Gastric Microenvironment—A Partnership between Innate Immunity and Gastric Microbiota Tricks Helicobacter pylori

Helicobacter pylori (H. pylori) carcinogenicity depends on three major factors: bacterial virulence constituents, environmental factors and host’s genetic susceptibility. The relationship between microenvironmental factors and H. pylori virulence factors are incontestable. H. pylori infection has a major impact on both gastric and colonic microbiota. The presence of non-H. pylori bacteria within the gastric ecosystem is particularly important since they might persistently act as an antigenic stimulus or establish a partnership with H. pylori in order to augment the subsequent inflammatory responses. The gastric ecosystem, i.e., microbiota composition in children with H. pylori infection is dominated by Streptoccocus, Neisseria, Rothia and Staphylococcus. The impairment of this ecosystem enhances growth and invasion of different pathogenic bacteria, further impairing the balance between the immune system and mucosal barrier. Moreover, altered microbiota due to H. pylori infection is involved in increasing the gastric T regulatory cells response in children. Since gastric homeostasis is defined by the partnership between commensal bacteria and host’s immune system, this review is focused on how pathogen recognition through toll-like receptors (TLRs—an essential class of pathogen recognition receptors—PRRs) on the surface of macrophages and dendritic cells impact the immune response in the setting of H. pylori infection. Further studies are required for delineate precise role of bacterial community features and of immune system components.

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Dissecting the Helicobacter pylori-regulated transcriptome of B cells

Pathogens and Disease ◽

10.1093/femspd/ftaa049 ◽

2020 ◽

Vol 78 (7) ◽

Author(s):

Bianca E Chichirau ◽

Tamara Scheidt ◽

Sebastian Diechler ◽

Theresa Neuper ◽

Jutta Horejs-Hoeck ◽

...

Keyword(s):

Helicobacter Pylori ◽

Immune System ◽

B Cells ◽

Mhc Class Ii ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Group I ◽

Cytotoxin Associated Gene A ◽

And Migration ◽

H Pylori

ABSTRACT Persistent infections with the bacterial group-I carcinogen Helicobacter pylori (H. pylori) have been associated with a broad range of gastric disorders, including gastritis, ulceration, gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma. Pathogenesis of H. pylori requires a balance between immune tolerance and defense. Although H. pylori induces inflammatory responses, the immune system cannot eliminate the pathogen. The detailed molecular mechanisms of how H. pylori interferes with cells of the immune system, in particular infiltrated B cells, are not well investigated. Previously, it was shown that the bacterial effector and oncoprotein cytotoxin-associated gene A (CagA) is delivered into B cells followed by its tyrosine-phosphorylation. To investigate the functional consequences in B cells colonized by CagA-positive H. pylori, we analyzed the global transcriptome of H. pylori-infected Mec-1 cells by RNA sequencing. We found 889 differentially expressed genes (DEGs) and validated JUN, FOSL2, HSPA1B, SRC, CXCR3, TLR-4, TNF-α, CXCL8, CCL2, CCL4, MHC class I and MHC class II molecules by qPCR, western blot, flow cytometry and ELISA assays. The H. pylori-specific mRNA expression signature reveals a downregulation of inflammation- and migration-associated genes, whereas central signal transduction regulators of cell survival and death are upregulated.

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Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

Frontiers in Microbiology ◽

10.3389/fmicb.2021.629163 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cristina Campestre ◽

Viviana De Luca ◽

Simone Carradori ◽

Rossella Grande ◽

Vincenzo Carginale ◽

...

Keyword(s):

Helicobacter Pylori ◽

Pathogenic Bacteria ◽

Acid Tolerance ◽

Membrane Vesicles ◽

Research Field ◽

Outer Membrane Vesicles ◽

Bacterial Toxin ◽

Carbonic Anhydrases ◽

Ph Homeostasis ◽

H Pylori

Our understanding of the function of bacterial carbonic anhydrases (CAs, EC 4.2.1.1) has increased significantly in the last years. CAs are metalloenzymes able to modulate CO2, HCO3– and H+ concentration through their crucial role in catalysis of reversible CO2 hydration (CO2 + H2O ⇄ HCO3– + H+). In all living organisms, CA activity is linked to physiological processes, such as those related to the transport and supply of CO2 or HCO3–, pH homeostasis, secretion of electrolytes, biosynthetic processes and photosynthesis. These important processes cannot be ensured by the very low rate of the non-catalyzed reaction of CO2 hydration. It has been recently shown that CAs are important biomolecules for many bacteria involved in human infections, such as Vibrio cholerae, Brucella suis, Salmonella enterica, Pseudomonas aeruginosa, and Helicobacter pylori. In these species, CA activity promotes microorganism growth and adaptation in the host, or modulates bacterial toxin production and virulence. In this review, recent literature in this research field and some of the above-mentioned issues are discussed, namely: (i) the implication of CAs from bacterial pathogens in determining the microorganism growth and virulence; (ii) the druggability of these enzymes using classical CA inhibitors (CAIs) of the sulfonamide-type as examples; (iii) the role played by Helicobacter pylori CAs in the acid tolerance/adaptation of the microbe within the human abdomen; (iv) the role of CAs played in the outer membrane vesicles spawned by H. pylori in its planktonic and biofilm phenotypes; (v) the possibility of using H. pylori CAIs in combination with probiotic strains as a novel anti-ulcer treatment approach. The latter approach may represent an innovative and successful strategy to fight gastric infections in the era of increasing resistance of pathogenic bacteria to classical antibiotics.

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Genetic Polymorphisms of CXCL8 (−251) Are Associated with the Susceptibility of Helicobacter pylori Infection Increased the Risk of Inflammation and Gastric Cancer in Thai Gastroduodenal Patients

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v18i4.1417 ◽

2019 ◽

Cited By ~ 1

Author(s):

Wongwarut Boonyanugomol ◽

Kamolchanok Rukseree ◽

Worrarat Kongkasame ◽

Prasit Palittapongarnpim ◽

Seung-Chul Baik ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Progression ◽

Chemokine Receptor ◽

Gene Polymorphisms ◽

Inflammatory Responses ◽

Increased Risk ◽

Cxc Chemokine ◽

H Pylori

CXC Chemokine Ligand 8 (CXCL8) plays an important role in gastric inflammation and in the progression of gastric cancer induced by Helicobacter pylori (H. pylori) infection. The association of CXCL8, CXC Chemokine Receptor 1 (CXCR1), and CXC Chemokine Receptor 2 (CXCR2) polymorphisms with H. pylori infection and gastric cancer progression needs to be investigated in a population within an enigma area consisting of multiple ethnicities, such as Thailand. To analyze the relative risk of H. pylori infection and gastric cancer among Thai gastroduodenal patients, gene polymorphisms in CXCL8 (promoter region -251) and in CXCR1 and CXCR2 (receptors for CXCL8) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-PCR (AS-PCR). We also determined the presence of cytotoxin-associated gene A (cagA) in Thai patients with H. pylori infection. Correlation between the CXCL8 (-251) polymorphism and CXCL8 gene expression was evaluated by quantitative reverse transcriptase-PCR (qRT-PCR). We found a significant association between the T/A and A/A genotypes of CXCL8 (-251) with H. pylori infection. However, no significant correlation was found between the CXCR1 (+2607) and CXCR2 (+1208) gene polymorphisms with H. pylori infection among Thai gastroduodenal subjects. Within the H. pylori-infected group of Thai gastroduodenal patients, no significant differences in cagA were observed. In addition, the A/A genotype of CXCL8 (-251) significantly correlated with the risk of gastric cancer and correlated with higher CXCL8 gene expression levels in Thai gastroduodenal patients. These results suggest that CXCL8 (-251) polymorphisms are associated with H. pylori infection, an increased risk of stronger inflammatory responses, and gastric cancer in Thai gastroduodenal patients.

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The probiotic supplementation role in improving the immune system among people with ulcerative colitis: a narrative review

Drug Metabolism and Personalized Therapy ◽

10.1515/dmdi-2021-0150 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Lana M. Agraib ◽

Mohammed I. Yamani ◽

Yaser Mohammed Rayyan ◽

Awni Taleb Abu-Sneineh ◽

Tarek A. Tamimi ◽

...

Keyword(s):

Ulcerative Colitis ◽

Immune System ◽

Inflammatory Responses ◽

Narrative Review ◽

Mucosal Barrier ◽

Current Evidence ◽

Chronic Inflammatory Bowel Disease ◽

Inflammatory Factor ◽

Therapeutic Benefits ◽

Mucosal Barrier Function

Abstract Objectives The purpose of this paper is to summarize the current evidence on probiotics’ uses as an adjuvant for ulcerative colitis (UC) and provide an understanding of the effect of probiotics supplement on the immune system and inflammatory responses among UC patients and subsequent therapeutic benefits. Content A narrative review of all the relevant published papers known to the author was conducted. Summary UC is a chronic inflammatory bowel disease (IBD) that results in inflammation and ulceration of the colon and rectum. The primary symptoms of active disease are diarrhea, abdominal pain, and rectal bleeding. About 70% of the human immune system (mucosal-associated lymphoid tissue) originates in the intestine. Probiotics are live microorganisms that help in stabilizing the gut microbiota (nonimmunologic gut defense), restores normal flora, and enhance the humoral immune system. Probiotics especially Bifidobacterium, Saccharomyces boulardii, and lactic acid-producing bacteria have been used as an adjunct therapy for treating UC to ameliorate disease-related symptoms and reduce relapse rate. Probiotics, in general, modulate the immune system through their ability to enhance the mucosal barrier function, or through their interaction with the local immune system to enhance regulatory T cell responses, decrease the pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin 1 beta and increase anti-inflammatory factor interleukin 10. Outlook More studies are needed to explore the properties of the various probiotic bacterial strains, their different uses, as well as the dosage of probiotics and duration for treating different disorders. Further clinical investigations on mechanisms of action and how probiotics modulate the immune system may lead to further advances in managing IBD.

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Eradication of Helicobacter pylori: the power of nanosized formulations

Nanomedicine ◽

10.2217/nnm-2019-0329 ◽

2020 ◽

Vol 15 (5) ◽

pp. 527-542

Author(s):

Qianyu Zhang ◽

Wen Wu ◽

Jinqiang Zhang ◽

Xuefeng Xia

Keyword(s):

Helicobacter Pylori ◽

Antibiotic Resistance ◽

Peptic Ulcer ◽

Gastric Carcinoma ◽

Antibacterial Agents ◽

Antimicrobial Agents ◽

Mucosal Barrier ◽

Harsh Environment ◽

H Pylori ◽

Cure Rates

Helicobacter pylori is a pathogen that is considered to cause several gastric disorders such as chronic gastritis, peptic ulcer and even gastric carcinoma. The current therapeutic regimens mainly constitute of a combination of several antimicrobial agents and proton pump inhibitors. However, the prevalence of antibiotic resistance has been significantly lowering the cure rates over the years. Nanocarriers possess unique strengths in this regard owing to the fact that they can protect the drugs (such as antibiotics) from the harsh environment in the stomach, penetrate the mucosal barrier and deliver drugs to the desired site. In this review we summarized recent studies of different antibacterial agents orally delivered by nanosized carriers for the eradication of H. pylori.

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Detection of High Titers of Antibody against Helicobacter Cysteine-Rich Proteins A, B, C, and E in Helicobacter pylori-Infected Individuals

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.4.542-545.2003 ◽

2003 ◽

Vol 10 (4) ◽

pp. 542-545 ◽

Cited By ~ 12

Author(s):

Peer R. E. Mittl ◽

Lucas Lüthy ◽

Christoph Reinhardt ◽

Hellen Joller

Keyword(s):

Helicobacter Pylori ◽

Immune System ◽

Control Group ◽

Clear Correlation ◽

Weak Correlation ◽

The Family ◽

Genome Level ◽

Immunological Assays ◽

H Pylori

ABSTRACT The family of Helicobacter cysteine-rich proteins (Hcp) constitutes one of the largest protein families that are specific for proteobacteria from the delta/epsilon subgroup. Most of the proteins belonging to this family have so far only been recognized on the genome level. To investigate the expression of Hcp proteins in vivo we analyzed titers of antibody against HcpA (HP0211), HcpB (HP0336), HcpC (HP1098), and HcpE (HP0235) in sera from 30 Helicobacter pylori-positive individuals and in a control group of six H. pylori-negative individuals. Significantly higher titers of antibody were observed for H. pylori-positive individuals (P < 0.00005). The highest and lowest titers were observed for HcpC (Δ mean = 1.06) and HcpB (Δ mean = 0.333), respectively. There is a clear correlation among anti-HcpA, -HcpC, and -HcpE immunoglobulin G titers in H. pylori-positive individuals (correlation > 0.7), but there is only a weak correlation for HcpB (correlation < 0.4). These results confirm that Hcp proteins are expressed by H. pylori under natural environmental conditions and that these proteins are recognized by the immune system of the host. The observed correlations are in agreement with the expected distribution of Hcp proteins among H. pylori strains. HcpA, HcpC, and HcpE are present in the genomes of strains 26695 and J99, whereas HcpB is absent from most strains. Since Hcp proteins are specific for H. pylori, immunological assays including Hcp proteins might be of value to detect H. pylori infection and perhaps to distinguish among different groups of H. pylori-positive patients.

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Helicobacter pylori infection and inflammatory bowel diseases

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-hpi-1510 ◽

2021 ◽

Vol 11 (1) ◽

pp. 68-78

Author(s):

Yu. P. Uspenskiy ◽

N. V. Baryshnikova ◽

A. N. Suvorov ◽

A. V. Svarval

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Inflammatory Bowel Diseases ◽

Pathogenic Bacteria ◽

T Cell Response ◽

Aminosalicylic Acid ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

H Pylori

Helicobacter pylori is detected in the human intestine on average in 35% of clinical cases, but the question about its etiopathogenetic role in intestinal diseases has not been fully investigated. Many scientists study a relationship between the H. pylori persistence and development of various bowel diseases. Diverse viewpoints have been proposed regarding a potential link between H. pylori and inflammatory bowel diseases (IBD). Here we review the data from domestic and foreign studies aimed at examining potential role of H. pylori both as a trigger and protector resulting in the pathogenetic alterations leading to developing Crohn‘s disease and ulcerative colitis. The former is favored by the hypothesis wherein H. pylori may trigger IBD due to potential connection between extragastric infection and its direct damaging action as well as indirect effects contributing to the initiation of oxidative stress, autoimmune aggression and development of intestinal dysbiosis. In addition, the effects of enterohepatic Helicobacter spp. promoting IBD pathogenesis are discussed. The mechanisms underlying the protective role of H. pylori infection may be driven via differentially expressed acute and/or chronic local inflammatory mucosal response able to downmodulate systemic immune responses and suppress autoimmune reactions, as well as skewing host immune response from a pro-inflammatory Th1/Th17 cell-mediated towards regulatory T-cell response. Moreover, it was found that H. pylori may induce production of antibacterial peptides counteracting potentially pathogenic bacteria involved in IBD pathogenesis. In particular, it was found that IBD patients are dominated with moderate active antral gastritis coupled to atrophy, with the peak intensity observed in patients under 30 years of age. Intensity of intestinal metaplasia in the gastric mucosa of IBD patients accounted for by the duration of the disease course. Basal IBD therapy with 5-aminosalicylic acid lowers severity and activity of gastritis, degree of atrophy as well as magnitude H. pylori invasion in the gastric mucosa. There is evidence that 5-aminosalicylic acid-containing drugs may result in a so-called “spontaneous eradication” of H. pylori infection. Extended investigations are required to examine a role of H. pylori in IBD pathogenesis.

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T4SS-dependent TLR5 activation by Helicobacter pylori infection

Nature Communications ◽

10.1038/s41467-019-13506-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Suneesh Kumar Pachathundikandi ◽

Nicole Tegtmeyer ◽

Isabelle Catherine Arnold ◽

Judith Lind ◽

Matthias Neddermann ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Pathogenic Bacteria ◽

Type Iv Secretion ◽

Downstream Signaling ◽

Type Iv ◽

Efficient Control ◽

H Pylori ◽

Highly Virulent

AbstractToll-like receptor TLR5 recognizes a conserved domain, termed D1, that is present in flagellins of several pathogenic bacteria but not in Helicobacter pylori. Highly virulent H. pylori strains possess a type IV secretion system (T4SS) for delivery of virulence factors into gastric epithelial cells. Here, we show that one of the H. pylori T4SS components, protein CagL, can act as a flagellin-independent TLR5 activator. CagL contains a D1-like motif that mediates adherence to TLR5+ epithelial cells, TLR5 activation, and downstream signaling in vitro. TLR5 expression is associated with H. pylori infection and gastric lesions in human biopsies. Using Tlr5-knockout and wild-type mice, we show that TLR5 is important for efficient control of H. pylori infection. Our results indicate that CagL, by activating TLR5, may modulate immune responses to H. pylori.

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A Novel View of Human Helicobacter pylori Infections: Interplay between Microbiota and Beta-Defensins

Biomolecules ◽

10.3390/biom9060237 ◽

2019 ◽

Vol 9 (6) ◽

pp. 237 ◽

Cited By ~ 15

Author(s):

Pero ◽

Brancaccio ◽

Laneri ◽

Biasi ◽

Lombardo ◽

...

Keyword(s):

Helicobacter Pylori ◽

Immune System ◽

Gut Microbiota ◽

Host Response ◽

Pathogenic Bacteria ◽

Precancerous Lesions ◽

Innate Immune ◽

Microbial Infections ◽

Beta Defensins ◽

The Impact

The gut microbiota is significantly involved in the preservation of the immune system of the host, protecting it against the pathogenic bacteria of the stomach. The correlation between gut microbiota and the host response supports human gastric homeostasis. Gut microbes may be shifted in Helicobacter pylori (Hp)-infected individuals to advance gastric inflammation and distinguished diseases. Particularly interesting is the establishment of cooperation between gut microbiota and antimicrobial peptides (AMPs) of the host in the gastrointestinal tract. AMPs have great importance in the innate immune reactions to Hp and participate in conservative co-evolution with an intricate microbiome. β-Defensins, a class of short, cationic, arginine-rich proteins belonging to the AMP group, are produced by epithelial and immunological cells. Their expression is enhanced during Hp infection. In this review, we discuss the impact of the gut microbiome on the host response, with particular regard to β-defensins in Hp-associated infections. In microbial infections, mostly in precancerous lesions induced by Hp infection, these modifications could lead to different outcomes.

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Induction of Maturation and Cytokine Release of Human Dendritic Cells by Helicobacter pylori

Infection and Immunity ◽

10.1128/iai.72.8.4416-4423.2004 ◽

2004 ◽

Vol 72 (8) ◽

pp. 4416-4423 ◽

Cited By ~ 76

Author(s):

Katharina Kranzer ◽

Alexander Eckhardt ◽

Michael Aigner ◽

Gertrud Knoll ◽

Ludwig Deml ◽

...

Keyword(s):

Helicobacter Pylori ◽

Dendritic Cells ◽

Immune System ◽

Immune Escape ◽

Cell Surface Expression ◽

Cytokine Release ◽

Proinflammatory Response ◽

Ulcer Disease ◽

H Pylori ◽

Human Dendritic Cells

ABSTRACT Helicobacter pylori causes a persistent infection in the human stomach, which can result in chronic gastritis and peptic ulcer disease. Despite an intensive proinflammatory response, the immune system is not able to clear the organism. However, the immune escape mechanisms of this common bacterium are not well understood. We investigated the interaction between H. pylori and human dendritic cells. Dendritic cells (DCs) are potent antigen-presenting cells and important mediators between the innate and acquired immune system. Stimulation of DCs with different concentrations of H. pylori for 8, 24, 48, and 72 h resulted in dose-dependent interleukin-6 (IL-6), IL-8, IL-10 and IL-12 production. Lipopolysaccharide (LPS) from Escherichia coli, a known DC maturation agent, was used as a positive control. The cytokine release after stimulation with LPS was comparable to that induced by H. pylori except for IL-12. After LPS stimulation IL-12 was only moderately released compared to the large amounts of IL-12 induced by H. pylori. We further investigated the potential of H. pylori to induce maturation of DCs. Fluorescence-activated cell sorting analysis of cell surface expression of maturation marker molecules such as CD80, CD83, CD86, and HLA-DR revealed equal upregulation after stimulation with H. pylori or LPS. We found no significant differences between H. pylori seropositive and seronegative donors of DCs with regard to cytokine release and upregulation of surface molecules. These data clearly demonstrate that H. pylori induces a strong activation and maturation of human immature DCs.

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