Elena Tsiaousi

Helicobacter pylori Infection Might Contribute to Esophageal Adenocarcinoma Progress in Subpopulations With Gastroesophageal Reflux Disease and Barrett's Esophagus

To the Editor, Fischbach et al. [1] concluded that estimates for the effect of Helicobacter pylori (H. pylori) on Barrett’s esophagus (BE) were heterogenous across studies; although overall H. pylori, and particularly cagA cytotoxin, tended to be protective for BE in most studies, H. pylori effect on BE varied by geographic location. Barrett’s esophagus is a complication of long-standing gastroesophageal reflux disease (GERD) and wellrecognized premalignant condition playing a pivotal role in the development of esophageal adenocarcinoma (EA), the most common esophageal malignancy in Western countries with increasing faster incidence than any other cancer [2]; GERD plays a crucial role in the pathophysiology and the clinical identification of BE [2]. In this regard, our data show that H. pylori infection (H. pylori-I) is frequent in Greek patients with GERD and even with nonendoscopical reflux disease [2], and H. pylori eradication leads to better control of GERD symptoms and improves esophagitis [2,3]. Moreover, consistent associations with the Greek data were shown by others [3] also reporting improvement in reflux symptoms following H. pylori treatment. It is important to note that some other authors, usually prior supporters of the theory that H. pylori “protects” against GERD, relented their initial findings, claiming that H. pylori eradication does not cause or protect against GERD and, moreover, recommending H. pylori eradication in GERD [4]. Additionally, although epidemiologic studies do not suggest causality with H. pylori, however, such studies support our and others’ findings; for instance, a large study (~21,000 cases) showed that the decrease in H. pylori-I parallels the decrease in peptic ulcer prevalence, and the increase in GERD and reappearance of GERD after H. pylori eradication is rare. Moreover, contrary to expectation, patients hospitalized with duodenal ulcers (61,548 cases), obviously attributed to H. pylori-I, had a significant 70% excess risk of EA. Much evidence further potentiates the concern that H. pylori is not “protective” against GERD [5] and its complications including BE and EA. The interplay between H. pylori and host factors plays an important role in the pathogenesis of GERD. Specifically, H. pylori may contribute to GERD pathogenesis by several mechanisms including release of several mediators, cytokines, and nitric oxide, which may adversely affect the lower esophageal sphincter (LES); direct damage of the esophageal mucosa by bacterial products; increased production of prostaglandins that sensitize afferent nerves and reduce LES pressure; and augmented acidity (by gastrin release) that exacerbate GERD [3]. The authors considered some putative pathways involving H. pylori and a decreased risk of BE [1]. However, these pathways might represent the one BE pathogenic “coin’s” side. Regarding the other alternative side, gastrin, induced by H. pylori-I, is an oncogenic growth factor contributing to esophageal, gastric, and colon carcinogenesis and, in particular, playing a potential causal effect on neoplastic progression in BE; gastrin stimulates proliferation via JAK2and Akt-dependent NF-kappaB (NF-jB) activation in Barrett’s EA cells, shows antiapoptotic activity through upregulation of Bcl-2 and survivin, and upregulates cyclooxygenase (COX)-2 expression [2]. In this regard, H. pylori-I activates NF-jB, an oxidantsensitive transcription regulator of inducible expression of inflammatory genes such as COX-2, which regulates gastrointestinal cancer cell growth and proliferation. In particular, H. pylori-I induced NF-jB and COX-2 expression in esophageal epithelial cells, playing a role in inflammation associated with BE and tumorigenesis in the esophagus [2]; upon colonizing esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA [6]. Moreover, recent evidence indicates that 1, H. pylori-I prevalence is high in BE; 2, neither H. pylori-I nor H. pylori-I by CagA+ strains reduce the risk of BE in certain populations with high prevalence of H. pylori-I; 3, the expected incidence of EA with persistent H. pylori-I is higher than that of EA after eradication of infection [5]; H. pylori-I may affect specific molecular alterations (genetic instability, E-cadherin methylation, and monoclonal antibody Das-1) associated with the pathogenesis of BE; and 4, H. pylori induces

Potential implications of Helicobacter pylori-related neutrophil-activating protein

Helicobacter pylori (H. pylori) virulence factors promote the release of various chemoattractants/inflammatory mediators, including mainly the neutrophil-attractant chemokine interleukin-8 and neutrophil-activating protein (NAP), involved in H. pylori-induced gastric pathologies. Co-administration of Chios mastic gum (CMG), which inhibits H. pylori NAP, with an H. pylori eradication regimen might add clinical benefits against H. pylori-related gastric pathologies, but possibly not CMG as main therapy. Although H. pylori NAP and other H. pylori-related cytotoxins [i.e., vaculating cytotoxin (VacA)] appear to play a major role in generating and maintaining the H. pylori-associated gastric inflammatory response and H. pylori NAP is a promising vaccine candidate against H. pylori infection (H. pylori-I), concerns regarding its potential drawbacks, particularly neurogenic ones, due to possible cross-mimicry, should be considered. Possible cross-mimicry between H. pylori NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica patients. Moreover, the sequence homology found between H. pylori VacA and human Na+/K+-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients. A series of factors have been implicated in inducing blood-brain barrier (BBB) disruption, including inflammatory mediators (e.g., cytokines and chemokines induced by H. pylori-I) and oxidative stress. BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, thereby playing a major role in multiple sclerosis pathogenesis. Relative studies show a strong association between H. pylori-I and MS. H. pylori-I induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and perpetuating neural tissue damage. Finally, H. pylori NAP also plays a possible pathogenetic role in both gastric and colon oncogenesis.

Neuroprotection in glaucoma: is there a future role of Helicobacter pylori eradication?

Dear Editor, We read with considerable interest the paper by Baltmr A et al. (Baltmr et al., 2010) summarizing the mechanisms in initiating the apoptotic glaucomatous damage and reviewing “current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic”. However, the authors did not mention the role of environmental agents involved in the pathophysiology of glaucomatous neuropathy and the potential neuroprotective strategies against these agents. In this regard, although degenerative diseases, including glaucoma, have an increasingly high impact on aged population, their association with Helicobacter pylori (H. pylori) infection has only recently been addressed (Kountouras et al., 2001, 2003; Kountouras et al., 2004a; Kountouras, 2009). A relationship between glaucoma andH. pylori infection appears to exist based on the following comparable data: (a) both diseases affect mainly old people; (b) H. pylori infection has been implicated in a variety of extradigestive vascular conditions including functional vascular disorders caused by the release of diverse vasoactive and proinflammatory substances, hypertension, arteriosclerosisinduced increased platelet activation/aggregation, ischemic heart disease, and ischemic cerebrovascular disorders, also detected in glaucoma and other neurodegenerative diseases contributing to their clinical manifestations (Kountouras et al., 2001; Kountouras et al. 2003; Kountouras et al., 2004a; Kountouras, 2009); and (c) in the nervous system,H. pylori infection is thought to be associated with the development of autoimmune sequelae observed in peripheral neuropathies, Alzheimer’s disease (AD) and glaucomatous optic neuropathy (defined as “ocular” AD) (Kountouras et al., 2001, 2003, 2004a, 2007; Kountouras, 2009).

Impact of Helicobacter pylori Infection on colon oncogenesis.

To the Editor: Th e paradigm of Clostridium diffi cile -associated diarrhea (CDAD) is changing. Its incidence and severity are increasing. Th e emergence of hypervirulent strains of C. diffi cile is worrisome. Treatment failure rates are on the rise, and recurrence rates in treated patients are disappointing. Lately, CDAD has been described in populations previously thought to be at low risk. Nisin is a peptide antibiotic that exhibits bactericidal activity against Gram-positive organisms. It belongs to a class called the lantibiotics and is produced by the bacterium Lactococcus lactis subsp. Lactis ( 1 ). Nisin is safe and was granted GRAS status (Generally Recognized As Safe; notice no. GRN 000065) by the United States Food and Drug Administration. It is currently used as an additive to prevent food spoilage. Th e mode of action of nisin has been studied extensively. Th e cytoplasmic membrane is the primary target of nisin. It incorporates into the cytoplasmic membrane, leading to the formation of transient multistate pores that allow the effl ux of low-molecular mass molecules such as amino acids, K + , and internal adenosine triphosphate . As a result, both the membrane potential and pH gradients across the cytoplasmic membrane are dissipated, leading to cell lysis and death ( 2 ). More recently, nisin was found to interact with the lipid II molecule, which is an essential membrane-bound precursor for cell-wall biosynthesis ( 3 ). Nisin exhibits excellent in vitro activity against C. diffi cile . In fact, Bartoloni et al. ( 4 ) tested metronidazole, vancomycin, and nisin against 60 toxigenic strains of C. diffi cile collected from subjects with CDAD in hospital settings and found nisin to be eight times more eff ective than the current standard treatments ( 4 ). Preliminary animal studies have shown that nisin is poorly absorbed from the large intestine, which makes systemic toxicity less likely. It also attains high concentrations in the intestinal lumen and has no toxic eff ects on the intestinal epithelium ( 5 ). Nisin ’ s other advantage is its poor bactericidal activity against the most common gastrointestinal microbiota, Bacteroides and Prevotella ( 4 ). Nisin undergoes proteolytic degradation in the upper gastrointestinal tract, hence, it will require delivery directly to the colon of infected patients. Options include administering the medication as an enema or perhaps oral delivery via a coated capsule that will release the intact drug at the target site. For the reasons mentioned, nisin appears to be an excellent candidate agent for the treatment of CDAD and it merits further investigation in phase I clinical trials.

Autologous haematopoietic stem cell transplantation in a patient with refractory Crohn's disease

Dear Sir, Recent series reported successful autologous bone marrow-derived mesenchymal stromal cells transplantation in 10 patients with fistulising Crohns disease (CD).1 We wish to provide a relative experience on the long-term successful autologous haematopoietic stem cell transplantation (HSCT) in a patient with refractory CD who has completed a 31-month follow up. A 39-year-old male with moderate–severe CD, first diagnosed in 1994 involving the jejunum, ileum and colon was treated for eight years with conventional treatment schedules including corticosteroids mainly in disease relapses, mesalazine and one immunosuppressor (azathioprine). Because of a severe relapse in 2002, the patient was successfully treated by surgery (right colectomy/sigmoidectomy). He remains disease free for two years while on treatment …

Potential oncogenic properties of mobilized stem cells in a subpopulation of inflammatory bowel disease patients infected with Helicobacter pylori.

To the Editor: Marlicz et al concluded that Crohn’s disease (CD) triggers the mobilization of various types of stem cells, such as hematopoietic stem progenitor cells, into peripheral blood in patients suffering from this disease, while the significance and precise role of these mobilized cells in repair of damaged intestine requires further study. However, the authors did not discuss the possibility of potential oncogenic properties of the mobilized stem cells, at least in the subgroup of patients possibly infected with Helicobacter pylori (H. pylori). In this regard, although relative data indicate an absence or inverse association between H. pylori and inflammatory bowel disease (IBD), the prevalence of H. pylori infection in the IBD patients appears to be 38.2%– 47% in Europe. Moreover, enterohepatic and gastric Helicobacter species have been documented in fecal specimens from children with CD using polymerase chain reaction (PCR), and H. pylori, for example, was recently found in the intestinal mucosa of a patient affected by CD. Experimental data indicate that H. pylori infection leads to development of chronic inflammation, hyperplasia, metaplasia, dysplasia, and recruitment and accumulation of bone marrow-derived cells (BMDCs) in the mouse gastric epithelial mucosa. Nearly 25% of dysplastic lesions include cells originating from BMDCs, thereby indicating that BMDCs can participate in preneoplastic lesions preceding gastric carcinoma development; there is a role for engraftment of circulating BMDCs, which may contribute to tumor formation in animal models with H. pylori-induced chronic gastric inflammatory processes, thus further suggesting the possibility of the potential contribution of BMDCs in human gastrointestinal carcinoma. In this regard, we recently conducted a pilot study using tissue sections of biopsies of human gastric cancer in which H. pylori was detected by Cresyl violet staining. Moreover, stem cells and neovessels were detected by immunohistochemical method using a monoclonal antibody, anti-CD34; CD34, also mentioned by the authors, is a surface glycoprotein expressed on hematopoietic stem cells and is used as an important marker of these cells and neovessels. In addition, cyclin D1, involved in the regulation of cell proliferation, was also detected by immunohistochemical method. Other relative data indicate that H. pyloriinduced cytotoxin VacA exhibits chemotactic activities to the BMDCs and induces BMDCs to produce proinflammatory cytokines, leading to chronic inflammation with potential oncogenic consequences. Therefore, it would be reasonable to speculate that chronic H. pylori infection in both mice and humans induces repopulation of the stomach with BMDCs that may facilitate gastric cancer progression. These findings present a new way of thinking about the pathogenesis of upper gastrointestinal malignancy. The observation that BMDCs are the origin of H. pylori-induced gastric cancer can also be combined with supporting observations of BMDCs in other tumors such as Barrett’s esophageal adenocarcinoma, Kaposi sarcoma, cancer-associated fibroblasts, or benign and malignant tumors of the skin. Other relative data, using the stem cell marker CD44 (the integral membrane molecule CD44 is a marker of human hematopoietic stem and progenitor cells), indicate that the CD44þ gastric cancer stem cells show the stem cell properties of selfrenewal, the ability to form differentiated progeny, and, moreover, increased resistance for chemotherapy or radiation-induced cell death; H. pylori either directly or through a local inflammatory response is responsible for increased expression of CD44 and its variant CD44 v9, thereby suggesting a possible H. pylori induction of CD44þ BMDCs/gastric cancer stem cells involved in gastric cancer development and progression. Because H. pylori also induces inflammatory changes in colonic mucosa, it would be reasonable to further speculate that chronic H. pylori infection in humans induces repopulation of the colon with BMDCs that might facilitate colon cancer development and progression. In this respect, our own preliminary studies indicated the presence of H. pylori in malignant colonic tissue in 34 of 41 (82.9%) patients with colorectal cancer (23 men, mean age 73.6 6 7.9 years). Moreover, increased expression of CD44 in malignant tissue but not in the adjacent normal colonic mucosa was noticed in 31 of 41 (75.6%) patients with colorectal cancer. Extending these preliminary data we currently included 50 patients (28 men, mean age 71.3 6 9.7 years) with colorectal cancer and 25 patients (13 men, mean age 72.8 6 10.1 years) with colonic polyps with the following results: H. pylori presence and increased expression of CD44 in malignant tissue of patients were observed in 84% and 78%, respectively, confirming our preliminary data. Comparable data in adenomatous tissue of patients with colonic polyps were also observed in 64% and 16% of patients, respectively Copyright VC 2012 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.22911 Published online inWiley Online Library (wileyonlinelibrary.com).

Relationship between Helicobacter pylori infection and autoimmune disorders.

* Corresponding author: Jannis Kountouras , MD, PhD, Professor of Medicine, Department of Gastroenterology, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Greece, Phone: + 3

Adverse effects of smoking in ulcerative colitis

Dear Sir, In their recent article in the JCC, Calabrese et al.1 concluded that resumption of low-dose smoking in ex-smokers with refractory ulcerative colitis (UC) may ameliorate signs and symptoms and smokers should be followed for smoking-associated risks including cardiovascular disorders and cancers; they discussed only anecdotal data suggesting that smoking may be associated with a decreased risk of colon carcinoma in UC. Although their considerations might be partially correct, they probably reflect only one side of the coin. A considerable body of evidence has linked smoking with UC-associated colorectal cancer.2, …

P499 Folate regimen may reduce high homocysteine levels in a Greek cohort of patients with inflammatory bowel disease

Background: The degree of association between homocysteine metabolism and inflammatory bowel diseases (IBD) remains unknown and the association between hyperhomocysteinemia and thrombosis and oncogenesis remains controversial in IBD. The aim of this study was to investigate the serum homocysteine levels in patients with Crohn’s disease (CD) and ulcerative colitis (UC) and the potential folate therapeutic regimen against hyperhomocysteinemia. Methods: Serum levels of homocysteine were measured in 55 patients with (IBD) (28/55 CD and 31/55 UC patients). Patients with hyperhomocysteinemia received 15mg folate/day for 2 12 months. Levels of serum homocysteine were measured during folate treatment. Results: Hyperomocysteinemia was prevalent in 28/55 (50.90%) of patients studied (13 CD and 15 UC patients). Mean homocysteine levels among the patients with hyperhomocysteinemia were 17.72mmol/L with range 14.23 29.88mmol/L (normal values 3.7 13.9mmol/L) (Table 1). Folate was administered in 24/28 patients and serum levels of homocysteine were re-measured in 17 patients. In 14/17 patients lower levels of homocysteine were observed with a mean reduction of 5.25mmol/L by folate treatment. The baseline levels of homocysteine in these patients were 17.01 mmol/L and posttreatment 11.75mmol/L.