastrointestinal tract. It is not a disease on its own, but it is associated with a wide spectrum of diseases. With approximately 25% of western populations experiencing dyspepsia each year, dyspepsia is one of the most common causes for consulting a physician for a gastrointestinal complaint . An estimated minority of 10 to 12% of dyspeptic patients achieve a significant improvement after H. pylori eradication and the relief may be delayed for several months up to one year after eradication .
2) Can Cause Stomach Ulcers
A U.S.-based study suggests that approximately half of peptic (stomach) ulcers are caused by H. pylori infection and half by nonsteroidal anti-inflammatory drugs (NSAIDs) .
Patients in the U.S. who are infected with H. pylori have a 3.5-times higher risk of developing peptic ulcer disease .
Around 15 – 20% of subjects infected with H. pylori develop peptic ulcers, which are associated with increased inflammation, elevated gastrin levels, and increased hydrochloric acid secretion [2, 8]. The ulcers resulting from infection may be gastric (in the stomach) or duodenal (in the intestines).
Patients whose H. pylori infection is successfully treated have a significantly lower rate of duodenal or gastric ulcer recurrence .
3) Increases Gastric Cancer Risk
The World Health Organization (WHO) has classified H. pylori as a class I carcinogen .
Gastric cancer is one of the leading types of cancer worldwide, particularly in East Asian populations . Death from gastric cancer is second only to lung cancer in men and thus contributes to approximately 10% of all cancer deaths annually .
H. pylori infection has been established as a major risk factor for gastric (stomach) cancer .
A number of trials have demonstrated the possibility of cancer prevention through H. pylori screening and eradication, particularly in high‑risk populations . Six clinical trials showed a decline in the incidence of gastric cancer from 2.4% to 1.6% in asymptomatic adults after eradication therapy .
However, gastric cancer may sometimes develop even after eradication of H. pylori . Despite the lack of ongoing H. pylori infection, H. pylori-specific Th17 cells persist in the blood and gastric lining, and this persistent inflammation may contribute to the persistent increased gastric cancer risk despite the eradication of H. pylori .
4) Is A Strong Risk Factor for MALT Lymphoma
Persistent H. pylori colonization is also the strongest risk factor for mucosa‑associated lymphoid tissue (MALT) lymphoma and is associated with more the 90% of cases .
Eradication of H. pylori has been shown to induce lasting remission in approximately 80% of patients with early-stage gastric MALT lymphoma .
5) Can Cause Malnutrition in Children
If H. pylori is acquired very early during childhood, as is the case in developing countries, it may lead to malnutrition and growth retardation, especially when either food intake or variety is poor .
In children, H. pylori infection has been associated with iron deficiency anemia, diarrheic disease, and impairment of growth and cognitive function .
H. pylori infection is associated with decreased secretion of hydrochloric acid, one of the main stomach acids, in both in adults and children .
Low hydrochloric acid impairs the absorption of several nutrients and increases the susceptibility to gut infections from harmful microorganisms . The lack of protection from microorganisms may increase rates of malnutrition and reduced growth in children .
6) Can Cause Iron Deficiency Anemia
H. pylori is a common cause of iron deficiency anemia. Many studies have reported an association between H. pylori infection and iron deficiency anemia (IDA) .
Even in countries with low H. pylori prevalence, more IDA is caused by H. pylori than by Celiac disease, another condition considered a major cause of IDA .
The association of H. pylori infection and iron deficiency anemia is more frequent in children than adults .
H. pylori causes IDA by several mechanisms: (1) increased iron loss due to hemorrhage caused by gastritis, peptic ulcer disease or gastric cancer, (2) decreased gastric acid and ascorbic acid secretion due to inflammation, (3) competition, since iron is an essential growth factor for H. pylori, it competes with the host for iron absorption [16, 43].
The association between iron deficiency anemia and H. pylori infection is so strong that a test-and-treat strategy for H. pylori infection is strongly recommended in Europe in all patients with unexplained IDA .
When compared to oral iron supplementation alone, H. pylori eradication therapy administered with iron supplementation significantly increased iron, ferritin and hemoglobin levels . Eradication of H. pylori also improved symptoms of iron deficiency anemia even in patients not receiving iron supplementation therapy .
7) Can Cause Vitamin B12 Deficiency
H. pylori eradication has been shown to improve vitamin B12 absorption .
H. pylori and Auto-Immune Diseases
8) Can Cause Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura (ITP) is characterized by the autoimmune destruction of platelets (thrombocytes), which leads to bruising. Significant evidence points to H. pylori as a causative agent in some ITP cases .
The prevalence of H. pylori infection in patients with ITP is higher than in healthy individuals .
Significant increase in platelet count was found in ITP patients following H. pylori eradication. This effect was confirmed in several reports .
The long-term prognosis of H. pylori-related ITP has been favorable. In an 8-year follow-up study, after successful eradication, no recurrence was seen .
The current American Society of Hematology has suggested eradication therapy in ITP patients who are infected with H. pylori .
9) Associated with Autoimmune Thyroid Disease
Infection with H. pylori significantly increased the risk for Grave’s disease, but not for Hashimoto’s thyroiditis .
Patients with normal thyroid function who had thyroid nodules (unusual growth of the thyroid), were significantly more likely to be infected with H. pylori than patients without thyroid nodules .
Autoantibodies against thyroid peroxidase (TPO) and thyroglobulin dropped significantly in H. pylori-positive patients who accepted eradication therapy, but not in those who refused to be treated .
10) May be Associated with Rheumatoid Arthritis
When B cells (a type of white blood cells) get chronically stimulated with urease produced by H. pylori, they can acquire the potential to produce autoantibodies, including IgM rheumatoid factor antibodies .
Rheumatoid arthritis patients have an increased risk for the development of peptic ulcers but it is not clear if this is directly related to an increased H. pylori infection prevalence or due to the abundant usage of non-steroidal anti-inflammatory drugs (NSAIDs), which can also lead to ulcers .
After H. pylori eradication, some studies found improvement while others reported no change in arthritis symptoms. Currently, the data are conflicting, and it appears that the link between H. pylori and rheumatoid arthritis is weak .
11) Associated with Other Autoimmune Diseases
A few small studies have found higher H. pylori bacterial load in patients with Guillain-Barré syndrome. Associations were particularly strong in patients with the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) type of Guillain-Barré syndrome .
The presence of H. pylori infection in systemic sclerosis patients is associated with worse gastrointestinal, skin, and joint symptoms, suggesting that the association may be significant .
H. pylori may or may not be associated with Sjögren’s syndrome .
H. pylori infection seems to be one of the risk factors for the development of anti-aquaporin 4 (AQP4) antibody-positive Neuromyelitis optica, and the eradication of H. pylori may be a possible adjunct therapy in this disease .
H. pylori and Metabolic Health
12) Effects of H. pylori on Blood Sugar and Cholesterol
H. pylori infection is associated with elevated cholesterol , elevated HbA1c , and a higher BMI . Other studies, however, have found no such relationship, and these effects of H. pylori are still a subject of debate.
Successful H. pylori eradication significantly decreased fasting insulin, HbA1c and HOMA-IR levels in some studies. However, there are also reports showing no effect of H. pylori eradication on mean HOMA-IR and CRP levels or HbA1c levels .
The effects of H. pylori on BMI and obesity are unclear. One study showed that adults with H. pylori had higher BMI levels , while another study showed that the eradication of H. pylori increased BMI and the incidence of obesity in patients with peptic ulcer disease . Yet another set of studies have shown no association between H. pylori infection and BMI . A meaningful causative association between H. pylori and obesity is unlikely .
13) Fatty Liver Disease
H. pylori infection may contribute to the development of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis. The worsening of liver inflammation of different origins also occurs during H. pylori infection. Some studies have also indicated that H. pylori infection induces autoimmunological diseases in the liver and biliary tract .
14) Associated with Diabetes
Patients with type 2 diabetes are more prone to become infected by H. pylori .
There are several factors that may explain this relationship: (1) a diabetes-induced impairment of immunity may enhance an individual’s sensitivity to H. pylori infection; (2) diabetes-induced reduction of gastrointestinal motility and acid secretion may promote pathogen colonization and infection in the gut; (3) Altered glucose metabolism may produce chemical changes in the stomach lining that promote H. pylori colonization; and (4) individuals with diabetes are more frequently exposed to pathogens than their healthy counterparts, as they regularly attend hospital settings .
Patients with diabetes are also more resistant to common anti-H. pylori treatment, and have a higher risk of re-infection .
On the other hand, H. pylori contributes to insulin resistance and diabetes complications . H. pylori may exacerbate diabetes by increasing oxidative stress and decreasing the total antioxidant capacity of the blood .
In a hospital-based study, H. pylori infection was associated with decreased insulin secretion and sensitivity in participants younger than 45 years old .
A large study of Japanese patients revealed a significant relationship between H. pylori infection and metabolic syndrome, a precursor of diabetes .
Studies suggest that there is a higher rate of complications, such as nephropathy, neuropathy, and retinopathy, in H. pylori-positive diabetics. Coronary heart disease is also more prevalent in H. pylori-positive diabetics .
However, in type 2 and type 1 diabetics, H. pylori eradication did not improve glycemic control .
Finally, type 2 diabetics are at higher risk for eradication failure . Therefore, some studies discourage treatment of H. pylori infection in diabetic patients to avoid worsening the infection .
15) May Exacerbate Cardiovascular Disease
Whether patients with cardiovascular disease should be tested for H. pylori and treated is still a subject of debate. There is an indication that H. pylori infection is associated with cardiovascular disease, but the studies are inconclusive surrounding the cause and mechanism of the association.
Several studies have linked H. pylori infection to alterations in cholesterol levels . Studies show that increased LDL cholesterol correlates with the degree of gastric inflammation and that H. pylori eradication normalizes cholesterol levels [32, 16]. H. pylori infection was also associated with the hardening of the arteries, and increased the risk of peripheral artery disease in some studies but not in others [32, 43].
H pylori-related peptic ulcer disease has long been associated with an increased risk for cardiovascular disease . An association with H. pylori infection has also been found with a condition related to vitamin B12 deficiency called hyperhomocysteinemia (abnormally high level of homocysteine in the blood) .
A higher prevalence of H. pylori infection was found in young acute myocardial infarction (AMI) survivors, and in patients who died of AMI . H. pylori infection was also associated with higher stroke incidence .
H. pylori was associated with premature coronary artery disease in some, but not other, studies .
H. pylori and Neurodegenerative Diseases
16) May Exacerbate Alzheimer’s Disease
A very large cross-sectional study found that H. pylori infection was strongly associated with poorer cognition among adults aged 60 – 90 years .
A protein from H. pylori was shown to form amyloid structures in the laboratory and therefore has the potential to play a role in Alzheimer’s disease. Whether this actually happens in the body is yet to be studied .
A small study of Alzheimer’s patients found that H. pylori eradication significantly improved the cognitive status and the five-year survival rate .
17) May Exacerbate Parkinson’s Disease
H. pylori can bind L-dopa, one of the main drugs used to treat Parkinson’s disease . This decreases the drug’s absorption and potentially makes this treatment less effective.
A large Danish study found an association between Parkinson’s disease diagnosis and H. pylori eradication treatment 5 or more years prior to Parkinson’s disease diagnosis. This suggests that past H. pylori infection may be as relevant to Parkinson’s disease as a current infection .
Some studies indicate that H. pylori eradication reduces motor fluctuations in Parkinson’s disease, but one study found that motor fluctuations were lower in infected patients than in uninfected patients .
One study found improvements in stride length, but worsening of rigidity, following eradication therapy. Alarmingly, patients who experienced eradication failure and remained H. pylori-positive following treatment experienced a rapid decline in motor functions . At present, treatment of H. pylori in Parkinson’s disease patients is not recommended due to the potential for deterioration of motor function associated with eradication failure .
18) May Cause or Exacerbate Skin Disease
In one study, 100% of patients with moderate or severe psoriasis were H. pylori-positive, while only 37% of mild psoriasis patients were infected. The improvement of psoriasis symptoms was more rapid when H. pylori eradication was added to psoriasis treatment. Furthermore, psoriasis also improved in patients receiving eradication treatment only .
In one study, H. pylori was present in 81% of rosacea patients who also had gastric complaints . Significant improvement in the severity of rosacea was observed in H. pylori-positive patients who received eradication therapy .
H. pylori may be one of several causes of chronic spontaneous urticaria (hives). In chronic urticaria patients, the overall remission rate following H. pylori eradication was 31% .
19) May Cause Migraine
Multiple studies have shown improvement in symptoms of migraine following successful eradication therapy . However, the strength of this association varies across studies, and more research may is needed to explain the variations .
For example, in one study, complete resolution of migraine headaches was observed in 17% of patients with remaining patients reporting clinical improvement following H. pylori eradication. Another study found significant improvement in the severity of clinical migraine attacks in 84% of patients following infection clearance .
20) May Worsens Respiratory Diseases
A few studies suggested a potential association between H. pylori infection and chronic obstructive pulmonary disease (COPD), while other studies showed no relationship between H. pylori infection and COPD .
Bronchiectasis, tuberculosis, and lung cancer were also associated with higher H. pylori . It is possible that H. pylori may exacerbate pre-existing infections rather than exerting a more direct mechanism.
H. pylori infection may be a risk factor for osteoporosis in Japan .
Protective Effects of H. pylori Infections
Although H. pylori infection is associated with many negative health outcomes, the infection might be protective against some health conditions.
1) May Protect from Gastroesophageal Reflux Disease
H. pylori reduces acid secretion, which may protect against acid reflux, a condition where excess stomach acid can cause persistent heartburn and other complications .
2) Can Mitigate Other Gastrointestinal Infections
H. pylori infection can mitigate the course of infection with other more virulent intestinal pathogens, such as cholera, and may protect against diarrhea from other gastrointestinal infections in children .
3) May Protect from IBD
The H. pylori infection rate in Asian IBD patients was significantly lower than in non-IBD patients, indicating that H. pylori infection may protect against the development of IBD . This correlation is not yet fully explained, and more research is likely needed to determine the significance of this finding.
4) Infection Is Lower in Celiac disease
Celiac disease is associated with lower H. pylori infection . This raises the question of whether H. pylori infection confers any protection against Celiac disease, and more study would be needed to determine the underlying mechanisms and their significance .
5) May Protect Against Asthma & Allergies
While the prevalence of H. pylori infection is decreasing in many countries due to improvements in sanitation and living conditions, the prevalence of allergic diseases like asthma and rhinitis has increased by 32% in Western populations .
Individuals carrying H. pylori were 30% less likely to have concomitant allergic conditions, including asthma, eczema, and allergic rhinitis .
H. pylori skews the adaptive immune response toward immune tolerance rather than immunity, which promotes persistent infection on the one hand and inhibits auto-aggressive and allergic T-cell responses on the other .
Atopic dermatitis, allergic rhinitis, and asthma are mediated through Th2 pathway cytokines, including IL-4, IL-5, IL-9, and IL-13 . Tregs suppress the Th2 response, and allergy-associated IgE production .
Early infection of mice with H. pylori increases the number of Treg cells in the airways and thereby prevents the development of asthma .
Interestingly, mice that had been infected with H. pylori as newborns showed lower levels of allergic airway inflammation in response to allergens than mice infected during adulthood .
A study in humans found an inverse correlation between allergy and H. pylori infection in children, but not adults .
The acquisition of H. pylori in childhood seems to be linked to reduced asthma and allergy risk . Children with severe allergies were significantly more likely to be either H. pylori‑negative or infected with a less virulent strain of the bacteria than children with mild or no allergy . One explanation for this phenomenon may be the “hygiene effect”, which states that exposure to microbes early in life prevents the later development of allergic diseases .
A Korean study demonstrated increased levels of allergy in patients after H. pylori eradication compared to H. pylori positive patients without eradication and H. pylori negative controls .
However, in some parts of the world, low incidence of H. pylori infection is not associated with higher allergy prevalence in children . H. pylori infection is most likely only one of several other infectious pathogens, associated with poor hygiene, that can reduce the likelihood of developing allergies [61, 32].
6) May Protect Against Multiple Sclerosis
Surprisingly, several studies indicate a protective effect of H. pylori infection on multiple sclerosis . H. pylori infection is significantly less frequent in patients with conventional multiple sclerosis than in healthy controls or patients with opticospinal multiple sclerosis . However, very little solid epidemiological data is available to date to support a protective effect of H. pylori on the development of MS .
To be Continued In:
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