Interplay and cooperation of Helicobacter pylori and gut microbiota in gastric carcinogenesis.

Chronic Helicobacter pylori infection is a critical risk factor for gastric cancer (GC). However, only 1-3 % of people with H. pylori develop GC. In gastric carcinogenesis, non-H. pylori bacteria in the stomach might interact with H. pylori. Bacterial dysbiosis in the stomach can strengthen gastric neoplasia development via generating tumor-promoting metabolites, DNA damaging, suppressing antitumor immunity, and activating oncogenic signaling pathways. Other bacterial species may generate short-chain fatty acids like butyrate that may inhibit carcinogenesis and inflammation in the human stomach. The present article aimed at providing a comprehensive overview of the effects of gut microbiota and H. pylori on the development of GC. Next, the potential mechanisms of intestinal microbiota were discussed in gastric carcinogenesis. We also disserted the complicated interactions between H. pylori, intestinal microbiota, and host in gastric carcinogenesis, thus helping us to design new strategies for preventing, diagnosing, and treating GC.

Oral microbiota and Helicobacter pylori in gastric carcinogenesis: what do we know and where next?

Gastric cancer (GC) is one of the most common malignancies causing death worldwide, and Helicobacter pylori is a powerful inducer of precancerous lesions and GC. The oral microbiota is a complex ecosystem and is responsible for maintaining homeostasis, modulating the immune system, and resisting pathogens. It has been proposed that the gastric microbiota of oral origin is involved in the development and progression of GC. Nevertheless, the causal relationship between oral microbiota and GC and the role of H. pylori in this relationship is still controversial. This study was set to review the investigations done on oral microbiota and analyze various lines of evidence regarding the role of oral microbiota in GC, to date. Also, we discussed the interaction and relationship between H. pylori and oral microbiota in GC and the current understanding with regard to the underlying mechanisms of oral microbiota in carcinogenesis. More importantly, detecting the patterns of interaction between the oral cavity microbiota and H. pylori may render new clues for the diagnosis or screening of cancer. Integration of oral microbiota and H. pylori might manifest a potential method for the assessment of GC risk. Hence it needs to be specified the patterns of bacterial transmission from the oral cavity to the stomach and their interaction. Further evidence on the mechanisms underlying the oral microbiota communities and how they trigger GC may contribute to the identification of new prevention methods for GC. We may then modulate the oral microbiota by intervening with oral-gastric bacterial transmission or controlling certain bacteria in the oral cavity.

Relevance of Helicobacter pylori vacA 3'-end Region Polymorphism to Gastric Cancer.

BACKGROUND: Helicobacter pylori vacA genotypes play an important role in the pathogenesis of severe gastrointestinal disease. MATERIALS AND METHODS: We identified a novel polymorphic site in the 3'-end region of H. pylori vacA gene, denoted by c1/-c2 (c1: with deletion of 15 bp), and examined associations of this and the previous four sites as well as cagA status with gastroduodenal diseases, in a total of 217 Iranian H. pylori isolates. Histopathologic evaluations were performed and patients with gastric cancer (GC) were further classified based on the anatomic site of tumor, including cardia and noncardia GC, and the histopathologic type of tumor, including intestinal- and diffuse-type GC. RESULTS: The vacA m1, i1, d1, c1, and cagA genotypes were significantly associated with an increased risk of GC, the odds ratio (95% confidence interval) was 4.29 (2.03-9.08), 6.11 (2.63-14.19), 3.18 (1.49-6.76), 15.13 (5.86-39.01), and 2.59 (1.09-6.12), respectively. The vacA c1 genotype had an increased age- and sex-adjusted risk for GC by the multiple logistic regression analysis; the OR was 38.32 (95% CI, 6.60-222.29). This association was independent of and larger than the associations of the m-, i-, and d-type of vacA or cagA status with GC. No significant correlation was found between s1, whether independently or in combination, and the risk of GC or peptic ulcer disease (PUD). The vacA i1 and cagA genotypes were linked to an increased risk of PUD; the OR (95% CI) was 2.80 (1.45-5.40) and 2.62 (1.23-5.61), respectively. The presence of both the vacA i1 and cagA genotypes further increased the risk of PUD; the OR was 5.20 (95% CI, 1.92-14.03). CONCLUSION: The H. pylori vacA c1 genotype might therefore be one of the strongest risk predictors of GC in male patients aged ≥55 in Iran.

Non-coding RNA-Encoded Peptides/Proteins in Human Cancer: The Future for Cancer Therapy.

Although non-coding RNAs (ncRNAs) were initially thought to be a class of RNA transcripts with no encoding capability, it has been established that some ncRNAs actually contain open reading frames (ORFs), which can be translated into micropeptides or microproteins. Recent studies have reported that ncRNAs-derived micropeptides/ microproteins have regulatory functions on various biological and oncological processes. Some of these micropeptides/microproteins act as tumor inhibitors and some as tumor inducers. Understanding the carcinogenic role of ncRNAs-encoded micropeptides/ microproteins seems to pose potential challenges to cancer research and offer promising practical perspectives on cancer treatment. In this review, we summarized the present information on the association of ncRNAs-derived micropeptides/microproteins with different types of human cancers. We also mentioned their carcinogenic mechanisms in cancer metabolism, signaling pathways, cell proliferation, angiogenesis, metastasis, and so on. Finally, we discussed the potential clinical value of these micropeptides/ microproteins and their potential use in the diagnosis and treatment of cancer. This information may help discover, optimize, and develop new tools based on biological micropeptides/ microproteins for the early diagnosis and development of anticancer drugs.

Contrasting association of Helicobacter pylori oipA genotype with risk of peptic ulceration and gastric cancer.

Helicobacter pylori OipA (outer inflammatory protein A) is an outer membrane protein that involves in the binding and colonization of the bacterium in the stomach. The oipA status is associated with the risk of peptic ulcerations (PUs) and gastric cancer (GC) diseases. However, the association trend with PUs compared to GC is often different and highly challenging. We therefore aimed to determine the presence of this genotype in Iranian strains and assess its association with the risk of PUs and GC in a larger number of samples. A total of 319 strains were obtained from 172 patients with non-atrophic gastritis (NAG), 52 with PUs and 95 with GC. The prevalence of the oipA+vs. oipA- genotype was 67.7% (216/319). The total frequency of the oipA+vs. oipA- genotypes in NAG, PUs, GC, non-peptic ulceration (including NAG and GC), and non-tumor (including NAG and PUs) groups was 121/172 (70.3%), 50/52 (96.2%), 45/95 (47.4%), 166/267 (62.2%), and 171/224 (76.3%), respectively. In multiple logistic regression analysis, the oipA+vs. oipA- genotype showed a strong direct association with PUs; the ORadj (95% CI) was 18.751 (4.421-79.531), (p = 0.00007). In contrast, it had a significant reverse association with GC; the ORadj (95% CI) was 0.330 (0.179-0.607), (p = 0.00036). In the present study, we interestingly found a contrasting association of the H. pylori oipA genotype with the risk of PUs and GC in Iran. Therefore, the contrasting effect of this genotype may emphasize its independent role in predicting clinical outcomes.

Unique constellations of five polymorphic sites of Helicobacter pylori vacA and cagA status associated with risk of gastric cancer.

Helicobacter pylori possesses virulence genes that are involved in the pathogenesis of the bacterium. There are little data regarding all constellations of five polymorphic sites of H. pylori vacA and cagA status. We therefore aimed to i) find any associations between H. pylori vacA alleles (s1/s2, m1/m2, i1/i2, d1/d2, and c1/c2) and cagA status and ii) determine the frequency of all five-genotype combinations of the vacA alleles with and without cagA gene, and their associations with risk of gastric cancer (GC). A total of 290 Iranian H. pylori isolates from gastrointestinal patients were obtained successfully by the cultivation of biopsies and genotyped. The patients included 144/290 with non-atrophic gastritis (NAG), 57/290 with peptic ulcer disease (PUD), and 89/290 with GC. We found that each of the vacA m1-, i1-, d1-, and c1-genotypes was significantly associated with cagA+ status. The odds ratio(OR) and 95% confidence interval (95% CI) was 2.316 (1.241-4.301) for cagA+/vacA m1, 2.764 (1.540-4.960) for cagA+/vacA i1, 4.288 (2.305-7.977) for cagA+/vacA d1, and 2.639 (1.488-4.680) for cagA+/vacA c1, respectively. In this study, 43 five- and six-genotype combinations were found among 224 strains. The highest frequencies were observed for vacA s1m2i2d2c2 (85/224, 37.9%), s1m2i2d2c2/cagA (48/222, 21.6%), s1m1i1d1c1 (40/224, 17.9%) and s1m1i1d1c1/cagA (35/222, 15.8%). Logistic regression analysis showed that vacA s1m1i1d1c1, s1m2i1d2c1, s1m2i2d2c1, and s1m2i2d2c1/cagA had a high prevalence in GC patients compared to non-atrophic gastritis patients (p < .05). The ORs and 95% CI were 2.433 (1.070-5.531), 11.524 (1.253-106.023), 4.200 (1.261-13.993), and 6.263 (1.494-26.256), respectively. These results were also confirmed when the controls were non-tumors (NAG/PUD). We found novel five- and six-genotype combinations associated with the risk of GC. These associations seem to be strongly dependent on the presence of c1-type of vacA. Therefore, analysis of all combined genotypes of the vacA alleles and cagA status may play a significant role in determining H. pylori-related clinical outcomes.

Helicobacter pylori-related risk predictors of gastric cancer: The latest models, challenges, and future prospects.

Helicobacter pylori is known as an important determinant of preneoplastic lesions or gastric cancer (GC) risk. The bacterial genotypes may determine the clinical outcomes. However, the evidence for these associations has varied between and within continents, and the actual effect of each gene and corresponding allelic variants are still debatable. In recent years, two new models have been proposed to predict the risk of GC; the phylogeographic origin of H. pylori strains and a disrupted co-evolution between H. pylori and its human host, which potentially explain the geographic differences in the risk of H. pylori-related cancer. However, these models and earlier ones based on putative virulence factors of the bacterium may not fully justify differences in the incidence of GC, reflecting that new theories should be developed and examined. Notably, the new findings also support the role of ancestry-specific germline alteration in contributing to the ethnic/population differences in cancer risk. Moreover the high and low incidence areas of GC have shown differences in transmission ecology, largely affecting the composition of H. pylori populations. As a new hypothesis, it is proposed that any high-risk population may have its own specific risk loci (or variants) as well as new H. pylori strains with national/maybe regional gene pools that should be considered. The latter is seen in the Americas where the rapid evolution of distinct H. pylori subpopulations has been occurred. It is therefore proposed that the deep sequencing of both H. pylori and its human host is simultaneously performed in GC patients and age-sex-matched controls from high-risk areas. The expression and functional activities of the identified new determinants of GC must then be assessed and matched with human and pathogen ancestry, because some of risk loci are ancestry-specific. In addition, potential study-level covariates and moderator variables (eg physical conditions, life styles, gastric microbiome, etc) linked to causal relationships, and their impact, should be recognized and controlled.

Which genotype of Helicobacter pylori-cagA or cagE-Is better associated with gastric Cancer risk? Lessons from an extremely high-risk area in Iran.

The association of the H. pylori cagA- /cagE-positive genotypes with the risk of gastric cancer (GC) in Ardabil-a high-risk area in North-West Iran-was assessed. Genotyping was performed in DNA from fresh gastric biopsies (N = 218). Occurrence of H. pylori infection was 85.32% (186/218). The total frequency of the cagA+vs. cagA-, cagE+vs. cagE-, cagA+/cagE-vs. AGCs (all genotype combinations), cagA-/cagE+vs. AGCs, cagA-/cagE-vs. AGCs, cagA+/cagE+vs. AGCs, cagA+/cagE-vs. cagA-/cagE+, and cagA+/cagE+vs. cagA-/cagE- genotypes was 102/186 (54.8%), 89/186 (47.8%), 38/186 (20.4%), 25/186 (13.4), 59/186 (31.7%), 64/186 (34.4%), 38/63 (38.63%), and 64/123 (52.0%), respectively. The cagE+vs. cagE- (59.6% (65/109) in GC vs. 31.2% (24/77) in non-atrophic gastritis, NAG) and the cagA+/cagE+vs. cagA-/cagE- genotypes (66.7% (40/60) in GC vs. 38.1% (24/63) in NAG) showed an increased association with the risk of GC in Ardabil (odds ratio [OR] = 3.262, 95% confidence interval [CI]: 1.763-6.038, p = .0001 and OR = 3.250; 95% CI: 1.552-6.808, p = .002, respectively). We propose that the H. pylori cagE+ but not cagA+ genotype significantly increased the risk of GC in this extremely high-risk population. Therefore, it may play a significant role in determining H. pylori-related clinical outcome.

Inverse association of Helicobacter pylori cagPAI genotypes with risk of cardia and non-cardia gastric adenocarcinoma.

Iran is a high-risk country for cardia gastric adenocarcinoma (CGA) in Central Asia, with an incidence rate five times the average global rate, and shows a high infection rate for Helicobacter pylori (69%). The aim was to examine the associations of multiple H. pylori cagPAI genotypes (ie cagH, cagL, cagG, and orf17) with the risk of CGA, non-CGA, and different histological types of GA in Iran. A large number of H. pylori strains (N = 336) were successfully cultured and genotyped. Histopathological evaluations were performed. The analysis showed an inverse association between the cagH+ genotype and the risk of CGA and intestinal-type gastric adenocarcinoma (IGA) (adjusted ORs; 0.312 and 0.283, respectively), where the controls were nontumors. The orf17+ genotype decreased the risk of non-CGA and diffuse-type gastric adenocarcinoma (DGA)(adjusted ORs; 0.310 and 0.356, respectively). When the controls were those with nonatrophic gastritis, the cagG+ genotype was negatively associated with the risk of CGA, non-CGA, IGA, and DGA (adjusted ORs; 0.324, 0.366, 0.306, and 0.303, respectively). We did not find such a significant association for the cagL+ genotype in multiple logistic regression analysis. Combination of the vacA c2 and cagPAI genotypes further decreased the risk estimates for GAs. This study showed the reverse association of H. pylori cagPAI genotypes-cagH+ and cagG+ -with the risk of CGA in male patients aged ≥ 55 in Iran. Presence of the vacA c2 genotype in combination with cagPAI genotypes showed strong inverse associations with the risk of CGA and non-CGA. These findings may reveal a coordinated relationship between the vacA c2 and cagPAI genotypes.

Role of Plasticity Region Genes and cagE gene of cagPAI of Helicobacter pylori in Development of Gastrointestinal (GI) Diseases

Background: Helicobacter pylori is a Gram-negative, micro aerophilic bacterium in the human stomach that is associated with the development of gastrointestinal ailments such as peptic ulcer (PU) and gastric cancer (GC). In the present study, plasticity region genes (jhp0940, jhp0945 and jhp0947) and and cagE gene of cagPAI were assessed independently and in combination for their ability to predict clinical consequences. Materials and Methods: A total of 211 strains which were isolated from patients with different gastrointestinal diseases (114 with non-atrophic gastritis, 59 with PU, and 38 with GC) were genotyped by PCR and sequencing. Data were collected and analyzed using SPSS software version 19. Logistic regression models were applied to determine relationships between the plasticity region genes and cagE of H.pylori and clinical status. Results: The cagE gene (71.1%) had the highest frequency and jhp0945 (13.7%) was the least abundant among the genes examined. The jhp0940 gene was significantly associated with GC (P = 0.0007), but not PU. On multiple logistic regression analysis, adjusted for both age and sex, the jhp0940 genotype was significantly associated with GC (odds ratio, OR = 2.8, 95%CI = 1.1­7.0; P = 0.027). The jhp0940+/ jhp0945+/ jhp0947+genotype was also linked to an increased risk of GC (OR = 50.4, 95%CI = 5.1­500.0; P = 0.0008) while no genotype correlation was found with PU in Iran (P > 0.05). Conclusions: Given the high frequency of cagE, this gene could be a suitable marker for the presence of cagPAI in Iranian strains. The jhp0940 genotype could also be a strong predictor of GC in Iran.

Are Helicobacter pylori highly cytotoxic genotypes and cardia gastric adenocarcinoma linked? Lessons from Iran.

BACKGROUND: Although the most extensive studies revealed the role of H. pylori VacA and CagA toxins in the development of gastric adenocarcinoma, the magnitude of this association and the correlations of vacA mosaicism and cagA status with cardia gastric adenocarcinoma (CGA) still remain controversial. OBJECTIVE: We aimed to examine the linkage of H. pylori highly cytotoxic genotypes to CGA in Iranian populations as a model. METHODS: A total of 601 Iranian patients were enrolled. Biopsies were cultured, genotyped, and anatomically and histologically classified. RESULTS: The vacA c1 genotype, but not cagA status, showed a strong association with the risk of both CGA and non-cardia adenocarcinoma (NCGA), whether the controls were non-tumors, as those with either non-atrophic gastritis or peptic ulcerations, (the OR (95%CI) was 14.11 (4.91-40.52) and 9.59 (4.06-22.65), respectively) or those with NAG (the OR (95%CI) was 10.71 (3.49-32.82) and 8.11 (3.26-20.16), respectively). The vacA c1/cagA+ genotype was significantly associated with an increased risk of NCGA, whether the controls were non-tumors or those with NAG; the adjusted risk was 4.706 (1.41-15.67) and 4.85 (1.42-16.51), respectively. CONCLUSIONS: The H. pylori vacA c1 genotype, but not cagA status, might be the first important bacterial biomarker for predicting the cardia adenocarcinoma risk in male patients aged ⩾ 55 in Iran.