Nikolaos Kapetanakis

Association between Helicobacter pylori infection and mild cognitive impairment

The association of Helicobacter pylori infection and Alzheimers disease (AD) has recently been addressed, but no relative data exist regarding mild cognitive impairment (MCI), a prodromal phase of AD. The aim of this prospective study was to evaluate H. pylori infection, by histology in a Greek MCI cohort. Sixty‐three consecutive patients with amnestic MCI and 35 normal controls underwent upper gastrointestinal endoscopy, histologic and serological examinations. The prevalence of H. pylori infection was 88.9% (56/63) in MCI patients and 48.6% (17/35) in anaemic controls, as confirmed by biopsy (P < 0.001, odds ratio: 8.47, 95% CI: 3.03–23.67). Mean serum anti‐H. pylori IgG concentration and plasma total homocysteine (Hcy) titre were higher in MCI patients than controls (74.86 ± 57.22 vs. 17.37 ± 9.30 U/ml; and 16.03 ± 4.28 vs. 13.5 ± 1.20 μmol/l; P < 0.001 and P = 0.015, respectively). When compared with the anaemic participants, MCI patients exhibited more often multifocal (body and antral) gastritis (92.1% vs. 68.6%; P = 0.03); in H. pylori positive MCI patients cognitive state correlated with serum anti‐H. pylori IgG concentration. In conclusion, H. pylori prevalence was significantly higher in MCI patients than controls. This infection might contribute, at least in part, to the pathophysiology of MCI, possibly through induction of chronic atrophic gastritis and elevated Hcy consequences.

Helicobacter pylori infection and colorectal carcinoma: pathologic aspects

To the Editor, Fleming et al. (1), by reviewing the pathologic aspects of colorectal neoplasms, summarized the pathogenesis and molecular classification of colorectal carcinoma (CRC) including mainly molecular pathways and environmental factors. However, they did not mention the potential pathologic aspects of environmental factors involved in colorectal oncogenesis, particularly in sporadic CRC. More than 95% of colorectal cancers are sporadic, also mentioned by the authors (1), without a significant hereditary risk. Geographic variation in the incidence of CRC is substantial with a higher incidence observed in the West. Environmental factors contribute considerably to this variation (2); the majority of the sporadic cancer is believed to be due to modification of mutation risk by other genetic and/or environmental factors. Dietary factors may influence the oncogenic process by modifying intestinal transit time, altering the flow and recycling of bile, or changing the intestinal bacterial flora composition. Numerous studies support a role for the gut microbiota in colorectal oncogenesis and the colonic microbiota drives the progression towards colorectal malignancy including generation of reactive metabolites and carcinogens, alterations in host carbohydrate expression and induction of chronic mucosal inflammation (3); long-term colonization of the colon by rogue commensal bacteria capable of inducing chronic DNA damage could contribute to sporadic CRC developement, thereby suggesting sporadic CRC as an infectious disease (4). In this regard, Helicobacter pylori (Hp), a curved spiral gram-negative bacterium found in the gastric mucosa of a large proportion of humans worldwide (>50%), has been evaluated as a possible etiologic agent for CRC and recent data indicate that there is a serological association between Hp infection (Hp-I) and the risk of CRC, especially for left-sided and early-stage cancers (5). Moreover, Hp seropositive subjects are associated with a modest increase in the risk for colorectal adenoma, and since Hp-I can increase the risk especially of advanced adenomas, the medical community should take into account that a preventive strategy is needed, and, furthermore, elucidating the pathophysiological role of Hp in the development of CRC is highly warranted (6). However, as mentioned by the authors (5,6), the serologic measurement of infection status is less than perfect, thereby representing a specific limitation of their studies. Indeed, the serological test does not discriminate between current and past infections and, apart from past infection that may even be more relevant for oncogenesis, such a distinction is essential because only current Hp-I induces humoral and cellular immune responses that produce or perpetuate chronic inflammatory processes in gastrointestinal tract with potential oncogenic sequelae; many neoplasms including colorectal adenomas and cancers arise at the sites of chronic inflammation and infection (7-10). Based on histology, the practical gold standard for Hp-I diagnosis, our own preliminary studies indicated Hp presence in malignant tissue in 34 of 41 (82.9%) patients with CRC (23 men, mean age 73.6±7.9 years) (11). Extending these preliminary data we currently included 50 patients (28 men, mean age 71.3±9.7 years) with CRC and 25 patients (13 men, mean age 72.8±10.1 years) with colonic polyps with the following results: Hp presence in malignant and polyp tissues of patients were observed in 84% and 64%, respectively, confirming our preliminary data (12). It is important to note that, apart from Cresyl fast violet staining mainly used to detect Hp, its presence was also documented by immunohistochemical method (using polyclonal rabbit anti-Hp antibody (dilution 1:50, DAKO, Athens, Greece) in adenoma and malignant colonic tissues. Specifically, in accordance with Hong et al. (6), Hp progressive increased presence was observed in our patients with adenomas associated with mild (50%) and moderate/high-grade (80%) dysplasia; the latter lesions are frequently described as advanced adenomas. However, contrary to the authors’ considerations (6), our series showed an increased Hp presence in left-sided (79%) than in the proximal colon (21%) adenomas; left-sided cancers were also observed in 70.7% of our patients, a finding also noticed by Zhang et al. (5), thereby suggesting that Hp-I might be associated with a rather relevant risk increase in the left CRC. The multistep model of gastric cancer postulates that there is initially an inflammation, caused mainly by Hp-I, which can lead to the development of chronic active gastritis. In a subset of these patients, this inflammatory process leads to the development of atrophic gastritis, followed by intestinal metaplasia, dysplasia, and, ultimately, early and advanced gastric cancer (13). It is considered that all stages prior to the development of high-grade dysplasia are potentially reversible, although this is still controversial (13). Because, Hp also induces inflammatory changes in colonic mucosa (14), it would be reasonable to further speculate, in view of our data, that chronic inflammatory process induced by Hp-I in colonic mucosa may lead to adenoma - mild-moderate/high grade dysplasia - CRC development sequence. These findings may emphasize the need for Hp eradication to prevent the development of both colon and gastric cancer (13). In addition, we found that presence of Hp in malignant colonic tissue was associated with Ki-67 oncogene increased expression in all tumor specimens and low expression in all adjacent tissue specimens (15). Moreover, p53 increased and low expression was observed in 72.5% and 100% of tumor and adjacent tissues specimens, respectively. Likewise, antiapoptotic Bcl-2 protein was observed in 60% and 9% of tissue specimens, respectively, whereas proapoptotic Bax protein was observed in 9% and 100% of tissue specimens, respectively (15). Therefore, Hp colonizing colonic neoplasm tissue seems to be associated with an increased cell proliferation and impaired apoptotic process in malignant tissue compared with normal adjacent colonic mucosa, thereby possibly contributing to colon normal mucosa-adenoma-cancer sequence (15). In this regard, Hp-induced gastrin as an oncogenic growth factor, shows antiapoptotic activity through the Bcl-2 upregulation and contributes to gastric and colon carcinogenesis through stimulation of mutagenic and tumorigenic cyclooxygenase-2 expression (16). Animal models suggested the mitogenic action of gastrin to be limited to the left colon, elevated gastrin levels are more pronounced in their associations with rectal than with colon cancer, and the relation between hypergastrinemia and colorectal adenomas confers an increased risk only for distal colon adenomas. These findings are consistent with and may explain our findings and Zhang et al. (5) findings of selective risk increase with respect to left-sided CRC and adenomas. Experimental data indicate that Hp-I leads to development of chronic inflammation, hyperplasia, metaplasia, dysplasia and recruitment and accumulation of bone marrow-derived cells (BMDCs) which may contribute to tumor formation in animal models with Hp-induced chronic gastric inflammatory process (9,13). Because Hp similarly induces the mentioned inflammatory changes in colonic mucosa (14), it would be reasonable to further speculate that chronic Hp-I in humans also induces repopulation of the colon with BMDCs that might facilitate colon adenoma and cancer development and progression (9,13). In this regard, our own preliminary studies indicated increased expression of CD44 [a marker of human hematopoietic stem and progenitor cells and cancer stem cells (CSCs)] in malignant colonic tissue in 75.6% patients with CRC (11). Extending these preliminary data, increased expression of CD44 was observed in 78% and 16% of patients with cancers and polyps, respectively (12). We also obtained comparable data with gastric cancer (9,13). Therefore, these findings suggest the possible BMDCs and/or CSCs involvement in Hp-associated gastric cancer development and colon adenoma and cancer growth and/or progression (9,13). However, larger-scale future studies are warranted to show that the BMDCs move into areas of the upper and lower gastrointestinal tract and/or CSCs might be induced in the context of Hp chronic injury or inflammation with potential long-term colon adenoma malignant consequences in Hp-positive subjects. Finally, it is important to know if the authors (1) considered relative pathologic aspects in their studies.

Impact of Helicobacter pylori infection on normal colorectal mucosa, adenomatous polyps and adenocarcinoma sequence.

Dear Sir, When considering the prevention of parastomal herniation, colostomy rather than ileostomy, the proverb ‘prevention is better than cure’ is most apt. Indeed the special article by Hansson [1] is an important synopsis of the problems faced by patients and surgeons. As outlined in her commentary the use of prophylactic mesh has been advocated since 2004 with short-term results demonstrating its efficacy. Although longer-term results are still awaited, Hotouras et al. [2] thought it difficult for clinicians not to use mesh routinely. Whilst this may be the ideal, what are the thoughts ‘on the ground’? We conducted an email survey of the corresponding authors of 200 original articles recently published in Colorectal Disease and Diseases of the Colon and Rectum to ascertain current views with regard to the use of mesh. There were 111 (55%) respondents, 65 of whom were colorectal specialists with at least 10 years in practice including 31 with 5– 10 years and 15 with less than 5 years of experience in specialist practice. Overall only 17% of respondents said that they had used or observed the use of prophylactic mesh at the last elective permanent colostomy at which they had been present. On the question of emergency end colostomy, if the patient was unlikely to later undergo reversal, 43% of respondents said they would ‘consider’ the use of a prophylactic mesh. This uncertainty was independent of the level of specialist experience (range 42–49%), but when asked to consider what they would do personally, 73% said that they would not use mesh. Thus despite earlier published results, this analysis of current attitudes among colorectal surgeons demonstrates a high incidence of conservative views towards prophylactic mesh. This is a pity and suggests that there may be more ‘talk than action on the street’. Large prospective ‘personal’ audits and trials, preferably randomized, are clearly required to evaluate various methods of stoma formation and to influence our mind-set.

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.

Distant cutaneous metastasis preceding the diagnosis of ductal cholangiocarcinoma

© 2008 The Authors JEADV 2009, 23, 169–243 Journal compilation

Active Helicobacter pylori infection on colorectal mucosa--adenomatous polyp--adenocarcinoma sequence.

Acknowledgements Conflicts of interest There are no conflicts of interest. References 1 Cuthbertson FM, Davies M, McKibbin M. Is screening for interferon retinopathy in hepatitis C justified? Br J Ophthalmol 2004; 88: 1518–1520. 2 Okuse C, Yotsuyanaqi H, Nagase Y, Kobayashi Y, Yasuda K, Koike K, et al. Risk factors for retinopathy associated with interferon-2b and ribavirin combination therapy in patients with chronic hepatitis C. World J Gastroenterol 2006; 12:3756–3759. 3 Sène D, Touitou V, Bodaghi B, Saadoun D, Perlemuter G, Cassoux N, et al. Intraocular complications of IFN-alpha and ribavirin therapy in patients with chronic viral hepatitis C. World J Gastroenterol 2007; 13:3137–3140. 4 Helal J Jr, Zacharias LC, de Alencar LM. Central vein occlusion in a patient using interferon and ribavirin: case report. Arq Bras Oftalmol 2006; 69:601–604.

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).

Letter: is Helicobacter pylori behind Barrett's oesophagus and colorectal neoplasms?

SIRS, Andrichi et al.’s meta-analysis showed that Barrett’s oesophagus (BO) was associated with an increased risk of both colorectal adenomas and colorectal cancer (CRC). They concluded that if the risk estimates for CRC in BO patients reflects a real relationship, an established association will warrant a search for common genetic or environmental risk factors. Some genetic alterations are common in both conditions; we initially found that specialised intestinal metaplasia indicating BO appeared in a significant percentage of patients with colon tumours (12/23) compared with controls (2/14) and was associated with increased oesophageal mucosal expression of oncogenes Ki-67 and p53/Bcl-2 that indicated mainly increased proliferation leading to oncogenesis. In this regard, Helicobacter pylori infection may be considered a promoter of both diseases. Our and others’ data indicate that H. pylori infection might contribute to oesophageal adenocarcinoma progress in subpopulations with gastro-oesophageal reflux disease and BO. In this respect, gastrin, induced by H. pylori infection, is an oncogenic growth factor contributing to oesophageal, gastric and colon carcinogenesis and, in particular, playing a potential causal effect on neoplastic progression in BO and left side CRC showing, for instance, anti-apoptotic activity through upregulation of the anti-apoptotic Bcl-2 and stimulation of mutagenic and tumourigenic cyclooxygenase-2 expression. Moreover, H. pylori infection is mostly frequent in colonic adenomas and tumour tissues (documented by immunohistochemical stain) and is accompanied by increased cell proliferation (mainly enhanced Ki-67 and Bcl-2 expression) and impaired apoptotic (decreased Bax) processes, thereby indicating its potential pathogenetic role. Apart from upper gastrointestinal tract (UGT), H. pylori infection might also cause chronic inflammatory colon mucosal damage and stimulate cancer stem cells and/or recruit bone-marrow–derived stem cells, which may ultimately facilitate UGT and colon tumour formation and progression. However, further studies are needed to elucidate the proposed pathophysiological mechanisms involved in H. pylori-associated colon oncogenesis; its eradication might inhibit these oncogenic processes.

Letter: Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia.

1. Takyar V, Surana P, Kleiner DE, et al. Noninvasive markers for staging fibrosis in chronic delta hepatitis. Aliment Pharmacol Ther 2017; 45: 127–38. 2. Huang R, Yan X, Jia B, Wang G, Liu Y, Wu C. Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis. Aliment Pharmacol Ther 2016; 45: 574–5. 3. WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization, 2015. 4. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology 2015; 61: 292–302. 5. Houot M, Ngo Y, Munteanu M, Marque S, Poynard T. Systematic review with meta-analysis: direct comparisons of biomarkers for the diagnosis of fibrosis in chronic hepatitis C and B. Aliment Pharmacol Ther 2016; 43: 16–29. 6. Lutterkort GL, Wranke A, Yurdaydin C, et al. Non-invasive fibrosis score for hepatitis delta. Liver Int 2016; doi:10.1111/liv. 13205 [Epub ahead of print]. 7. Kushner T, Serper M, Kaplan DE. Delta hepatitis within the Veterans Affairs medical system in the United States: prevalence, risk factors, and outcomes. J Hepatol 2015; 63: 586–92. 8. Gish RG, Yi DH, Kane S, et al. Coinfection with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. J Gastroenterol Hepatol 2013; 28: 1521–5.

Helicobacter pylori might contribute to cancer and/or bone marrow-derived stem cell-related gastrointestinal oncogenesis

Helicobacter pylori might contribute to cancer and/or bone marrow-derived stem cell-related gastrointestinal oncogenesis