Dimitri Tzivras

Impact of reactive oxygen species generation on Helicobacter pylori-related extragastric diseases: a hypothesis.

Abstract Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori-related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer’s disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions.

Potential impact of Helicobacter pylori-related metabolic syndrome on upper and lower gastrointestinal tract oncogenesis

Both Helicobacter pylori infection and metabolic syndrome present significant global public health burdens. Metabolic syndrome is closely related to insulin resistance, the major underlying mechanism responsible for metabolic abnormalities, and Helicobacter pylori infection has been proposed to be a contributing factor. There is growing evidence for a potential association between Helicobacter pylori infection and insulin resistance, metabolic syndrome and related morbidity, including abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, all of which increase mortality related to cardio-cerebrovascular disease, neurodegenerative disorders, nonalcoholic fatty liver disease and malignancies. More specifically, insulin resistance, metabolic syndrome and hyperinsulinemia have been associated with upper and lower gastrointestinal tract oncogenesis. Apart from cardio-cerebrovascular, degenerative diseases and nonalcoholic fatty liver disease, a number of studies claim that Helicobacter pylori infection is implicated in metabolic syndrome-related Barretts esophagus and esophageal adenocarcinoma development, gastric and duodenal ulcers and gastric oncogenesis as well as lower gastrointestinal tract oncogenesis. This review summarizes evidence on the potential impact of Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease-Barretts esophagus-esophageal adenocarcinoma, gastric atrophy-intestinal metaplasia-dysplasia-gastric cancer and colorectal adenoma-dysplasia-colorectal cancer sequences. Helicobacter pylori eradication might inhibit these oncogenic processes, and thus further studies are warranted.

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

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A potential impact of Helicobacter pylori -related galectin-3 in neurodegeneration

&NA; Neurodegeneration represents a component of the central nervous system (CNS) diseases pathogenesis, either as a disability primary source in the frame of prototype neurodegenerative disorders, or as a secondary effect, following inflammation, hypoxia or neurotoxicity. Galectins are members of the lectin superfamily, a group of endogenous glycan‐binding proteins, able to interact with glycosylated receptors expressed by several immune cell types. Glycan‐lectin interactions play critical roles in the living systems by involving and mediating a variety of biologically important normal and pathological processes, including cell‐cell signaling shaping cell communication, proliferation and migration, immune responses and fertilization, host‐pathogen interactions and diseases such as neurodegenerative disorders and tumors. This review focuses in the role of Galectin‐3 in shaping responses of the immune system against microbial agents, and concretely, Helicobacter pylori (Hp), thereby potentiating effect of the microbe in areas distant from the ordinary site of colonization, like the CNS. We hereby postulate that gastrointestinal Hp alterations in terms of immune cell functional phenotype, cytokine and chemokine secretion, may trigger systemic responses, thereby conferring implications for remote processes susceptible in immunity disequilibrium, namely, the CNS inflammation and/or neurodegeneration.

Active Helicobacter pylori Infection Is a Risk Factor for Colorectal Mucosa: Early and Advanced Colonic Neoplasm Sequence

To the Editor: Based on serology, Lee et al. concluded that Helicobacter pylori infection (Hp-I) increased the risk of advanced colorectal neoplasm (CRN), particularly when combined with atrophic gastritis (AG), thereby warranting strict colonoscopy screening and surveillance in Hp-positive AG patients. Indeed, Hp-related chronic gastritis could be involved in an increased risk of CRN that seems to be enhanced by the progression of gastric atrophy and the occurrence of active inflammation. However, the serological test does not accurately discriminate between current and past infections, also mentioned by the aurhors, and, apart from past infection that might even be more relevant for oncogenesis, such a distinction is crucial because only current Hp-I induces humoral and cellular immune responses that induce or perpetuate chronic inflammatory processes in gastrointestinal tract with potential oncogenic sequelae; many neoplasms including colorectal carcinoma (CRC) arise at the sites of chronic inflammation and infection. Based on histology, the practical gold standard for current Hp-I diagnosis, our data in 50 CRC patients, 25 patients with colorectal adenomas (CRA) and 10 controls, showed significantly higher presence of Hp-I in the CRA (68%) and CRC (84%) groups compared with controls (30%). Regarding the features of histological severity in CRA group, presence of Hp-I was observed in 50% of patients with mild and 80% of patients with moderate/severe dysplasia. Likewise, presence of Hp-I in the CRC group was observed in 89% of patients with mild and 83% of patients with moderate/severe grade. Noteworthy, Hp presence was documented by immunohistochemical stain in CRA and CRC tissues. In addition, presence of Hp-I with accompanying immunohistochemical expression of CD44 (indicator of cancer stem cells [CSCs] and/or bone marrow-derived stem cells [BMDSCs]) in biopsy specimens was found in a high proportion of CRA patients accompanied with moderate/severe dysplasia (88%) and CRC patients with moderate/severe degree of malignancy (91%). Comparable pictures were also obtained for proliferation marker Ki-67, anti-apoptotic Bcl-2 and CD45 (assessing mainly T and B lymphocytes locally) immunohistochemical expressions. By introducing univariate analysis, the authors found that metabolic syndrome (MetS) was significantly associated with overall and advanced CRN. In this regard, in a systematic review, we reported an association between Hp-I and insulin resistance (IR), the major underlying mechanism responsible for the MetS. Our data further indicate that Hp-I might represent one further hit contributing to nonalcoholic fatty liver disease (NAFLD) pathogenesis, representing the hepatic component of MetS; NAFLD closely related to IR is involved in colon oncogenesis. Other studies also suggest that Hp-I with concomitant MetS might further increase CRA risk. Components of MetS are also associated with esophageal adenocarcinoma (EAC) risk and Hp-related IR might associated with gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE) and EAC. Although epidemiologic studies do not suggest causality with Hp, the interplay between Hp and host factors plays an important role in the pathogenesis of GERD and its complications BE and EAC in certain subpopulations. Therefore, casting further light in the uncertain pathophysiological mechanisms underlying Hp and CRN association, apart from gastrin mitogenic action mentioned by the aurhors, our results indicate that Hp-I has an impact on colorectal oncogenesis by: causing a possible chronic inflammatory mucosal damage, comparable to upper gastrointestinal tract (UGT); stimulating CSCs or recruiting BMDSCs, similar to UGT Hp-I-associated

Helicobacter pylori Infection and Gastroesophageal Reflux Disease–Barrett’s Esophagus–Esophageal Adenocarcinoma Sequence

We would like to thank the authors (Kosmidou et al.) for their interest in our published manuscript. We also appreciate them highlighting reports from other groups investigating the role of methylated DNA markers in the non-endoscopic detection of Barrett’s esophagus (BE), using these biomarkers in combination with cell collection devices. These reports highlight the potential of developing these sensitive and accurate markers, which are measured quantitatively, are not susceptible to subjective interpretation and hence are scalable. We were unfortunately not able to reference these studies given the timeline of our manuscript submission and revision. In our study we discovered and then validated in independent cohorts (using biopsy and whole esophageal brushings and finally the sponge on a string device) novel methylated DNA markers for the non-endoscopic detection of BE. As explained in detail in the manuscript, markers chosen for these exploratory analyses were chosen from both BE and esophageal adenocarcinoma (EAC) discoveries conducted in parallel. This was done to specifically ensure that markers chosen in the final panel remain discriminant for not only BE without dysplasia but also BE with dysplasia/EAC. We agree that while promising, these initial reports need to be confirmed by subsequent large validation studies in independent populations to further optimize marker combinations and establish cut offs. We are happy to report that in our interim analysis of our larger ongoing multicenter validation study, results (presented at Digestive Disease Week 2018) are extremely encouraging in terms of high accuracy of these markers and safety and tolerability of the EsophaCap [1]. We hope to report full results of this trial early next year. The utility of these markers will ultimately need to be established in screening populations, which are the intended setting of their use. With respect to the issue of adequate sampling of the esophagus with cell collection devices, we have not faced issues of inadequate sampling for BE detection in our completed or ongoing studies but agree that optimization of sampling is critical. This issue may be germane to detection of BE-associated dysplasia as well. Given the well-known problem with endoscopic detection of dysplasia secondary to missed lesions with random biopsies, molecular testing of samples from these non-endoscopic cell collection devices, which sample the full circumference of the esophagus, have potential to complement endoscopy and increase diagnostic yield for dysplasia/EAC. Whether intended targets are BE or BE-associated dysplasia and whatever cell collection devices are used, the inherent discrimination of the biomarkers selected are of fundamental importance.

Potential Impact of Helicobacter Pylori on Hepatic Encephalopathy Pathophysiology

Wijarnpreecha et al. [1] demonstrated an association between Helicobacter pylori infection (Hp-I) and risk of hepatic encephalopathy (HE); focus only on Hp-related augmented ammonia level possibly associated with the frequent HE exacerbation, the authors concluded that its eradication to decrease urease activity could be one of the potential HE treatments [1]. In this regard, portal hypertension (PH) leads to devastating complications including HE from portosystemic shunting formation and bacterial translocation (BT) playing an important role in PH pathogenesis [2]. HE is a potentially reversible though not fully reversible condition, the mechanism behind the lack of reversibility of the neurocognitive status despite the resolution of mental status changes is unclear [3], and cognitive dysfunction (CD) associated with minimal or covert HE, also mentioned by the authors [1], is a factor associated with falls and traffic accidents (automobile crashes) in cirrhotic patients [4]. Hp-I appears to be a frequent denominator connected with CD-related falls and fractures and liver cirrhosis [5]. In this respect, we reported an association between Hp-I and neurodegenerative disorders including mild CD and Alzheimer’s disease (AD) and Hp eradication could positively influence AD manifestations at 2and 5-year clinical endpoints, thereby suggesting a role for this common infection in the pathobiology of the disease [6]. Other epidemiologic studies also reported that AD patients infected by Hp are more cognitively impaired [6]; Hp-I is strongly associated with viral-related cirrhosis in Europe [4]; recent meta-analysis supports the high Hp-I prevalence in patients with cirrhosis [7]; and Hp-I is common in cirrhotic patients with HE [3]. Apart from Hp-induced hyperammonemia, mentioned by the authors [1], Hp-I may be further involved in HE and post-HE persistent CD pathophysiology by promoting the release of proinflammatory and vasoactive substances involved, through blood–brain barrier (BBB) disruption, in brain pathologies [6]; promoting platelet–leukocyte aggregation proposed to play pathophysiologic roles in dementia and complications of cirrhosis [6]; producing reactive oxygen metabolites involved in the pathophysiology of AD and complications of cirrhosis [6]; or influencing the apoptotic process, an important form of cell death in AD and liver disease [6]. Moreover, Hp might access brain via the oral–nasal–olfactory pathway or by circulating monocytes (infected with Hp due to defective autophagy) through disrupted BBB, leading to neurodegeneration [6]. Likewise, human defensins might contribute to Hp-related brain pathophysiology by modulating innate and adaptive immune system responses [8]. Specifically, human β-defensin (hBD)-1 is upregulated and may serve as a biomarker of BT in cirrhotic patients [9]; BT observed in liver cirrhosis appears to play an important role in the pathogenesis of its complications such as infections and HE; and Hp-I induces hBD-1 mRNA expression [10], thereby possibly contributing to Hp-related defensinBT-HE sequence. Hp might be further involved in the BBB breakdown, by releasing defensins, particularly those that display unique distribution at BBB sites [8]. Hp can activate granulocytes and induce defensin release from granulocytes; consequently, defensins penetrate the BBB, gain access brain, thereby possibly contributing to neurodegeneration [8]; HBD-1 might be of importance early in the neurodegenerative process [10]. * Jannis Kountouras jannis@auth.gr

The emerging role of helicobacter pylori-induced metabolic gastrointestinal dysmotility and neurodegeneration.

Helicobacter pylori infection (Hp-I) is a prevalent disorder identified in the majority of the population in many countries around the world and is responsible for substantial gastrointestinal morbidity. Likewise, neurodegenerative diseases such as Alzheimers disease, Parkinsons diseases, multiple sclerosis or glaucoma defined as ocular Alzheimers disease, are associated with a large public health burden and are among the leading causes of disability. Emerging evidences suggest that Hp-I may be associated with neurodegenerative conditions. Moreover, Hp-I could be a predictor of metabolic syndrome (MetS). Hp-I and its related MetS may induce gastrointestinal tract dys-motility disorders with systemic complications possibly including central nervous system neurodegenerative pathologies. We hereby explore the emerging role of Hprelated metabolic gastrointestinal dys-motilities on the molecular pathophysiology of Hprelated neurodegenerative and gastrointestinal disorders. Improving understanding of such Hp-I pathophysiology in brain pathologies may offer benefits by application of new relative therapeutic strategies including novel opportunities toward enhancing Hp eradication.

Letter: Helicobacter pylori in lean and obese patients with non-alcoholic fatty liver disease

SIRS, In their review, Sookoian and Pirola concluded that lean and obese non-alcoholic fatty liver disease (NAFLD) patients share a common altered metabolic and cardiovascular profile. This profile is similar to that observed in the traditional metabolic syndrome-associated NAFLD. Investigating the pathophysiological mechanisms underlying the above-mentioned profiles, we wish to share some relative data on the potential role of Helicobacter pylori infection. Evidence suggests a probable association between H. pylori infection and insulin resistance or metabolic syndrome and its related morbidity (ie, NAFLD, abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease, the end-point of metabolic syndrome). In terms of epidemiology, both H. pylori and metabolic syndrome are very common worldwide. Also, the increasing prevalence of metabolic syndrome follows the ongoing epidemics of obesity and type 2 diabetes mellitus. Metabolic syndrome decreases the lifespan, mainly due to type 2 diabetes mellitus, cardiovascular disease, and certain malignancies. Likewise, H. pylori infection prevalence is still high in most countries including South and East Europe, South America and Asia. Moreover, there are still contradictory data on the association between H. pylori and overweight/obesity that require further elucidation. At a cellular level, impaired gastric ghrelin production is associated with ghrelin-immunoreactive cells reduction in the oxyntic mucosa of lean patients with chronic H. pylori associated gastritis. In a study, we reported that NAFLD patients had higher anti-H. pylori IgG, lower circulating adiponectin, and higher tumour necrosis factor (TNF)-a levels, thereby indicating that H. pylori infection might represent one further hit in NAFLD pathogenesis. Furthermore, we recently showed that H. pylori-positive patients had increased risk of cardiovascular disease, since H. pylori infection increased the levels of fibrinogen, an independent risk factor for cardiovascular disease. Helicobacter pylori-related metabolic syndrome could also influence the cardio-cerebrovascular disease pathophysiology through several mechanisms, such as TNF-a involvement in atherosclerosis and atrial fibrillation-related stroke. Helicobacter pylori eradication: first, decreases fibrinogen, increases high-density lipoprotein-cholesterol, and it decreases Creactive protein levels significantly; second, it improves NAFLD fibrosis score and HSENSI (homocysteine, serum glutamic oxaloacetic transaminase, erythrocyte sedimentation rate, non-alcoholic steatohepatitis index); third, it improves homoeostatic model of assessment and insulin resistance, also mentioned by the authors, and might display a positive effect on H. pylori-related NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents; and finally, it might benefit metabolic syndrome-related morbidity. In summary, H. pylori infection as a risk factor for NAFLD, appears to be a common denominator underlying the shared altered metabolic syndrome and cardiovascular profile between lean and obese patients. Its eradication might benefit the aforementioned profile, and these findings merit further investigation.