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From the Townsend Letter
June 2013

Helicobacter Pylori: Foe, Sometimes Friend
by Stephen Olmstead, MD; Kathleen Burns, MSN, RN, NP; Dennis Meiss, PhD; and Janet Ralston, BS
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The Gastric Microbiota and Helicobacter Pylori
Until 1983, conventional medical wisdom decreed that low gastric pH and vigorous motility rendered the stomach nearly sterile.1 While researchers had observed microorganisms, including curvilinear, gram-negative bacteria, adherent to gastric epithelial cells in the late 19th century, virtually all experts believed any microbes found in the stomach were transient, derived from swallowed secretions or ingested foods and liquids.2 Traditional culture-based techniques showed low numbers (<103 CFU/mL) of gastric microbes from the phyla Firmicutes, Proteobacteria, Actinobacteria, and Fusobacteria as well as yeasts.3,4 In 1983, Marshall and Warren first published their observation of a curved, gram-negative bacillus on the gastric epithelium in the setting of acute gastritis.5 Subsequently this organism came to be known as Helicobacter pylori. Colonizing about 50% of people worldwide, H. pylori was initially seen as an infectious agent causing gastritis and peptic ulcer disease.6 Subsequent studies linked H. pylori with gastric carcinoma and lymphoma.7,8 Current research shows that H. pylori can be part of a complex, yet to be understood gastric microbiota.9 When present, H. pylori dominates the gastric microbiome although the full implications of this dominance are currently unknown. Genetic studies suggest that H. pylori has been associated with humans as a gastric commensal microbe for at least 60,000 years, so it is likely that colonization confers some benefit and is pathogenic only in specific settings.10 The current emphasis on eradication of H. pylori may be increasing the risk of esophageal carcinoma, allergies, asthma, and autoimmune disorders.11

Helicobacter Pylori Microbiology
H. pylori is a flagellated, highly mobile, gram-negative bacterium.12 It is usually spiral shaped, but becomes coccoidal following antibiotic treatment or when invading the gastric mucosa.13 A fastidious, microaerophilic bacterium, while highly adapted to the gastric environment, H. pylori is not acidophilic, surviving only brief exposures to a pH less than 4. It copes with low pH by producing large amounts of urease. By splitting urea into NH3 and CO2, H. pylori buffers protons and maintains a neutral periplasmic pH.14 When H. pylori colonizes the stomach, the vast majority of the population resides in the mucus overlying the gastric mucosa. However, it often adheres to gastric epithelial cells and may even invade cells as a facultative intracellular microorganism.15 The ability to invade stomach and intestinal epithelial and immune cells may contribute to H. pylori's virulence.

Helicobacter Pylori Epidemiology
There is considerable age, geographic, and socioeconomic variation in the prevalence of H. pylori colonization.12 In developing countries, where over 80% of people are positive for H. pylori, colonization typically occurs during the first 5 years of childhood and persists for life without treatment. In developed countries, the prevalence of H. pylori colonization is about 40% and is much lower in children than in adults. The incidence of new H. pylori cases in adults in industrialized countries is about 0.5% per year. In general, lower socioeconomic status is associated with higher rates of H. pylori colonization.

Helicobacter Pylori Pathogenicity
H. pylori colonization is invariably associated with an immune response characterized by infiltration of the gastric lamina propria by polymorpholeukocytes and pro-inflammatory phenotypic immune cells.16 Almost always termed acute or chronic gastritis, this terminology may be misleading as the body normally mounts an inflammatory response to colonization of the mucosa and skin by microorganisms. The immune response to intestinal microbial colonization is never termed colitis or enteritis. Specific types of H. pylori-associated gastritis are associated with an increased risk of certain clinical outcomes. Nonatrophic, nodular, antral predominant gastritis is related to duodenal ulcer disease, and multifocal atrophic gastritis may lead to gastric cancer.17,18 Despite the high prevalence of H. pylori, only a minority of colonized people develop disease. The incidence of peptic ulcer disease among those harboring H. pylori is between 10% and 20%, of gastric adenocarcinoma 1% to 2%, and of gastric mucosal-associated lymphoid tissue (MALT) lymphoma <1%.1 Why certain individuals develop H. pylori-associated disease, while most do not, is not fully understood. No doubt it depends on the complex interplay between the virulence of the colonizing strain, host age at the time of infection, and host genetic and environmental susceptibilities. Among the better known H. pylori virulence factors are cytotoxin-associated gene A (cagA) and vacuolating toxin (vacA).19 However, even people colonized with H. pylori positive for cagA and vacA are unlikely to develop clinical disease. The current hypothesis is that H. pylori-associated disease represents an inappropriately modulated immune response to gastric colonization.19

Benefits of Helicobacter Pylori Colonization
It seems intuitive that an organism that has coevolved with humans since the origin of the species must confer some benefit by its commensal presence.16 What benefits, if any, H. pylori colonization may bestow on its host are the subject of vigorous debate.1,20,22 The dramatic treatment-mediated decline in H. pylori colonization rates has provided an opportunity to study what advantages H. pylori may have been offering all these millennia. Although the subject of dispute, there is epidemiological evidence that as the prevalence of H. pylori colonization has diminished, gastroesophageal reflux and its complications such as esophagitis, Barrett esophagus, and esophageal adenocarcinoma have become more widespread.22,23 Cross-sectional studies confirm an inverse relation between H. pylori prevalence and severity of GERD and a strong correlation of the absence of H. pylori with Barrett esophagus and esophageal carcinoma.24-28 A hypothetical mechanism is that H. pylori colonization, particularly with cagA+ strains, leads to pan- or corpus-predominant gastritis, which is associated with hypochlorhydria that may confer protection against esophageal reflux and its complications. Allergies and autoimmune diseases are another group of disorders that have increased over the past three decades while rates of H. pylori colonization have decreased. A recent meta-analysis of 14 studies found a significantly lower incidence of H. pylori colonization in people with asthma compared with controls.29 The role of immunologic response to H. pylori and the risk of autoimmune disease is less clear and more controversial. Good evidence suggests that H. pylori colonization may increase the risk of immune thrombocytopenia.30 There are also data supporting a protective role of high antibody titers to H. pylori and the risk of multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel disease.31 These possible associations are highly controversial and require further study. Possible mechanisms include the ability of H. pylori to elicit high regulatory T cell (Tregs) responses, especially in childhood, which may suppress excessive Th1 and/or Th2 responses.32,33 The disappearance of H. pylori has been hypothesized to contribute to the increasing incidence of obesity and metabolic syndrome. Weight gain is reliably observed following H. pylori eradication.34 Absence of H. pylori is associated with high gastric and serum ghrelin and low gastric leptin, which could provide mechanisms for weight increases.35,36 However, any association between obesity and metabolic syndrome and the absence of H. pylori colonization remains unproven.37 Among the many confounding factors that make understanding a possible relation between H. pylori status and obesity are that age of infection may be important, with childhood infection conferring protection, obesity itself may predispose to H. pylori infection, and H. pylori strain and distribution of gastritis may be critical variables.

Diagnostic Tests
No clear consensus exists on the best test to detect H. pylori colonization.38 Available noninvasive tests include C-urea breath test (UBT), serology, polymerase chain reaction (PCR) of Helicobacter DNA, and detection of Helicobacter stool antigen (HpSA).13,38-41 Invasive tests are rapid urease test (RUT), histological examination, and culture of gastric mucosal biopsies. PCR and antigen detection can also be done on gastric contents or biopsies.40 Culture and histological examination of biopsy specimens remain the "gold standard" for definitive diagnosis with sensitivities exceeding 95%. Many investigators and practitioners believe the UBT is the best noninvasive test with a sensitivity and specificity ranging from 80% to 100%. The RUT is a valuable rapid, cost-effective invasive test for H. pylori. Stool PCR has a sensitivity of around 70%, but is 100% specific. In contrast, studies show HpSA to have a very heterogeneous sensitivity ranging from 58% to 96% and specificities varying from 67% to 96%. This appears to be a problem of procuring consistently high quality polyclonal antibodies for antigen detection. Serologies are useful for epidemiological surveys and not recommended for clinical practice.

Whom to Treat?
In what is often termed the "test and treat" approach, clinicians have usually elected to treat H. pylori colonization when detected. The "test and treat" approach has been promoted by most consensus guidelines on management of H. pylori.42 However, the indiscriminant treatment of H. pylori whenever detected may not be in the patient's best interest and more rational treatment guidelines are in order.1,20 There is broad consensus that patients with peptic ulcer disease, gastric MALT, and early gastric adenocarcinoma, and those with first degree relatives with a history of gastric cancer should be treated. Generally, there is a consensus that people with functional dyspepsia and H. pylori should be treated although the benefits are unclear and 12 people must be treated to see 1 person improve.42 There is consensus that H. pylori should be tested for in the setting of immune thrombocytopenia, vitamin B12 deficiency, and iron deficiency anemia and treated if positive.42 Clearly, a positive test for H. pylori should not prompt treatment unless the full clinical scenario justifies the potential risks and costs of therapy.

Conventional Treatment
While H. pylori is sensitive to a variety of antibiotics in the laboratory, each antibiotic generally fails clinically when used alone. Clarithromycin, the most effective drug, only has a 40% success rate when used alone.43 Dual therapy, the combination of a proton pump inhibitor (PPI) with an antibiotic, usually amoxicillin, rapidly gave way to triple therapy, a combination of two antibiotics plus a PPI or bismuth salts.44 Triple therapy has become the standard regimen for H. pylori eradication although current data show that the success rate is 70% or less in treated patients.42 Quadruple therapies consisting of three antibiotics and a PPI or bismuth salts and "sequential treatment," which includes a five-day period with PPI-amoxicillin, followed by a five-day period with PPI-clarithromycin-metronidazole (or tinidazole), are now advocated. Poor success rates are usually attributed to H. pylori's microecological niche in the low pH gastric mucus layer as well as emergence of antibiotic resistance.41 However, two additional factors are likely to contribute significantly to treatment failure – biofilm formation and intracellular replication of H. pylori.

Helicobacter Pylori Biofilm
Biofilm is a gathering of sessile bacteria and/or fungi encased by a self-generated hydrated exopolysaccharide, protein matrix attached to a surface.45,46 Life within biofilms is the preferred mode of existence for microbes within the body as well as in the environment. Among the numerous benefits of living within biofilm are protection from host immune responses and a high degree of antibiotic resistance.45,47 H. pylori has long been known to make biofilm.48 H. pylori biofilms have been described in peptic acid disease; and in one endoscopic study, H. pylori biofilms covered an average of 97.3% of the gastric mucosa in urease positive patients.49 H. pylori biofilm undoubtedly contributes to the low success rate of conventional therapy. The magnitude of biofilm's contribution to treatment failure is illustrated by a study of 21 patients with dyspepsia previously treated for H. pylori with a standard seven-day triple therapy, a PPI, clarithromycin, and amoxicillin.50 Patients were biopsied three months after therapy. H. pylori were cultured in 7 out of 21 patients. However, through gene analysis (glmM), viable but not culturable H. pylori were detected in 19 out of 21 biopsies. In all of these subjects, the biofilm quorum-Sensing gene luxS was detected and metabolically quiescent coccoid and S-shaped H. pylori cells were clustered within biofilm. The study not only shows the importance of biofilm in limiting treatment success, but also suggests that treatment success rates based on standard negative tests may grossly overestimate eradication rates.

Helicobacter Pylori Invasion and Replication within Cells
H. pylori is usually thought to be a noninvasive pathogen residing within gastric mucus. However, numerous studies show that H. pylori can invade cells to reside in a cytoplasmic vacuole or replicate on the cell membrane or within the cell to form a microcolony.51 H. pylori can multiply within macrophages, bone marrow-derived dendritic cells, and gastric epithelial cells. H. pylori penetrates nonmetaplastic, metaplastic, and neoplastic gastric epithelium both intracellularly and interstitially.52 Residing and replicating within gastric cells have significant implications for antimicrobial treatment as antimicrobials may fail to penetrate gastric cells. Furthermore, metabolically dormant coccoid cells residing in cytoplasmic vacuoles have very low susceptibilities to antibiotics.

Need for Complementary Adjunctive Therapies for Helicobacter Pylori
The poor standard therapy success rate mandates other interventions to increase eradication rates.53 Conventional therapies are also expensive and associated with significant morbidities. Side effects commonly include diarrhea, nausea, vomiting, bloating, and abdominal discomfort. Less common but more serious is Clostridium difficile-associated disease. Complementary therapies not only improve treatment success rates, but reduce treatment adverse effects. Available therapies include probiotics, antibiofilm enzymes, lactoferrin, N-acetyl-L-cysteine, and quercetin.

Helicobacter Pylori and Probiotics
The preponderance of available evidence shows that probiotics can improve H. pylori treatment success rates and reduce side effects.54-56 Among the mechanisms by which probiotics antagonize H. pylori are the production of lactic acid, acetic acid, bacteriocins and other antimicrobial compounds, stimulation of mucus production, inhibition of adhesion to gastric epithelial cells, and favorable modulation of host immune responses.54,55 The yeast probiotic Saccharomyces boulardii damages the cellular structure of H. pylori.57 Probiotics in addition to standard triple and bismuth-based quadruple therapy effectively prevent antibiotic-associated side effects, decrease H. pylori density and gastritis, and reduce H. pylori reinfection rates.55,58 In a review of nine clinical trials of probiotic lactic acid bacteria administered along with standard therapy, probiotics significantly increased eradication rates (81% vs. 71%, p =0.03). S. boulardii reduces the side-effects of the standard triple therapy and when used alone eradicated H. pylori in 12% of colonized children.59,60 However, the addition of S. boulardii to standard antibiotics does not significantly improve clearance rates.59,61

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