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Moraes FCAD, Sobreira LER, Kelly FA, Rodríguez Burbano RM. Impact of helicobacter pylori infection status on outcomes among patients with gastric cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Microb Pathog 2025; 202:107407. [PMID: 39988067 DOI: 10.1016/j.micpath.2025.107407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Helicobacter pylori (H. pylori), a microaerophilic gram-negative bacterium, is one of the most common chronic bacterial infections in humans, affecting about 50 % of the global population. Recently, it has been proposed that H. pylori infection might impact the efficacy of immune checkpoint inhibitors (ICIs), which are used in the treatment of various cancers, including gastric cancer (GC). However, the impact of H. pylori infection on clinical outcomes in patients with GC treated with ICIs is not yet fully elucidated. OBJECTIVES Evaluating the impact of H. pylori infection status on overall survival (OS) and progression-free survival (PFS) on GC treated with ICIs. METHODS A meticulous literature search was conducted across PubMed, EMBASE, and Web of Science databases, focusing on studies that compared the effect of H. pylori-positive status versus H. pylori-negative status on patients with GC undergoing ICI treatment. The Newcastle-Ottawa Scale was utilized for the risk of bias assessment of individual studies. For binary outcomes, we used hazard ratios (HRs) or odds ratios (OR) with 95 % confidence intervals (CI) to estimate the effect size. RESULTS In total, 3 studies were included, involving 928 patients, of which 396 had H. pylori-positive status. Analysis showed that: PFS was prolonged but not statistically significant in H. pylori-negative patients (HR: 1.11; 95 % CI:0.94-1.31; p = 0.17), OS was significantly prolonged in H. pylori-negative patients (HR: 1.25; 95 % CI: 1.05-1.50; p=0.012), and the H. pylori-negative group had a significant clinical response compared with the H. pylori-positive group (OR: 0.40; 95 % CI: 0.28-0.57; p < 0.000001). CONCLUSION In this systematic review and meta-analysis, the status of H. pylori provides a perspective to reshape ICI treatment paradigms and advocates for early eradication treatment of this bacterium.
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Tachiyama S, Rosinke K, Khan MF, Zhou X, Xin Y, Botting JM, Yue J, Roujeinikova A, Hoover TR, Liu J. FlgY, PflA, and PflB form a spoke-ring network in the high-torque flagellar motor of Helicobacter pylori. Proc Natl Acad Sci U S A 2025; 122:e2421632122. [PMID: 40261933 DOI: 10.1073/pnas.2421632122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 03/19/2025] [Indexed: 04/24/2025] Open
Abstract
Helicobacter pylori has evolved distinct flagellar motility to colonize the human stomach. Rotation of the H. pylori flagella is driven by one of the largest known bacterial flagellar motors. In addition to the core motor components found in Escherichia coli and Salmonella enterica, the flagellar motor in H. pylori possesses many accessories that enable the bacteria to penetrate the gastric mucus layer. Here, we utilize cryoelectron tomography with molecular genetics and biochemical approaches to characterize three accessory proteins, FlgY, PflA, and PflB, and their roles in H. pylori flagellar assembly and motility. Comparative analyses of in situ flagellar motor structures from pflA, pflB, and flgY mutants and wild-type H. pylori reveal that FlgY forms a 13-fold proximal spoke-ring around the MS-ring and that PflA and PflB form an 18-fold distal spoke-ring enclosing 18 torque-generating stator complexes. We build a pseudoatomic model of the H. pylori motor by leveraging AlphaFold-predicted structures, protein-protein interactions, and in situ motor structures. Our model suggests that the FlgY spoke-ring functions as a bearing around the rotating MS-ring and as a template for stabilizing the PflA-PflB spoke-ring, thus enabling the recruitment of 18 stator complexes for high-torque generation. Overall, our study sheds light on how this spoke-ring network between the MS-ring and stator complexes enables the unique motility of H. pylori. As these accessory proteins are conserved in the phylum Campylobacterota, our findings apply broadly to a better understanding of how polar flagella help bacteria thrive in gastric and enteric niches.
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Affiliation(s)
- Shoichi Tachiyama
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536
- Microbial Sciences Institute, Yale University, West Haven, CT 06516
| | - Kyle Rosinke
- Department of Microbiology, University of Georgia, Athens, GA 30602
| | - Mohammad F Khan
- Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - Xiaotian Zhou
- Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
| | - Yue Xin
- Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
| | - Jack M Botting
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536
- Microbial Sciences Institute, Yale University, West Haven, CT 06516
| | - Jian Yue
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536
- Microbial Sciences Institute, Yale University, West Haven, CT 06516
| | - Anna Roujeinikova
- Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - Timothy R Hoover
- Department of Microbiology, University of Georgia, Athens, GA 30602
| | - Jun Liu
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536
- Microbial Sciences Institute, Yale University, West Haven, CT 06516
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Retnakumar RJ, Chettri P, Lamtha SC, Sivakumar KC, Dutta P, Sen P, Biswas S, Agarwal N, Nath AN, Devi TB, Thapa N, Tamang JP, Chattopadhyay S. Genome-wide accumulations of non-random adaptive point mutations drive westward evolution of Helicobacter pylori. BMC Microbiol 2025; 25:229. [PMID: 40263995 DOI: 10.1186/s12866-025-03944-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/01/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND For last seven decades we remained convinced that the natural point mutations occur randomly in the genome of an organism. However, our whole genome sequence analyses show that for the gastric pathogen Helicobacter pylori, which causes peptic ulcer and gastric cancer, accumulations of point mutations in the genome are non-random and they contribute to its unidirectional evolution. Based on the oncoprotein CagA, the pathogen can be classified into Eastern (East Asian countries like China and Japan; high incidence of gastric cancer) and Western (Europe, Africa, South-West Asian countries like India; low incidence of gastric cancer) types. RESULTS We have found a unique high-altitude Himalayan region, Sikkim (an Indian state bordering China, Nepal and Bhutan), where the evolving Eastern and Western H. pylori types co-exist and show the signs of genetic admixtures. Here, we present genomic evidence for more virulent Eastern-H. pylori getting converted to less virulent Western-H. pylori by accumulating non-random adaptive point mutations. CONCLUSION The lesser virulence of the westernized H. pylori is beneficial since this pathogen typically remains colonized in the stomach for decades before causing terminal diseases like gastric cancer. Moreover, the mutation-driven westward evolution of H. pylori is a global phenomenon, which occurred in the geographical regions where people from Eastern and Western ethnicities met and cohabited. The identified evolution of virulent Eastern H. pylori strains to lesser virulent Western variants by accumulation of point mutations also provides insight into the pathogenic potentials of different H. pylori strains.
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Affiliation(s)
- R J Retnakumar
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Prakash Chettri
- Biotech Hub, Department of Zoology, Nar Bahadur Bhandari Degree College, Tadong, Sikkim, India
| | | | - K C Sivakumar
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Priya Dutta
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Pahil Sen
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Sanjit Biswas
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
- Barry Marshall Research Centre for Helicobacter pylori, Asian Institute of Gastroenterology, Telangana, 500032, Hyderabad, India
| | - Nikita Agarwal
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Angitha N Nath
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - T Barani Devi
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Namrata Thapa
- Biotech Hub, Department of Zoology, Nar Bahadur Bhandari Degree College, Tadong, Sikkim, India.
| | | | - Santanu Chattopadhyay
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
- Barry Marshall Research Centre for Helicobacter pylori, Asian Institute of Gastroenterology, Telangana, 500032, Hyderabad, India.
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Bryant KN, Frick-Cheng AE, Solecki LE, Kroh HK, McDonald WH, Lacy DB, McClain MS, Ohi MD, Cover TL. Species-specific components of the Helicobacter pylori Cag type IV secretion system. Infect Immun 2025:e0049324. [PMID: 40208031 DOI: 10.1128/iai.00493-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 03/08/2025] [Indexed: 04/11/2025] Open
Abstract
Helicobacter pylori strains containing the cag pathogenicity island (PAI) deliver an effector protein (CagA) and non-protein substrates into gastric cells through a process that requires the Cag type IV secretion system (T4SS). The Cag T4SS outer membrane core complex (OMCC) contains multiple copies of five proteins, two of which are species-specific proteins. By using modifications of a previously described OMCC immunopurification method and optimized mass spectrometric methods, we have now isolated additional cag PAI-encoded proteins that are present in lower relative abundance. Four of these proteins (CagW, CagL, CagI, and CagH) do not exhibit sequence relatedness to T4SS components in other bacterial species. Size exclusion chromatography analysis of immunopurified samples revealed that CagW, CagL, CagI, and CagH co-elute with OMCC components. These four Cag proteins are copurified with the OMCC in immunopurifications from a Δcag3 mutant strain (lacking peripheral OMCC components), but not from a ΔcagX mutant strain (defective in OMCC assembly). Negative stain electron microscopy analysis indicated that OMCC preparations isolated from ΔcagW, cagL::kan, ΔcagI, and ΔcagH mutant strains are indistinguishable from wild-type OMCCs. In summary, by using several complementary methods, we have identified multiple species-specific Cag proteins that are associated with the Cag T4SS OMCC and are required for T4SS activity.
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Affiliation(s)
- Kaeli N Bryant
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Lauren E Solecki
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Heather K Kroh
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - W Hayes McDonald
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA
| | - D Borden Lacy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark S McClain
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Melanie D Ohi
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Timothy L Cover
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Ziogou A, Giannakodimos A, Giannakodimos I, Schizas D, Charalampakis N. Effect of Helicobacter Pylori infection on immunotherapy for gastrointestinal cancer: a narrative review. Immunotherapy 2025:1-14. [PMID: 40087147 DOI: 10.1080/1750743x.2025.2479410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025] Open
Abstract
Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.
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Affiliation(s)
- Afroditi Ziogou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
| | | | - Ilias Giannakodimos
- Departement of Urology, Attikon University Hospital of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Scholz KJ, Höhne A, Wittmer A, Häcker G, Hellwig E, Cieplik F, Waidner B, Al-Ahmad A. Co-culture of Helicobacter pylori with oral microorganisms in human saliva. Clin Oral Investig 2025; 29:79. [PMID: 39849235 PMCID: PMC11757641 DOI: 10.1007/s00784-025-06160-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/10/2025] [Indexed: 01/25/2025]
Abstract
OBJECTIVE Helicobacter pylori is known for colonizing the gastric mucosa and instigating severe upper gastrointestinal diseases such as gastritis, gastroduodenal ulcers, and gastric cancer. To date, there is no data available on the oral cavity as transmission site, whether H. pylori can survive in the oral cavity or in human saliva. The aim of the study was to investigate the influence of oral microorganisms and human saliva on the survival of H. pylori in human saliva. METHODS H. pylori strains KE, a motile derivate of type strain H. pylori 26695, and H. pylori SS1, a clinical isolate from a gastric biopsy, were grown in human pooled saliva (pooled from 4 healthy human donors, 0.22 μm filter-sterilized) or in BBF (Brucella browth formula; control) either as mono-cultures or in co-culture with Streptococcus mutans, Streptococcus oralis, Actinomyces naeslundii, Lacticaseibacillus casei and Candida dubliniensis. Bacterial survival of H. pylori and the oral microorganisms were investigated using colony forming units (CFU) assay and MALDI-TOF MS at baseline and after 24, 48 and 168 h. RESULTS In saliva, H. pylori KE demonstrated enhanced survival in co-culture with S. mutans, A. naeslundii, and C. dubliniensis, enduring for at least 48 h. In contrast, L. casei and S. oralis inhibited H. pylori KE in saliva. H. pylori KE could not be cultured after 168 h in saliva, neither in mono- nor co-culture. In contrast, H. pylori SS1 in saliva could be cultured after 168 h in co-culture with S. mutans and C. dubliniensis, but not in mono-culture. In BBF, H. pylori KE could be cultured after 168 h with S. mutans, L. casei and C. dubliniensis, and H. pylori SS1 with L. casei and C. dubliniensis, but not with S. mutans. Notably, the co-cultured microorganisms survived at high CFU numbers similar to those of the monocultures. CONCLUSION The study suggests that H. pylori can transiently survive in human saliva and even with presence of certain oral microorganisms. However, it may not be a permanent resident of the oral microbiota. The co-survival with oral microorganisms emphasizes the necessity for studying the role of the oral microbiota in the infectious and transmission cycle of H. pylori.
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Affiliation(s)
- Konstantin Johannes Scholz
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, University of Freiburg, Freiburg, Germany.
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Regensburg, Germany.
| | - Annabelle Höhne
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Annette Wittmer
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Georg Häcker
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Elmar Hellwig
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Fabian Cieplik
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Barbara Waidner
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany
- Department of Biochemistry and Chemistry, Philipps University of Marburg, Marburg, Germany
| | - Ali Al-Ahmad
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, University of Freiburg, Freiburg, Germany
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7
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Nguyen D, Ivester RG, Rosinke K, Hoover TR. Helicobacter pylori HP0135 Is a Small Lipoprotein That Has a Role in Outer Membrane Stability. Molecules 2025; 30:204. [PMID: 39860075 PMCID: PMC11768039 DOI: 10.3390/molecules30020204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/28/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Helicobacter pylori is a Gram-negative bacterium and human pathogen that is linked to various gastric diseases, including peptic ulcer disease, chronic gastritis, and gastric cancer. The filament of the H. pylori flagellum is surrounded by a membranous sheath that is contiguous with the outer membrane. Proteomic analysis of isolated sheathed flagella from H. pylori B128 identified the lipoprotein HP0135 as a potential component of the flagellar sheath. HP0135 is a small protein, with the mature HP0135 lipoprotein only 28 amino acid residues in length. Deletion of hp0135 in H. pylori B128 resulted in morphological abnormalities that included extensive formation of outer membrane vesicles and increased frequency of mini-cells. Introducing a plasmid-borne copy of hp0135 into the H. pylori Δhp0135 mutant suppressed the morphological abnormalities. The phenotype of the Δhp0135 mutant suggests HP0135 has roles in stabilizing the cell envelope and cell division.
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Affiliation(s)
- Doreen Nguyen
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (D.N.); (K.R.)
| | - Rachel G. Ivester
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA;
| | - Kyle Rosinke
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (D.N.); (K.R.)
| | - Timothy R. Hoover
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (D.N.); (K.R.)
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8
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Proença M, Tanoeiro L, Fox JG, Vale FF. Prophage dynamics in gastric and enterohepatic environments: unraveling ecological barriers and adaptive transitions. ISME COMMUNICATIONS 2025; 5:ycaf017. [PMID: 39981300 PMCID: PMC11840440 DOI: 10.1093/ismeco/ycaf017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 01/31/2025] [Accepted: 02/03/2025] [Indexed: 02/22/2025]
Abstract
Phage predation plays a critical role in shaping bacterial genetic diversity, with prophages playing a comparable role. However, the prevalence and genetic variability of prophages within the Helicobacter genus remain inadequately studied. Helicobacter species are clinically significant and occupy distinct digestive system regions, with gastric species (e.g. Helicobacter pylori) residing in the gastric mucosa and enterohepatic species colonizing the liver and intestines of various vertebrates. Here, we address this knowledge gap by analyzing prophage presence and diversity across 343 non-pylori Helicobacter genomes, mapping their distribution, comparing genomic features between gastric and enterohepatic prophages, and exploring their evolutionary relationships with hosts. We identified and analyzed a catalog of 119 new complete and 78 incomplete prophages. Our analysis reveals significant differences between gastric and enterohepatic species. Gastric prophages exhibit high synteny, and cluster in a few groups, indicating a more conserved genetic structure. In contrast, enterohepatic prophages show greater diversity in gene order and content, reflecting their adaptation to varied host environments. Helicobacter cinaedi stands out, harboring a large number of prophages among the enterohepatic species, forming a distinct cohesive group. Phylogenetic analyses reveal a co-evolutionary relationship between several prophages and their bacterial hosts-though exceptions, such as the enterohepatic prophages from H. canis, H. equorum, H. jaachi, and the gastric prophage from H. himalayensis-suggesting more complex co-evolutionary dynamics like host jumps, recombination, and horizontal gene transfer. The insights gained from this study enhance our understanding of prophage dynamics in Helicobacter, emphasizing their role in bacterial adaptation, virulence, and host specificity.
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Affiliation(s)
- Marta Proença
- Pathogen Genomics and Translational Microbiology Lab, BioISI – Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Luís Tanoeiro
- Pathogen Genomics and Translational Microbiology Lab, BioISI – Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, United States
| | - Filipa F Vale
- Pathogen Genomics and Translational Microbiology Lab, BioISI – Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
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Rosinke K, Tachiyama S, Mrásek J, Liu J, Hoover TR. A Helicobacter pylori flagellar motor accessory is needed to maintain the barrier function of the outer membrane during flagellar rotation. PLoS Pathog 2025; 21:e1012860. [PMID: 39792952 PMCID: PMC11756786 DOI: 10.1371/journal.ppat.1012860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 01/23/2025] [Accepted: 12/26/2024] [Indexed: 01/12/2025] Open
Abstract
The Helicobacter pylori flagellar motor contains several accessory structures that are not found in the archetypal Escherichia coli and Salmonella enterica motors. H. pylori hp0838 encodes a previously uncharacterized lipoprotein and is in an operon with flgP, which encodes a motor accessory protein. Deletion analysis of hp0838 in H. pylori B128 showed that the gene is not required for motility in soft agar medium, but the mutant displayed a reduced growth rate and an increased sensitivity to bacitracin, which is an antibiotic that is normally excluded by the outer membrane. Introducing a plasmid-borne copy of hp0838 into the H. pylori Δhp0838 mutant suppressed the fitness defect and antibiotic sensitivity of the strain. A variant of the Δhp0838 mutant containing a frameshift mutation in pflA, which resulted in paralyzed flagella, displayed wild-type growth rate and resistance to bacitracin, suggesting the fitness defect and antibiotic sensitivity of the Δhp0838 mutant are dependent on flagellar rotation. Comparative analysis of in-situ structures of the wild type and Δhp0838 mutant motors revealed the Δhp0838 mutant motor lacked a previously undescribed ring structure with 18-fold symmetry located near the outer membrane. Given its role in formation of the motor outer ring, HP0838 was designated FapH (flagellar accessory protein in Helicobacter pylori) and the motor accessory formed the protein was named the FapH ring. Our data suggest that the FapH ring helps to preserve outer membrane barrier function during flagellar rotation. Given that FapH homologs are present in many members of the phylum Campylobacterota, they may have similar roles in protecting the outer membrane from damage due to flagellar rotation in these bacteria.
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Affiliation(s)
- Kyle Rosinke
- Department of Microbiology, University of Georgia, Athens, Georgia, United States of America
| | - Shoichi Tachiyama
- Department of Microbial Pathogenesis, Microbial Sciences Institute, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Jan Mrásek
- Department of Microbiology, University of Georgia, Athens, Georgia, United States of America
- Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States of America
| | - Jun Liu
- Department of Microbial Pathogenesis, Microbial Sciences Institute, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Timothy R. Hoover
- Department of Microbiology, University of Georgia, Athens, Georgia, United States of America
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10
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Liu X, Wang D, Wei X, Yang D, Ma Y, Liu G. Selectively Antagonizing the NOD1-Mediated Inflammatory Signaling Pathway Mitigates the Gastric Inflammation Induced by Helicobacter pylori Infection. J Med Chem 2024; 67:22145-22167. [PMID: 39637404 DOI: 10.1021/acs.jmedchem.4c02139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Helicobacter pylori (H. pylori) infection is characterized by the complex interplay between H. pylori and gastric disorders. It has been established that NOD1 can be activated by the peptidoglycan (PGN) present in the cell wall of H. pylori, serving as a key mediator of inflammation and initiating the RIP2/NF-κB and MAPK inflammatory signaling pathways. In this article, we reported on the development of a 2-chloroquinazolin-4-ol derivative 66 as a potent and selective antagonist of both human and mouse NOD1, which effectively inhibited the expression of inflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL1, CXCL8) in immune and epithelial cells, as well as inflammatory cytokines (KC, IL-6) in a H. pylori-induced murine model of gastritis following oral administration. This study laid a foundation for treating gastritis induced by H. pylori infection.
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Affiliation(s)
- Xinhua Liu
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist, Beijing 100084, PR China
| | - Dan Wang
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist, Beijing 100084, PR China
| | - Xiduan Wei
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist, Beijing 100084, PR China
| | - Dan Yang
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist, Beijing 100084, PR China
| | - Yao Ma
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Rd, Xicheng Dist, Beijing 100050, PR China
| | - Gang Liu
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist, Beijing 100084, PR China
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11
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Elger W, Tegtmeyer N, Rohde M, Linz B, Hirsch C, Backert S. Cultivation and molecular characterization of viable Helicobacter pylori from the root canal of 170 deciduous teeth of children. Cell Commun Signal 2024; 22:578. [PMID: 39627817 PMCID: PMC11613870 DOI: 10.1186/s12964-024-01948-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/16/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Helicobacter pylori is a persistent pathogen in the human stomach. However, the proposed transmission route via the oral cavity is not understood and under intense debate. While dozens of studies have shown by PCR that H. pylori DNA is frequently present in the oral cavity, data on the growth and characterization of viable H. pylori from this compartment are very scarce, and it is unclear whether the bacteria can survive in the oral cavity for longer time periods or even colonize it. METHODS Selective growth methods, scanning electron microscopy, urease assay, Western blotting, PCR, and gene sequencing were applied to identify and examine viable H. pylori in decayed milk teeth. RESULTS Here, we studied viable H. pylori in the plaque and root canals of 170 endodontically infected deciduous teeth that were extracted from 54 children. While H. pylori DNA was detected in several plaque and many root canal samples by PCR, live bacteria could only be cultivated from 28 root canals, but not from plaque. These 28 isolates have been identified as H. pylori by PCR and sequencing of vacA, cagA and htrA genes, phylogenetic analyses, protein expression of major H. pylori virulence factors, and by signal transduction events during infection of human cell lines. CONCLUSIONS Thus, the microaerobic environment in the root canals of endodontically infected teeth may represent a protected and transient reservoir for live H. pylori, especially in individuals with poor dental hygiene, which could serve as a potential source for re-infection of the stomach after antibiotic therapy or for transmission to other individuals.
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Affiliation(s)
- Wieland Elger
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Hirsch
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany.
| | - Steffen Backert
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
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12
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Neuper T, Frauenlob T, Dang HH, Krenn PW, Posselt G, Regl C, Fortelny N, Schäpertöns V, Unger MS, Üblagger G, Neureiter D, Mühlbacher I, Weitzendorfer M, Singhartinger F, Emmanuel K, Huber CG, Wessler S, Aberger F, Horejs-Hoeck J. ADP-heptose attenuates Helicobacter pylori-induced dendritic cell activation. Gut Microbes 2024; 16:2402543. [PMID: 39288239 PMCID: PMC11409497 DOI: 10.1080/19490976.2024.2402543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 09/19/2024] Open
Abstract
Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.
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Affiliation(s)
- Theresa Neuper
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Tobias Frauenlob
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Hieu-Hoa Dang
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Peter W Krenn
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Christof Regl
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Nikolaus Fortelny
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Veronika Schäpertöns
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Michael S Unger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Gunda Üblagger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Daniel Neureiter
- Cancer Cluster Salzburg, Salzburg, Austria
- Institute of Pathology, Uniklinikum Salzburg, Salzburg, Austria
| | - Iris Mühlbacher
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Michael Weitzendorfer
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Franz Singhartinger
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Klaus Emmanuel
- Cancer Cluster Salzburg, Salzburg, Austria
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Christian G Huber
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Silja Wessler
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Fritz Aberger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
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13
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Li X, Zhu Y, Yao Z, Ge R. The lysine 2-hydroxyisobutyrylome of Helicobacter pylori: Indicating potential roles of lysine 2-hydroxyisobutyrylation in the bacterial metabolism. Microb Pathog 2024; 186:106510. [PMID: 38147967 DOI: 10.1016/j.micpath.2023.106510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 12/28/2023]
Abstract
Helicobacter pylori (H. pylori) is a pathogen which colonizes the stomach, causing ulcers, chronic gastritis and other related diseases. Protein post-translational modifications (PTMs) in bacteria mainly include glycosylation, ubiquitination, nitrosylation, methylation, phosphorylation and acetylation, all of which have divergent functions in the physiology and pathology of the bacterium. Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered type of PTM in recent years in some kinds of organisms, and this PTM is involved in the regulation of a variety of metabolic process, such as bacterial glucose metabolism, lipid metabolism and protein synthesis. This study performed the first qualitative lysine 2-hydroxyisobutyrylome in H. pylori, and a total of 4419 Khib sites in 812 proteins were identified. The results show that Khib sites are mainly located in the key functional regions or active domains of proteins involved in nickel-trafficking, energy production, virulence factors, anti-oxidation, metal resistance, and ribosome biosynthesis in H. pylori. The study presented here provides new hints in the metabolism and pathology of H. pylori and the proteins with Khib modification may be potentially promising targets for the further development of antibiotics, especially considering the high occurrence of treatment failure of H. pylori failure due to development of antibiotics-resistance.
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Affiliation(s)
- Xinhang Li
- School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Yulin Zhu
- School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Zihui Yao
- School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Ruiguang Ge
- School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
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14
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O'Connor HJ. Forty years of Helicobacter pylori infection and changes in findings at esophagogastroduodenoscopy. Helicobacter 2023; 28:e13026. [PMID: 37818739 DOI: 10.1111/hel.13026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND It is 40 years since the discovery of Helicobacter pylori infection. Over that time major changes have occurred in esophagogastroduodenoscopy (EGD) findings. The aim of this review is to describe these changes, and the important role H. pylori infection has played in their evolution. METHODS References were identified through searches of PubMed using the search terms-endoscopy time trends, peptic ulcer disease, gastroesophageal reflux disease, upper gastrointestinal cancer, gastric polyps, H. pylori, eosinophilic gastrointestinal disorders, and celiac disease, from 1970 through December 2021. RESULTS The prevalence of H. pylori infection has fallen and consequently, H. pylori-positive peptic ulcer disease has become rare. Gastroesophageal reflux disease is now the commonest disorder diagnosed at EGD, and Barrett's esophagus has increased in parallel. Cancer of the distal stomach has fallen while esophageal adenocarcinoma and reflux-related cardia cancer have risen. Gastric polyps have changed from hyperplastic and adenomas to sporadic fundic gland polyps. Antimicrobial resistance has made H. pylori infection more difficult to eradicate. Eosinophilic gastrointestinal disorders, particularly eosinophilic esophagitis, have emerged as important new allergic disorders. Celiac disease has changed and increased. CONCLUSIONS EGD findings appear to have changed from features suggesting a H. pylori-positive "phenotype" 40 years ago to a H. pylori-negative "phenotype" today. These changes have major implications for the management of gastrointestinal disorders.
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Affiliation(s)
- Humphrey J O'Connor
- Trinity Academic Gastroenterology Group, Trinity Centre for Health Sciences, The University of Dublin, Tallaght University Hospital, Dublin, Ireland
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15
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Gomez-Ramirez U, Nolasco-Romero CG, Contreras-Rodríguez A, Zuñiga G, Mendoza-Elizalde S, Prado-Galbarro FJ, Pérez Aguilar F, Pedraza Tinoco JE, Valencia-Mayoral P, Velázquez-Guadarrama N. Dysbiosis by Eradication of Helicobacter pylori Infection Associated with Follicular Gastropathy and Pangastropathy. Microorganisms 2023; 11:2748. [PMID: 38004759 PMCID: PMC10673246 DOI: 10.3390/microorganisms11112748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Dysbiosis plays an important role in the development of bacterial infections in the gastric mucosa, particularly Helicobacter pylori. The international guidelines for the treatment of H. pylori infections suggest standard triple therapy (STT). Nevertheless, because of the increasing resistance rates to clarithromycin, metronidazole has been widely considered in several countries. Unfortunately, the non-justified administration of antibiotics induces dysbiosis in the target organ. We characterized the gastric microbiota of patients diagnosed with follicular gastropathy and pangastropathy attributed to H. pylori infection, before and after the administration of STT with metronidazole. Dominant relative abundances of Cutibacterium were observed in pre-treatment patients, whereas H. pylori was observed at <11%, suggesting the multifactor property of the disease. The correlation of Cutibacterium acnes and H. pylori with gastric infectious diseases was also evaluated using quantitative real-time polymerase chain reaction. The dominance of C. acnes over H. pylori was observed in gastritis, gastropathies, and non-significant histological alterations. None of the microorganisms were detected in the intestinal metaplasia. Post-treatment alterations revealed an increase in the relative abundances of Staphylococcus, Pseudomonas, and Klebsiella. Non-H. pylori gastrointestinal bacteria can be associated with the initiation and development of gastric diseases, such as pathobiont C. acnes.
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Affiliation(s)
- Uriel Gomez-Ramirez
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (C.G.N.-R.); (S.M.-E.)
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Carolina G. Nolasco-Romero
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (C.G.N.-R.); (S.M.-E.)
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Araceli Contreras-Rodríguez
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Gerardo Zuñiga
- Laboratorio de Variación Biológica y Evolución, Departamento de Zoología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Sandra Mendoza-Elizalde
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (C.G.N.-R.); (S.M.-E.)
| | | | - Fernando Pérez Aguilar
- Servicio de Endoscopía Gastrointestinal, Hospital General Dr. Fernando Quiroz, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico City 01140, Mexico;
| | | | - Pedro Valencia-Mayoral
- Departamento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Norma Velázquez-Guadarrama
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (C.G.N.-R.); (S.M.-E.)
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16
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Tran SC, McClain MS, Cover TL. Role of the CagY antenna projection in Helicobacter pylori Cag type IV secretion system activity. Infect Immun 2023; 91:e0015023. [PMID: 37638724 PMCID: PMC10501215 DOI: 10.1128/iai.00150-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/07/2023] [Indexed: 08/29/2023] Open
Abstract
Helicobacter pylori strains containing the cag pathogenicity island (PAI) are associated with the development of gastric adenocarcinoma and peptic ulcer disease. The cag PAI encodes a secreted effector protein (CagA) and a type IV secretion system (Cag T4SS). Cag T4SS activity is required for the delivery of CagA and non-protein substrates into host cells. The Cag T4SS outer membrane core complex (OMCC) contains a channel-like domain formed by helix-loop-helix elements (antenna projections, AP) from 14 copies of the CagY protein (a VirB10 ortholog). Similar VirB10 antenna regions are present in T4SS OMCCs from multiple bacterial species and are predicted to span the outer membrane. In this study, we investigated the role of the CagY antenna region in Cag T4SS OMCC assembly and Cag T4SS function. An H. pylori mutant strain with deletion of the entire CagY AP (∆AP) retained the capacity to produce CagY and assemble an OMCC, but it lacked T4SS activity (CagA translocation and IL-8 induction in AGS gastric epithelial cells). In contrast, a mutant strain with Gly-Ser substitutions in the unstructured CagY AP loop retained Cag T4SS activity. Mutants containing CagY AP loops with shortened lengths were defective in CagA translocation and exhibited reduced IL-8-inducing activity compared to control strains. These data indicate that the CagY AP region is required for Cag T4SS activity and that Cag T4SS activity can be modulated by altering the length of the CagY AP unstructured loop.
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Affiliation(s)
- Sirena C. Tran
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark S. McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Timothy L. Cover
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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17
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Klever AM, Alexander KA, Almeida D, Anderson MZ, Ball RL, Beamer G, Boggiatto P, Buikstra JE, Chandler B, Claeys TA, Concha AE, Converse PJ, Derbyshire KM, Dobos KM, Dupnik KM, Endsley JJ, Endsley MA, Fennelly K, Franco-Paredes C, Hagge DA, Hall-Stoodley L, Hayes D, Hirschfeld K, Hofman CA, Honda JR, Hull NM, Kramnik I, Lacourciere K, Lahiri R, Lamont EA, Larsen MH, Lemaire T, Lesellier S, Lee NR, Lowry CA, Mahfooz NS, McMichael TM, Merling MR, Miller MA, Nagajyothi JF, Nelson E, Nuermberger EL, Pena MT, Perea C, Podell BK, Pyle CJ, Quinn FD, Rajaram MVS, Mejia OR, Rothoff M, Sago SA, Salvador LCM, Simonson AW, Spencer JS, Sreevatsan S, Subbian S, Sunstrum J, Tobin DM, Vijayan KKV, Wright CTO, Robinson RT. The Many Hosts of Mycobacteria 9 (MHM9): A conference report. Tuberculosis (Edinb) 2023; 142:102377. [PMID: 37531864 PMCID: PMC10529179 DOI: 10.1016/j.tube.2023.102377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.
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Affiliation(s)
- Abigail Marie Klever
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Kathleen A Alexander
- Department of Fish and Wildlife Conservation, Virginia Tech, Blacksburg, VA, USA; CARACAL/Chobe Research Institute Kasane, Botswana
| | - Deepak Almeida
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Matthew Z Anderson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | | | - Gillian Beamer
- Host Pathogen Interactions and Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Paola Boggiatto
- Agricultural Research Service, United States Department of Agriculture, Ames, IA, USA
| | - Jane E Buikstra
- Center for Bioarchaeological Research, Arizona State University, Tempe, AZ, USA
| | - Bruce Chandler
- Division of Public Health, Alaska Department of Health, AK, USA
| | - Tiffany A Claeys
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Aislinn E Concha
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Paul J Converse
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Keith M Derbyshire
- Division of Genetics, The Wadsworth Center, New York State Department of Health, Albany, NY, USA; Department of Biomedical Sciences, University at Albany, Albany, NY, USA
| | - Karen M Dobos
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Kathryn M Dupnik
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Janice J Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Mark A Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kevin Fennelly
- Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD, USA
| | - Carlos Franco-Paredes
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA; Hospital Infantil de México Federico Gómez, México, USA
| | | | - Luanne Hall-Stoodley
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Don Hayes
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Courtney A Hofman
- Department of Anthropology, University of Oklahoma, Norman, OK, USA; Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, OK, USA
| | - Jennifer R Honda
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - Natalie M Hull
- Department of Civil, Environmental, and Geodetic Engineering, The Ohio State University, Columbus, OH, USA
| | - Igor Kramnik
- Pulmonary Center, The Department of Medicine, Boston University Chobanian & Aveedisian School of Medicine, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
| | - Karen Lacourciere
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Ramanuj Lahiri
- United States Department of Health and Human Services, Health Resources and Services Administration, Health Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Elise A Lamont
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Michelle H Larsen
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Sandrine Lesellier
- French Agency for Food, Environmental & Occupational Health & Safety (ANSES), Laboratory for Rabies and Wildlife,Nancy, France
| | - Naomi R Lee
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Najmus S Mahfooz
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Temet M McMichael
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Marlena R Merling
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Michele A Miller
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jyothi F Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA
| | - Elizabeth Nelson
- Microbial Paleogenomics Unit, Dept of Genomes and Genetics, Institut Pasteur, Paris, France
| | - Eric L Nuermberger
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Maria T Pena
- United States Department of Health and Human Services, Health Resources and Services Administration, Health Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Claudia Perea
- Animal & Plant Health Inspection Service, United States Department of Agriculture, Ames, IA, USA
| | - Brendan K Podell
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Charlie J Pyle
- Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Fred D Quinn
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Murugesan V S Rajaram
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Oscar Rosas Mejia
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | | | - Saydie A Sago
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Liliana C M Salvador
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Andrew W Simonson
- Department of Microbiology and Molecular Genetics and the Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - John S Spencer
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Srinand Sreevatsan
- Pathobiology & Diagnostic Investigation Department, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Selvakumar Subbian
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | | | - David M Tobin
- Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - K K Vidya Vijayan
- Department of Microbiology and Immunology, Center for AIDS Research, and Children's Research Institute, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Caelan T O Wright
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA
| | - Richard T Robinson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA.
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18
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Shakir SM, Shakir FA, Couturier MR. Updates to the Diagnosis and Clinical Management of Helicobacter pylori Infections. Clin Chem 2023; 69:869-880. [PMID: 37473423 DOI: 10.1093/clinchem/hvad081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/12/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) affects nearly half of the world's populations with high incidence and prevalence rates in developing countries. Infection with H. pylori increases the risk of developing peptic ulcer disease and gastric cancer. This review provides a summary of the prevalence and microbiology of H. pylori with emphasis on the current diagnostic methods and clinical management strategies. CONTENT This review discusses current options and developments in H. pylori diagnosis with the challenges and advantages associated with both noninvasive and invasive methods. The advantages of molecular methods for the diagnosis of H. pylori infection and prediction of clarithromycin resistance directly from stool or tissue biopsies are discussed. In addition, we provide a brief review on the treatment for H. pylori indicated in patients with evidence of active infection with the organism's antimicrobial resistance patterns taken into consideration. SUMMARY Testing for H. pylori has largely centered around fecal antigen testing, urea breath testing, and immunohistochemical staining from tissue biopsies. Culture-based diagnostics followed by phenotypic antimicrobial susceptibility testing is the gold standard for detection of resistance patterns. Due to the fastidious nature of the organism, culture methods are time consuming and labor intensive. Rapid nucleic acid amplification tests for H. pylori identification from direct specimens and molecular determination of drug resistance markers are accurate alternatives for H. pylori diagnosis but are not widely adopted. H. pylori antimicrobial resistance rates are on the rise due to the widespread use of antibiotics. Antibiotic regimens including the quadruple therapy and non-clarithromycin triple therapies have a higher success rate, with newer vonoprazon-based regimens showing promising eradication rates.
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Affiliation(s)
- Salika Mehreen Shakir
- Department of Pathology, University of Utah, Salt Lake City, UT, United States
- ARUP Laboratories, Salt Lake City, UT, United States
| | | | - Marc Roger Couturier
- Department of Pathology, University of Utah, Salt Lake City, UT, United States
- ARUP Laboratories, Salt Lake City, UT, United States
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19
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Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, Bungau AF, Radu AF. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomed Pharmacother 2023; 164:115015. [PMID: 37321055 DOI: 10.1016/j.biopha.2023.115015] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023] Open
Abstract
Among the most extensively researched processes in the development and treatment of cancer is inflammatory condition. Although acute inflammation is essential for the wound healing and reconstruction of tissues that have been damaged, chronic inflammation may contribute to the onset and growth of a number of diseases, including cancer. By disrupting the signaling processes of cells, which result in cancer induction, invasion, and development, a variety of inflammatory molecules are linked to the development of cancer. The microenvironment surrounding the tumor is greatly influenced by inflammatory cells and their subsequent secretions, which also contribute significantly to the tumor's growth, survivability, and potential migration. These inflammatory variables have been mentioned in several publications as prospective diagnostic tools for anticipating the onset of cancer. Targeting inflammation with various therapies can reduce the inflammatory response and potentially limit or block the proliferation of cancer cells. The scientific medical literature from the past three decades has been studied to determine how inflammatory chemicals and cell signaling pathways related to cancer invasion and metastasis are related. The current narrative review updates the relevant literature while highlighting the specifics of inflammatory signaling pathways in cancer and their possible therapeutic possibilities.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, 9300 Bloemfontein, South Africa.
| | - Vishal Kumar Deb
- Dietetics and Nutrition Technology Division, CSIR Institute of Himalayan Bioresource Technology, 176061 Palampur, Himanchal Pradesh, India
| | - Deen Bandhu Dimri
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology BHU, Varanasi 221005, Uttar Pradesh, India
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Alexa Florina Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei-Flavius Radu
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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20
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Zarzecka U, Tegtmeyer N, Sticht H, Backert S. Trimer stability of Helicobacter pylori HtrA is regulated by a natural mutation in the protease domain. Med Microbiol Immunol 2023:10.1007/s00430-023-00766-9. [PMID: 37183214 DOI: 10.1007/s00430-023-00766-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/26/2023] [Indexed: 05/16/2023]
Abstract
The human pathogen Helicobacter pylori is a major risk factor for gastric disease development. Serine protease HtrA is an important bacterial virulence factor that cleaves the cell junction proteins occludin, claudin-8 and E-cadherin, which causes gastric tissue damage. Using casein zymography, we discovered that HtrA trimer stability varies in clinical H. pylori strains. Subsequent sequence analyses revealed that HtrA trimer stability correlated with the presence of leucine or serine residue at position 171. The importance of these amino acids in determining trimer stability was confirmed by leucine-to-serine swapping experiments using isogenic H. pylori mutant strains as well as recombinant HtrA proteins. In addition, this sequence position displays a high sequence variability among various bacterial species, but generally exhibits a preference for hydrophilic amino acids. This natural L/S171 polymorphism in H. pylori may affect the protease activity of HtrA during infection, which could be of clinical importance and may determine gastric disease development.
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Affiliation(s)
- Urszula Zarzecka
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Department of General and Medical Biochemistry, Faculty of Biology, University of Gdańsk, Gdańsk, Poland
| | - Nicole Tegtmeyer
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
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21
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Zang H, Wang J, Wang H, Guo J, Li Y, Zhao Y, Song J, Liu F, Liu X, Zhao Y. Metabolic alterations in patients with Helicobacter pylori-related gastritis: The H. pylori-gut microbiota-metabolism axis in progression of the chronic inflammation in the gastric mucosa. Helicobacter 2023:e12984. [PMID: 37186092 DOI: 10.1111/hel.12984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 02/15/2023] [Accepted: 03/13/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE To characterize the serum metabolism in patients with Helicobacter pylori-positive and H. pylori-negative gastritis. METHODS Clinical data and serum gastric function parameters, PGI (pepsinogen I), PGII, PGR (PGI/II), and G-17 (gastrin-17) of 117 patients with chronic gastritis were collected, including 57 H. pylori positive and 60 H. pylori negative subjects. Twenty cases in each group were randomly selected to collect intestinal mucosa specimens and serum samples. The gut microbiota profiles were generated by 16S rRNA gene sequencing, and the serum metabolites were analyzed by a targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) technology. RESULTS Altered expression of 20 metabolites, including isovaleric acid, was detected in patients with HPAG. Some taxa of Bacteroides, Fusobacterium, and Prevotella in the gut microbiota showed significant correlations with differentially expressed metabolites between H. pylori positive and H. pylori negative individuals. As a result, an H. pylori-gut microbiota-metabolism (HGM) axis was proposed. CONCLUSION Helicobacter pylori infection may influence the progression of mucosal diseases and the emergence of other complications in the host by altering the gut microbiota, and thus affecting the host serum metabolism.
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Affiliation(s)
- Hongmin Zang
- Hebei University of Chinese Medicine, Shijiazhuang, China
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Jin Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Huijie Wang
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Jiaxuan Guo
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yuchan Li
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yinuo Zhao
- School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Jinzhong Song
- Hebei University of Chinese Medicine, Shijiazhuang, China
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Fengshuang Liu
- Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Academy of Traditional Chinese Medicine, Shijiazhuang, China
| | - Xuzhao Liu
- North China University of Science and Technology, Tangshan, China
| | - Yubin Zhao
- Hebei University of Chinese Medicine, Shijiazhuang, China
- North China University of Science and Technology, Tangshan, China
- Shijiazhuang People's Hospital, Shijiazhuang, China
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22
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Cao Z, An L, Han Y, Jiao S, Zhou Z. The Hippo signaling pathway in gastric cancer. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 36924251 DOI: 10.3724/abbs.2023038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control and tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks of cancer. The last decade witnessed a burst of investigations dissecting how Hippo dysregulation contributes to tumorigenesis, highlighting the therapeutic potential of targeting this pathway for tumor intervention. In this review, we systemically document studies on the Hippo pathway in the contexts of gastric tumor initiation, progression, metastasis, acquired drug resistance, and the emerging development of Hippo-targeting strategies. By summarizing major open questions in this field, we aim to inspire further in-depth understanding of Hippo signaling in GC development, as well as the translational implications of targeting Hippo for GC treatment.
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Affiliation(s)
- Zhifa Cao
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China.,CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Liwei An
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Yi Han
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.,Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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23
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Di Fermo P, Di Lodovico S, Di Campli E, D'Arcangelo S, Diban F, D'Ercole S, Di Giulio M, Cellini L. Helicobacter pylori Dormant States Are Affected by Vitamin C. Int J Mol Sci 2023; 24:ijms24065776. [PMID: 36982855 PMCID: PMC10057322 DOI: 10.3390/ijms24065776] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Helicobacter pylori colonizes human gastric mucosa, overcoming stressful conditions and entering in a dormant state. This study evaluated: (i) H. pylori's physiological changes from active to viable-but-non-culturable (VBNC) and persister (AP) states, establishing times/conditions; (ii) the ability of vitamin C to interfere with dormancy generation/resuscitation. A dormant state was induced in clinical MDR H. pylori 10A/13 by: nutrient starvation (for VBNC generation), incubating in an unenriched medium (Brucella broth) or saline solution (SS), and (for AP generation) treatment with 10xMIC amoxicillin (AMX). The samples were monitored after 24, 48, and 72 h, 8-14 days by OD600, CFUs/mL, Live/Dead staining, and an MTT viability test. Afterwards, vitamin C was added to the H. pylori suspension before/after the generation of dormant states, and monitoring took place at 24, 48, and 72 h. The VBNC state was generated after 8 days in SS, and the AP state in AMX for 48 h. Vitamin C reduced its entry into a VBNC state. In AP cells, Vitamin C delayed entry, decreasing viable coccal cells and increasing bacillary/U-shaped bacteria. Vitamin C increased resuscitation (60%) in the VBNC state and reduced the aggregates of the AP state. Vitamin C reduced the incidence of dormant states, promoting the resuscitation rate. Pretreatment with Vitamin C could favor the selection of microbial vegetative forms that are more susceptible to H. pylori therapeutical schemes.
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Affiliation(s)
- Paola Di Fermo
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Silvia Di Lodovico
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Emanuela Di Campli
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Sara D'Arcangelo
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Firas Diban
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Simonetta D'Ercole
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Mara Di Giulio
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Luigina Cellini
- Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
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24
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Fenneman AC, Weidner M, Chen LA, Nieuwdorp M, Blaser MJ. Antibiotics in the pathogenesis of diabetes and inflammatory diseases of the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2023; 20:81-100. [PMID: 36258032 PMCID: PMC9898198 DOI: 10.1038/s41575-022-00685-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
Antibiotic use is increasing worldwide. However, the use of antibiotics is clearly associated with changes in gut microbiome composition and function, and perturbations have been identified as potential environmental risk factors for chronic inflammatory disorders of the gastrointestinal tract. In this Review, we examine the association between the use of antibiotics and the onset and development of both type 1 and type 2 diabetes, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, as well as coeliac disease and eosinophilic oesophagitis. We discuss the key findings of epidemiological studies, provide mechanistic insights into the pathways by which the gut microbiota might contribute to these diseases, and assess clinical trials investigating the effects of antibiotics. Such studies indicate that antibiotic exposures, varying in type, timing and dosage, could explain differences in disease risk. There seems to be a critical window in early life in which perturbation of the microbiome has a substantial effect on disease development. Identifying the antibiotic-perturbed gut microbiota as a factor that contributes to the pathophysiology of these inflammatory disorders might stimulate new approaches to prevention, diagnosis and treatment.
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Affiliation(s)
- Aline C Fenneman
- Department of Clinical and Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Melissa Weidner
- Department of Paediatrics, Rutgers University, New Brunswick, NJ, USA
| | - Lea Ann Chen
- Department of Medicine, Rutgers University, New Brunswick, NJ, USA
| | - Max Nieuwdorp
- Department of Clinical and Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Martin J Blaser
- Department of Medicine, Rutgers University, New Brunswick, NJ, USA.
- Department of Pathology and Laboratory Medicine, Rutgers University, New Brunswick, NJ, USA.
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25
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Lepcha TT, Kumar M, Sharma AK, Mal S, Majumder D, Jana K, Basu J, Kundu M. Uncovering the role of microRNA671-5p/CDCA7L/monoamine oxidase-A signaling in Helicobacter pylori mediated apoptosis in gastric epithelial cells. Pathog Dis 2023; 81:7143101. [PMID: 37140023 DOI: 10.1093/femspd/ftad006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/27/2023] [Accepted: 04/24/2023] [Indexed: 05/05/2023] Open
Abstract
Helicobacter pylori is a gram-negative microaerophilic bacterium and is associated with gastrointestinal diseases ranging from peptic ulcer and gastritis to gastric cancer and mucosa-associated lymphoid tissue lymphoma. In our laboratory, the transcriptomes and miRnomes of AGS cells infected with H. pylori have been profiled, and an miRNA-mRNA network has been constructed. MicroRNA 671-5p is upregulated during H. pylori infection of AGS cells or of mice. In this study, the role of miR-671-5p during infection has been investigated. It has been validated that miR-671-5p targets the transcriptional repressor CDCA7L, which is downregulated during infection (in vitro and in vivo) concomitant with miR-671-5p upregulation. Further, it has been established that the expression of monoamine oxidase A (MAO-A) is repressed by CDCA7L, and that MAO-A triggers the generation of reactive oxygen species (ROS). Consequently, miR-671-5p/CDCA7L signaling is linked to the generation of ROS during H. pylori infection. Finally, it has been demonstrated that ROS-mediated caspase 3 activation and apoptosis that occurs during H. pylori infection, is dependent on the miR-671-5p/CDCA7L/MAO-A axis. Based on the above reports, it is suggested that targeting miR-671-5p could offer a means of regulating the course and consequences of H. pylori infection.
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Affiliation(s)
- Thurbu Tshering Lepcha
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Manish Kumar
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Arun Kumar Sharma
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Soumya Mal
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Debayan Majumder
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Kuladip Jana
- Division of Molecular Medicine, Bose Institute, EN80 Sector V, Salt Lake City, Kolkata 700091, India
| | - Joyoti Basu
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
| | - Manikuntala Kundu
- Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road Kolkata 700009, India
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26
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Dawud LM, Holbrook EM, Lowry CA. Evolutionary Aspects of Diverse Microbial Exposures and Mental Health: Focus on "Old Friends" and Stress Resilience. Curr Top Behav Neurosci 2023; 61:93-117. [PMID: 35947354 PMCID: PMC9918614 DOI: 10.1007/7854_2022_385] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
The prevalence of inflammatory disease conditions, including allergies, asthma, and autoimmune disorders, increased during the latter half of the twentieth century, as societies transitioned from rural to urban lifestyles. A number of hypotheses have been put forward to explain the increasing prevalence of inflammatory disease in modern urban societies, including the hygiene hypothesis and the "Old Friends" hypothesis. In 2008, Rook and Lowry proposed, based on the evidence that increased inflammation was a risk factor for stress-related psychiatric disorders, that the hygiene hypothesis or "Old Friends" hypothesis may be relevant to psychiatric disorders. Since then, it has become more clear that chronic low-grade inflammation is a risk factor for stress-related psychiatric disorders, including anxiety disorders, mood disorders, and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD). Evidence now indicates that persons raised in modern urban environments without daily contact with pets, relative to persons raised in rural environments in proximity to farm animals, respond with greater systemic inflammation to psychosocial stress. Here we consider the possibility that increased inflammation in persons living in modern urban environments is due to a failure of immunoregulation, i.e., a balanced expression of regulatory and effector T cells, which is known to be dependent on microbial signals. We highlight evidence that microbial signals that can drive immunoregulation arise from phylogenetically diverse taxa but are strain specific. Finally, we highlight Mycobacterium vaccae NCTC 11659, a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, as a case study of how single strains of bacteria might be used in a psychoneuroimmunologic approach for prevention and treatment of stress-related psychiatric disorders.
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Affiliation(s)
- Lamya'a M Dawud
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Evan M Holbrook
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional VA Medical Center (RMRVAMC), Aurora, CO, USA.
- Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA.
- Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
- Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, USA.
- inVIVO Planetary Health, Worldwide Universities Network (WUN), West New York, NJ, USA.
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27
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Lee J, Kim MH, Kim H. Anti-Oxidant and Anti-Inflammatory Effects of Astaxanthin on Gastrointestinal Diseases. Int J Mol Sci 2022; 23:ijms232415471. [PMID: 36555112 PMCID: PMC9779521 DOI: 10.3390/ijms232415471] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
A moderate amount of reactive oxygen species (ROS) is produced under normal conditions, where they play an important role in cell signaling and are involved in many aspects of the immune response to pathogens. On the other hand, the excessive production of ROS destructs macromolecules, cell membranes, and DNA, and activates pro-inflammatory signaling pathways, which may lead to various pathologic conditions. Gastrointestinal (GI) mucosa is constantly exposed to ROS due to the presence of bacteria and other infectious pathogens in food, as well as alcohol consumption, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAID). Prolonged excessive oxidative stress and inflammation are two major risk factors for GI disorders such as ulcers and cancers. Bioactive food compounds with potent anti-oxidant and anti-inflammatory activity have been tested in experimental GI disease models to evaluate their therapeutic potential. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid that is naturally present in algae, yeast, salmon, shrimp, and krill. It has been shown that AST exhibits protective effects against GI diseases via multiple mechanisms. Residing at the surface and inside of cell membranes, AST directly neutralizes ROS and lipid peroxyl radicals, enhances the activity of anti-oxidant enzymes, and suppresses pro-inflammatory transcription factors and cytokines. In addition, AST has been shown to inhibit cancer cell growth and metastasis via modulating cell proliferation-related pathways, apoptosis, and autophagy. Considering the potential benefits of AST in GI diseases, this review paper aims to summarize recent advances in AST research, focusing on its anti-oxidant and anti-inflammatory effects against gastric and intestinal ulcers and cancers.
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Affiliation(s)
- Jaeeun Lee
- Department of Food and Nutrition, BK21 FOUR, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Min-Hyun Kim
- College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
- Correspondence: (M.-H.K.); (H.K.); Tel.: +1-602-496-4163 (M.-H.K.); +82-2-2123-3125 (H.K.)
| | - Hyeyoung Kim
- Department of Food and Nutrition, BK21 FOUR, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
- Correspondence: (M.-H.K.); (H.K.); Tel.: +1-602-496-4163 (M.-H.K.); +82-2-2123-3125 (H.K.)
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Gibson K, Chu JK, Zhu S, Nguyen D, Mrázek J, Liu J, Hoover TR. A Tripartite Efflux System Affects Flagellum Stability in Helicobacter pylori. Int J Mol Sci 2022; 23:ijms231911609. [PMID: 36232924 PMCID: PMC9570263 DOI: 10.3390/ijms231911609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/23/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022] Open
Abstract
Helicobacter pylori uses a cluster of polar, sheathed flagella for swimming motility. A search for homologs of H. pylori proteins that were conserved in Helicobacter species that possess flagellar sheaths but were underrepresented in Helicobacter species with unsheathed flagella identified several candidate proteins. Four of the identified proteins are predicted to form part of a tripartite efflux system that includes two transmembrane domains of an ABC transporter (HP1487 and HP1486), a periplasmic membrane fusion protein (HP1488), and a TolC-like outer membrane efflux protein (HP1489). Deleting hp1486/hp1487 and hp1489 homologs in H. pylori B128 resulted in reductions in motility and the number of flagella per cell. Cryo-electron tomography studies of intact motors of the Δhp1489 and Δhp1486/hp1487 mutants revealed many of the cells contained a potential flagellum disassembly product consisting of decorated L and P rings, which has been reported in other bacteria. Aberrant motors lacking specific components, including a cage-like structure that surrounds the motor, were also observed in the Δhp1489 mutant. These findings suggest a role for the H. pylori HP1486-HP1489 tripartite efflux system in flagellum stability. Three independent variants of the Δhp1486/hp1487 mutant with enhanced motility were isolated. All three motile variants had the same frameshift mutation in fliL, suggesting a role for FliL in flagellum disassembly.
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Affiliation(s)
- Katherine Gibson
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
| | - Joshua K. Chu
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
| | - Shiwei Zhu
- Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA
| | - Doreen Nguyen
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
| | - Jan Mrázek
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
- Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
| | - Jun Liu
- Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA
| | - Timothy R. Hoover
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
- Correspondence: ; Tel.: +1-706-542-2675
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Anti-Helicobacter pylori, anti-Inflammatory, and Antioxidant Activities of Trunk Bark of Alstonia boonei (Apocynaceae). BIOMED RESEARCH INTERNATIONAL 2022; 2022:9022135. [PMID: 36158881 PMCID: PMC9499789 DOI: 10.1155/2022/9022135] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/25/2022] [Indexed: 12/14/2022]
Abstract
An ulcer is an erosion of the gastric mucosa that occurs following an imbalance between the aggression and protective factors and/or an infection with Helicobacter pylori (H. pylori). About 90-100% of duodenal ulcers and 70-80% of gastric ulcers are caused by H. pylori. The objective of this work was to evaluate in vitro the anti-H. pylori activity and then the anti-inflammatory and antioxidant properties of aqueous and methanol extracts of Alstonia boonei. The anti-H. pylori tests (CMI and antiureasic activity) were determined using the agar well diffusion method, the microbroth dilution method, and the measurement of ammonia production by the indophenol method; the anti-inflammatory properties were evaluated by inhibition of proteinases, denaturation of albumin, production of NO by macrophages, cell viability, and hemolysis of red blood cells by heat; then, the antioxidant properties were evaluated by the FRAP method (ferric reducing antioxidant power) and the DPPH (1,1-diphenyl-2-picrylhydrazyl) test. The results show that the best trapping of the DPPH radical was obtained with the methanol extract (EC50 = 8.91 μg/mL) compared to the aqueous extract (EC50 = 19.86 μg/mL). The methanol extract also showed greater iron-reducing activity than the aqueous extract and vitamin C. Furthermore, at the concentration of 200 μg/mL, the methanol extract showed a percentage (96.34%) strains of H. pylori higher than that of the aqueous extract (88.52%). The MIC90 of the methanol extract was lower than that of the aqueous extract. The methanol extract showed a higher percentage inhibition (85%) of urease than the aqueous extract (73%). The methanol extract at a concentration of 1000 μg/mL showed the greatest ability to inhibit proteinase activity, albumin denaturation, and red blood cell hemolysis; on the other hand, maximum cell viability and greater production of nitrite oxide by macrophages were obtained with the aqueous extract. Aqueous and methanol extracts of Alstonia boonei possess anti-H. pylori which would probably be linked to their antioxidant and anti-inflammatory properties.
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Matar G, Bilen M. Culturomics, a potential approach paving the way toward bacteriotherapy. Curr Opin Microbiol 2022; 69:102194. [PMID: 35994842 DOI: 10.1016/j.mib.2022.102194] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 12/12/2022]
Abstract
The human microbiota has been extensively studied over the past decade to describe its role in health and diseases. Numerous studies showed the presence of bacterial imbalance in a variety of human health conditions, suggesting great potential for the development of bacteriotherapies. Identifying mechanisms involving the human microbiota has been very challenging due to the complex data generated by molecular approaches and the limited number of organisms isolated by culture and described. This review summarizes the efforts done to describe the human microbiota through culturomics and the advancements in culturing the organisms residing at different body sites.
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Affiliation(s)
- Ghassan Matar
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Melhem Bilen
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.
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31
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Zhang G, Wang J, Zhao Z, Xin T, Fan X, Shen Q, Raheem A, Lee CR, Jiang H, Ding J. Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections. Cell Death Dis 2022; 13:637. [PMID: 35869043 PMCID: PMC9307826 DOI: 10.1038/s41419-022-05066-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023]
Abstract
Since the discovery of cell apoptosis, other gene-regulated cell deaths are gradually appreciated, including pyroptosis, ferroptosis, and necroptosis. Necroptosis is, so far, one of the best-characterized regulated necrosis. In response to diverse stimuli (death receptor or toll-like receptor stimulation, pathogenic infection, or other factors), necroptosis is initiated and precisely regulated by the receptor-interacting protein kinase 3 (RIPK3) with the involvement of its partners (RIPK1, TRIF, DAI, or others), ultimately leading to the activation of its downstream substrate, mixed lineage kinase domain-like (MLKL). Necroptosis plays a significant role in the host's defense against pathogenic infections. Although much has been recognized regarding modulatory mechanisms of necroptosis during pathogenic infection, the exact role of necroptosis at different stages of infectious diseases is still being unveiled, e.g., how and when pathogens utilize or evade necroptosis to facilitate their invasion and how hosts manipulate necroptosis to counteract these detrimental effects brought by pathogenic infections and further eliminate the encroaching pathogens. In this review, we summarize and discuss the recent progress in the role of necroptosis during a series of viral, bacterial, and parasitic infections with zoonotic potentials, aiming to provide references and directions for the prevention and control of infectious diseases of both human and animals.
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Affiliation(s)
- Guangzhi Zhang
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Jinyong Wang
- grid.508381.70000 0004 0647 272XShenzhen Bay Laboratory, Institute of Infectious Diseases, Shenzhen, 518000 China ,grid.258164.c0000 0004 1790 3548Institute of Respiratory Diseases, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, 518020 Guangdong China
| | - Zhanran Zhao
- grid.47840.3f0000 0001 2181 7878Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200 USA
| | - Ting Xin
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Xuezheng Fan
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Qingchun Shen
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Abdul Raheem
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China ,grid.35155.370000 0004 1790 4137Present Address: Huazhong Agricultural University, Wuhan, China
| | - Chae Rhim Lee
- grid.47840.3f0000 0001 2181 7878Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200 USA ,grid.266093.80000 0001 0668 7243Present Address: University of California, Irvine, CA USA
| | - Hui Jiang
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Jiabo Ding
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
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Neuper T, Frauenlob T, Posselt G, Horejs-Hoeck J. Beyond the gastric epithelium - the paradox of Helicobacter pylori-induced immune responses. Curr Opin Immunol 2022; 76:102208. [PMID: 35569416 DOI: 10.1016/j.coi.2022.102208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 11/03/2022]
Abstract
Chronic infections are typically characterized by an ineffective immune response to the inducing pathogen. While failing to clear the infectious microbe, the provoked inflammatory processes may cause severe tissue damage culminating in functional impairment of the affected organ. The human pathogen Helicobacter pylori is a uniquely successful Gram-negative microorganism inhabiting the gastric mucosa in approximately 50% of the world's population. This bacterial species has evolved spectacular means of evading immune surveillance and influencing host immunity, leading to a fragile equilibrium between proinflammatory and anti-inflammatory signals, the breakdown of which can have serious consequences for the host, including gastric ulceration and cancer. This review highlights novel insights into this delicate interaction between host and pathogen from an immunological perspective.
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Affiliation(s)
- Theresa Neuper
- Department of Biosciences and Medical Biology, University of Salzburg, Austria
| | - Tobias Frauenlob
- Department of Biosciences and Medical Biology, University of Salzburg, Austria; Cancer Cluster Salzburg (CCS), Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, University of Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department of Biosciences and Medical Biology, University of Salzburg, Austria; Cancer Cluster Salzburg (CCS), Austria.
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Oster P, Vaillant L, McMillan B, Velin D. The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection. Front Immunol 2022; 13:899161. [PMID: 35677057 PMCID: PMC9168074 DOI: 10.3389/fimmu.2022.899161] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori infects the gastric mucosa of a large number of humans. Although asymptomatic in the vast majority of cases, H pylori infection can lead to the development of peptic ulcers gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Using a variety of mechanisms, H pylori locally suppresses the function of the host immune system to establish chronic infection. Systemic immunomodulation has been observed in both clinical and pre-clinical studies, which have demonstrated that H pylori infection is associated with reduced incidence of inflammatory diseases, such as asthma and Crohn’s disease. The introduction of immunotherapies in the arsenal of anti-cancer drugs has revealed a new facet of H pylori-induced immune suppression. In this review, we will describe the intimate interactions between H pylori and its host, and formulate hypothtyeses describing the detrimental impact of H pylori infection on the efficacy of cancer immunotherapies.
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Noto JM, Piazuelo MB, Shah SC, Romero-Gallo J, Hart JL, Di C, Carmichael JD, Delgado AG, Halvorson AE, Greevy RA, Wroblewski LE, Sharma A, Newton AB, Allaman MM, Wilson KT, Washington MK, Calcutt MW, Schey KL, Cummings BP, Flynn CR, Zackular JP, Peek RM. Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis. J Clin Invest 2022; 132:e147822. [PMID: 35316215 PMCID: PMC9106351 DOI: 10.1172/jci147822] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shailja C Shah
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Chao Di
- Division of Protective Immunity, and
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James D Carmichael
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alese E Halvorson
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Robert A Greevy
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lydia E Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ayushi Sharma
- Creighton University School of Medicine, Omaha, Nebraska, USA
| | | | - Margaret M Allaman
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Wade Calcutt
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Bethany P Cummings
- Department of Surgery, University of California, Davis, Davis, California, USA
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Joseph P Zackular
- Division of Protective Immunity, and
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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35
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Palacios-García I, Mhuireach GA, Grasso-Cladera A, Cryan JF, Parada FJ. The 4E approach to the human microbiome: Nested interactions between the gut-brain/body system within natural and built environments. Bioessays 2022; 44:e2100249. [PMID: 35338496 DOI: 10.1002/bies.202100249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/13/2022] [Accepted: 03/15/2022] [Indexed: 12/17/2022]
Abstract
The complexity of the human mind and its interaction with the environment is one of the main epistemological debates throughout history. Recent ideas, framed as the 4E perspective to cognition, highlight that human experience depends causally on both cerebral and extracranial processes, but also is embedded in a particular sociomaterial context and is a product of historical accumulation of trajectory changes throughout life. Accordingly, the human microbiome is one of the most intriguing actors modulating brain function and physiology. Here, we present the 4E approach to the Human Microbiome for understanding mental processes from a broader perspective, encompassing one's body physiology and environment throughout their lifespan, interconnected by microbiome community structure and dynamics. We review evidence supporting the approach theoretically and motivates the study of the global set of microbial ecosystem networks encountered by a person across their lifetime (from skin to gut to natural and built environments). We furthermore trace future empirical implementation of the approach. We finally discuss novel research opportunities and clinical interventions aimed toward developing low-cost/high-benefit integrative and personalized bio-psycho-socio-environmental treatments for mental health and including the brain-gut-microbiome axis.
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Affiliation(s)
- Ismael Palacios-García
- Centro de Estudios en Neurociencia Humana y Neuropsicología. Facultad de Psicología, Universidad Diego Portales, Santiago, Chile.,Laboratorio de Psicofisiología, Escuela de Psicología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gwynne A Mhuireach
- Biology and the Built Environment Center, University of Oregon, Oregon, USA
| | - Aitana Grasso-Cladera
- Centro de Estudios en Neurociencia Humana y Neuropsicología. Facultad de Psicología, Universidad Diego Portales, Santiago, Chile
| | - John F Cryan
- Department of Anatomy & Neuroscience, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Francisco J Parada
- Centro de Estudios en Neurociencia Humana y Neuropsicología. Facultad de Psicología, Universidad Diego Portales, Santiago, Chile
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Abu-Lubad MA, Helaly GF, Haddadin WJ, Jarajreh DAK, Aqel AA, Al-Zeer MA. Loss of p53 Expression in Gastric Epithelial Cells of Helicobacter pylori-Infected Jordanian Patients. Int J Microbiol 2022; 2022:7779770. [PMID: 35369042 PMCID: PMC8967579 DOI: 10.1155/2022/7779770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/27/2021] [Accepted: 02/25/2022] [Indexed: 11/18/2022] Open
Abstract
Background Around half of the global population is chronically infected with the stomach bacterium Helicobacter pylori, making it one of the most common chronic infections worldwide. H. pylori induces the production of reactive oxygen species, DNA damage, and accelerates the degradation of the tumor suppressor protein p53, which may lead to cancer development. In this study, we investigated the relationship between H. pylori infection and the expression of p53 in gastric mucosa in a group of patients from Jordan. Methods In this retrospective case-control study, the epithelium of gastric glands in subjects chronically infected with H. pylori was examined for the expression of p53. Paraffin-embedded gastric biopsy samples from the archives for 50 Jordanian patients diagnosed with chronic H. pylori infection and 25 samples free of H. pylori infection and any other gastric abnormalities were selected. Samples were analyzed for the presence of H. pylori as well as p53 expression levels in the mucosa and submucosa by immunohistochemical analyses and Western blotting. Results H. pylori was detected in the gastric tissues of infected individuals (n = 50); whereas, no H. pylori infection was detected in uninfected healthy individuals (n = 25) using immunohistochemistry. In contrast to the noninfected samples of gastric mucosa, no nuclear p53 expression was detected in the infected samples using immunohistochemistry. In addition, the levels of p53 in H. pylori-positive samples detected by Western blotting were significantly lower than those in the negative individuals. Conclusion Our data reveal that p53 protein expression decreased in gastric mucosa of patients infected with H. pylori. The loss of this tumor suppressor may play a role in the increased risk for tumor initiation associated with H. pylori carriage.
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Affiliation(s)
- Mohammad A. Abu-Lubad
- Department of Medical Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Ghada F. Helaly
- Department of Medical Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
- Department of Microbiology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | | | - Dua'a A. K. Jarajreh
- Department of Medical Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Amin A. Aqel
- Department of Medical Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Munir A. Al-Zeer
- Department of Applied Biochemistry, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
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Robinson JM, Redvers N, Camargo A, Bosch CA, Breed MF, Brenner LA, Carney MA, Chauhan A, Dasari M, Dietz LG, Friedman M, Grieneisen L, Hoisington AJ, Horve PF, Hunter A, Jech S, Jorgensen A, Lowry CA, Man I, Mhuireach G, Navarro-Pérez E, Ritchie EG, Stewart JD, Watkins H, Weinstein P, Ishaq SL. Twenty Important Research Questions in Microbial Exposure and Social Equity. mSystems 2022; 7:e0124021. [PMID: 35089060 PMCID: PMC8725600 DOI: 10.1128/msystems.01240-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Social and political policy, human activities, and environmental change affect the ways in which microbial communities assemble and interact with people. These factors determine how different social groups are exposed to beneficial and/or harmful microorganisms, meaning microbial exposure has an important socioecological justice context. Therefore, greater consideration of microbial exposure and social equity in research, planning, and policy is imperative. Here, we identify 20 research questions considered fundamentally important to promoting equitable exposure to beneficial microorganisms, along with safeguarding resilient societies and ecosystems. The 20 research questions we identified span seven broad themes, including the following: (i) sociocultural interactions; (ii) Indigenous community health and well-being; (iii) humans, urban ecosystems, and environmental processes; (iv) human psychology and mental health; (v) microbiomes and infectious diseases; (vi) human health and food security; and (vii) microbiome-related planning, policy, and outreach. Our goal was to summarize this growing field and to stimulate impactful research avenues while providing focus for funders and policymakers.
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Affiliation(s)
- Jake M. Robinson
- University of Sheffield, Department of Landscape Architecture, Sheffield, United Kingdom
| | - Nicole Redvers
- Department of Family & Community Medicine, University of North Dakota School of Medicine & Health Sciences, Grand Forks, North Dakota, USA
| | | | - Christina A. Bosch
- Department of Literacy, Early, Bilingual and Special Education, Kremen School of Education and Human Development, California State University, Fresno, California, USA
| | - Martin F. Breed
- College of Science and Engineering, Flinders University, Bedford Park, SA, Australia
| | - Lisa A. Brenner
- University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Megan A. Carney
- School of the Environment, Florida Agricultural and Mechanical University, Tallahassee, Florida, USA
| | - Ashvini Chauhan
- University of Arizona, School of Anthropology and Center for Regional Food Studies, Tucson, Arizona, USA
| | - Mauna Dasari
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA
| | - Leslie G. Dietz
- University of Oregon, Biology and the Built Environment Center, Eugene, Oregon, USA
| | - Michael Friedman
- American International College of Arts and Sciences of Antigua, Antigua and Barbuda, West Indies
| | - Laura Grieneisen
- Department of Genetics, Cell, and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Patrick F. Horve
- University of Oregon, Institute of Molecular Biology, Eugene, Oregon, USA
| | - Ally Hunter
- Department of Student Development, University of Massachusetts, Amherst, Massachusetts, USA
| | - Sierra Jech
- University of Colorado Boulder, Department of Ecology and Evolutionary Biology, Boulder, Colorado, USA
| | - Anna Jorgensen
- Department of Landscape Architecture, University of Sheffield, Sheffield, United Kingdom
| | - Christopher A. Lowry
- Department of Integrative Physiology, Center for Neuroscience, and Center for Microbial Exploration, University of Colorado Boulder, Boulder, Colorado, USA
| | - Ioana Man
- Architectural Association School of Architecture, London, United Kingdom
| | - Gwynne Mhuireach
- Department of Architecture, University of Oregon, Eugene, Oregon, USA
| | - Edauri Navarro-Pérez
- Program of Environmental Life Sciences, School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | - Euan G. Ritchie
- School of Life and Environmental Sciences and Centre for Integrative Ecology, Deakin University, Burwood, VIC, Australia
| | - Justin D. Stewart
- Department of Ecological Science, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Harry Watkins
- St. Andrews Botanic Garden, Canongate, St. Andrews, Fife, United Kingdom
- Bio-integrated Design Lab, Bartlett School of Architecture, London, United Kingdom
| | - Philip Weinstein
- School of Public Health, The University of Adelaide, Adelaide, SA, Australia
| | - Suzanne L. Ishaq
- University of Maine, School of Food and Agriculture, Orono, Maine, USA
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Kuo YC, Yu LY, Wang HY, Chen MJ, Wu MS, Liu CJ, Lin YC, Shih SC, Hu KC. Effects of Helicobacter pylori infection in gastrointestinal tract malignant diseases: From the oral cavity to rectum. World J Gastrointest Oncol 2022; 14:55-74. [PMID: 35116103 PMCID: PMC8790410 DOI: 10.4251/wjgo.v14.i1.55] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/03/2021] [Accepted: 12/09/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) has infected approximately fifty percent of humans for a long period of time. However, improvements in the public health environment have led to a decreased chance of H. pylori infection. However, a high infection rate is noted in populations with a high incidence rate of gastric cancer (GC). The worldwide fraction of GC attributable to H. pylori is greater than 85%, and a high H. pylori prevalence is noted in gastric mucosa-associated lymphoid tissue lymphoma patients. These results indicate that the majority of GC cases can be prevented if H. pylori infection is eliminated. Because H. pylori exhibits oral-oral or fecal-oral transmission, the relationship between this microorganism and other digestive tract malignant diseases has also attracted attention. This review article provides an overview of H. pylori and the condition of the whole gastrointestinal tract environment to further understand the correlation between the pathogen and the host, thus allowing improved realization of disease presentation.
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Affiliation(s)
- Yang-Che Kuo
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Lo-Yip Yu
- Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
| | - Horng-Yuan Wang
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Ming-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan
| | - Ying-Chun Lin
- Department of Anesthesia, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Shou-Chuan Shih
- Division of Gastroenterology, Department of Internal Medicine, Health Evaluate Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
| | - Kuang-Chun Hu
- Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, MacKay Junior College of Medicine, Nursing, and Management, Taipei 10038, Taiwan
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Meng B, Epp N, Wijaya W, Mrázek J, Hoover TR. Methylation Motifs in Promoter Sequences May Contribute to the Maintenance of a Conserved m5C Methyltransferase in Helicobacter pylori. Microorganisms 2021; 9:microorganisms9122474. [PMID: 34946076 PMCID: PMC8706393 DOI: 10.3390/microorganisms9122474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 01/22/2023] Open
Abstract
DNA methylomes of Helicobacter pylori strains are complex due to the large number of DNA methyltransferases (MTases) they possess. H. pylori J99 M.Hpy99III is a 5-methylcytosine (m5C) MTase that converts GCGC motifs to Gm5CGC. Homologs of M.Hpy99III are found in essentially all H. pylori strains. Most of these homologs are orphan MTases that lack a cognate restriction endonuclease, and their retention in H. pylori strains suggest they have roles in gene regulation. To address this hypothesis, green fluorescent protein (GFP) reporter genes were constructed with six putative promoters that had a GCGC motif in the extended −10 region, and the expression of the reporter genes was compared in wild-type H. pylori G27 and a mutant lacking the M.Hpy99III homolog (M.HpyGIII). The expression of three of the GFP reporter genes was decreased significantly in the mutant lacking M.HpyGIII. In addition, the growth rate of the H. pylori G27 mutant lacking M.HpyGIII was reduced markedly compared to that of the wild type. These findings suggest that the methylation of the GCGC motif in many H. pylori GCGC-containing promoters is required for the robust expression of genes controlled by these promoters, which may account for the universal retention of M.Hpy99III homologs in H. pylori strains.
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Affiliation(s)
- Bowen Meng
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (B.M.); (N.E.); (W.W.)
| | - Naomi Epp
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (B.M.); (N.E.); (W.W.)
| | - Winsen Wijaya
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (B.M.); (N.E.); (W.W.)
| | - Jan Mrázek
- Department of Microbiology and Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA;
| | - Timothy R. Hoover
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA; (B.M.); (N.E.); (W.W.)
- Correspondence: ; Tel.: +1-706-542-2675
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Prashar A, Capurro MI, Jones NL. Under the Radar: Strategies Used by Helicobacter pylori to Evade Host Responses. Annu Rev Physiol 2021; 84:485-506. [PMID: 34672717 DOI: 10.1146/annurev-physiol-061121-035930] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. Helicobacter pylori (Hp), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Using a combination of secreted virulence factors, immune subversion, and manipulation of cellular mechanisms, Hp can colonize and persist in the hostile environment of the human stomach. Here, we review the most recent and relevant information regarding how this successful pathogen overcomes gastric epithelial host defense responses to facilitate its own survival and establish a chronic infection. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Akriti Prashar
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Mariana I Capurro
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Nicola L Jones
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada; .,Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.,Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada
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Ansari H, Tahmasebi-Birgani M, Bijanzadeh M. DNA vaccine containing Flagellin A gene induces significant immune responses against Helicobacter pylori infection: An in vivo study. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:796-804. [PMID: 34630957 PMCID: PMC8487603 DOI: 10.22038/ijbms.2021.54415.12227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/23/2021] [Indexed: 11/17/2022]
Abstract
Objective(s): Helicobacter pylori is one of the most prevalent human infectious agents that is directly involved in various upper digestive tract diseases. Although antibiotics-based therapy and proton pump inhibitors eradicate the bacteria mostly, their effectiveness has been declined recently due to emergence of antibiotic-resistant strains. Development of a DNA vaccine is a promising approach against bacterial pathogens. Genes encoding motility factors are promising immunogens to develop a DNA vaccine against H. pylori infection due to critical role of these genes in bacterial attachment and colonization within the gastric lumen. The present study aimed to synthesize a DNA vaccine construct based on the Flagellin A gene (flaA), the predominant flagellin subunit in H. pylori flagella. Materials and Methods: The coding sequence of flaA was amplified through PCR and sub-cloned in the pBudCE4.1 vector. The recombinant vector was introduced into the human dermal fibroblast cells, and its potency to express the flaA protein was analyzed using SDS-PAGE. The recombinant construct was intramuscularly (IM) injected into the mice, and the profiles of cytokines and immunoglobulins were measured using ELISA. Results: It has been found that flaA was successfully expressed in cells. Recombinant-vector also increased the serum levels of evaluated cytokines and immunoglobulins in mice. Conclusion: These findings showed that the pBudCE4.1-flaA construct was able to activate the immune responses. This study is the first step towards synthesis of recombinant-construct based on the flaA gene. Immunization with such construct may inhibit the H. pylori-associated infection; however, further experiments are urgent.
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Affiliation(s)
- Hossein Ansari
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Biotechnology, Islamic Azad University of Ahvaz, Ahvaz Branch, Ahvaz, Iran
| | - Maryam Tahmasebi-Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahdi Bijanzadeh
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Mehrotra T, Devi TB, Kumar S, Talukdar D, Karmakar SP, Kothidar A, Verma J, Kumari S, Alexander SM, Retnakumar RJ, Devadas K, Ray A, Mutreja A, Nair GB, Chattopadhyay S, Das B. Antimicrobial resistance and virulence in Helicobacter pylori: Genomic insights. Genomics 2021; 113:3951-3966. [PMID: 34619341 DOI: 10.1016/j.ygeno.2021.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/10/2021] [Accepted: 10/01/2021] [Indexed: 12/26/2022]
Abstract
Microbes evolve rapidly by modifying their genome through mutations or acquisition of genetic elements. Antimicrobial resistance in Helicobacter pylori is increasingly prevalent in India. However, limited information is available about the genome of resistant H. pylori isolated from India. Our pan- and core-genome based analyses of 54 Indian H. pylori strains revealed plasticity of its genome. H. pylori is highly heterogenous both in terms of the genomic content and DNA sequence homology of ARGs and virulence factors. We observed that the H. pylori strains are clustered according to their geographical locations. The presence of point mutations in the ARGs and absence of acquired genetic elements linked with ARGs suggest target modifications are the primary mechanism of its antibiotic resistance. The findings of the present study would help in better understanding the emergence of drug-resistant H. pylori and controlling gastric disorders by advancing clinical guidance on selected treatment regimens.
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Affiliation(s)
- Tanshi Mehrotra
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - T Barani Devi
- Microbiome Laboratory, Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
| | - Shakti Kumar
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Daizee Talukdar
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Sonali Porey Karmakar
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Akansha Kothidar
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Jyoti Verma
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Shashi Kumari
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Sneha Mary Alexander
- Microbiome Laboratory, Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
| | - R J Retnakumar
- Microbiome Laboratory, Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
| | - Krishnadas Devadas
- Department of Gastroenterology, Government Medical College, Thiruvananthapuram, Kerala, India
| | - Animesh Ray
- Department of Medicine, All India Institute of Medical, Science, New Delhi, India
| | - Ankur Mutreja
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India; Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB20QQ, United Kingdom
| | - G Balakrish Nair
- Microbiome Laboratory, Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
| | - Santanu Chattopadhyay
- Microbiome Laboratory, Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India.
| | - Bhabatosh Das
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India.
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Gomez-Ramirez U, Valencia-Mayoral P, Mendoza-Elizalde S, Murillo-Eliosa JR, Solórzano Santos F, Contreras-Rodríguez A, Zúñiga G, Aguilar-Rodea P, Jiménez-Rojas VL, Vigueras Galindo JC, Salazar-García M, Velázquez-Guadarrama N. Role of Helicobacter pylori and Other Environmental Factors in the Development of Gastric Dysbiosis. Pathogens 2021; 10:1203. [PMID: 34578235 PMCID: PMC8467233 DOI: 10.3390/pathogens10091203] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/26/2021] [Accepted: 09/08/2021] [Indexed: 11/17/2022] Open
Abstract
Microbiomes are defined as complex microbial communities, which are mainly composed of bacteria, fungi, and viruses residing in diverse regions of the human body. The human stomach consists of a unique and heterogeneous habitat of microbial communities owing to its anatomical and functional characteristics, that allow the optimal growth of characteristic bacteria in this environment. Gastric dysbiosis, which is defined as compositional and functional alterations of the gastric microbiota, can be induced by multiple environmental factors, such as age, diet, multiple antibiotic therapies, proton pump inhibitor abuse, H. pylori status, among others. Although H. pylori colonization has been reported across the world, chronic H. pylori infection may lead to serious consequences; therefore, the infection must be treated. Multiple antibiotic therapy improvements are not always successful because of the lack of adherence to the prescribed antibiotic treatment. However, the abuse of eradication treatments can generate gastric dysbiotic states. Dysbiosis of the gastric microenvironment induces microbial resilience, due to the loss of relevant commensal bacteria and simultaneous colonization by other pathobiont bacteria, which can generate metabolic and physiological changes or even initiate and develop other gastric disorders by non-H. pylori bacteria. This systematic review opens a discussion on the effects of multiple environmental factors on gastric microbial communities.
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Affiliation(s)
- Uriel Gomez-Ramirez
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Pedro Valencia-Mayoral
- Departamento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (P.V.-M.); (J.R.M.-E.)
| | - Sandra Mendoza-Elizalde
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
| | - Juan Rafael Murillo-Eliosa
- Departamento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (P.V.-M.); (J.R.M.-E.)
| | - Fortino Solórzano Santos
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
| | - Araceli Contreras-Rodríguez
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Gerardo Zúñiga
- Laboratorio de Variación Biológica y Evolución, Departamento de Zoología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Pamela Aguilar-Rodea
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
| | - Verónica Leticia Jiménez-Rojas
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
| | - Juan Carlos Vigueras Galindo
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
| | - Marcela Salazar-García
- Laboratorio de Investigación en Biología del Desarrollo y Teratogénesis Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico;
| | - Norma Velázquez-Guadarrama
- Laboratorio de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (U.G.-R.); (S.M.-E.); (F.S.S.); (P.A.-R.); (V.L.J.-R.); (J.C.V.G.)
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Grover K, Gregory S, Gibbs JF, Emenaker NJ. A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach. J Gastrointest Oncol 2021; 12:S290-S300. [PMID: 34422393 DOI: 10.21037/jgo-2019-gi-07] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 06/10/2020] [Indexed: 12/27/2022] Open
Abstract
The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.
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Affiliation(s)
- Karan Grover
- Department of Surgery, Rutgers Biomedical Health Sciences-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Stephanie Gregory
- Department of Surgery, Rutgers Biomedical Health Sciences-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - John F Gibbs
- Department of Surgery, Hackensack Meridian Health School of Medicine at Seton Hall University, Nutley, NJ, USA
| | - Nancy J Emenaker
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
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Soutto M, Bhat N, Khalafi S, Zhu S, Poveda J, Garcia-Buitrago M, Zaika A, El-Rifai W. NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1. Cancer Cell Int 2021; 21:444. [PMID: 34419066 PMCID: PMC8380333 DOI: 10.1186/s12935-021-02140-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 08/08/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models. METHODS To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays. RESULTS Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models. CONCLUSION Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.
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Affiliation(s)
- Mohammed Soutto
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, 33136-1015, USA
| | - Nadeem Bhat
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Shayan Khalafi
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Shoumin Zhu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Julio Poveda
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Alexander Zaika
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, 33136-1015, USA
| | - Wael El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, 33136-1015, USA.
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Effect of Helicobacter pylori and Helminth Coinfection on the Immune Response to Mycobacterium tuberculosis. Curr Microbiol 2021; 78:3351-3371. [PMID: 34251513 DOI: 10.1007/s00284-021-02604-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023]
Abstract
Tuberculosis remains one of the main causes of morbidity and mortality worldwide despite decades of efforts to eradicate the disease. Although the immune response controls the infection in most infected individuals (90%), the ability of the bacterium to persist throughout the host's life leads to a risk of reactivation. Underlying conditions including human immunodeficiency virus (HIV) infection, organ transplantation, and immunosuppressive therapies are considered risk factors for progression to active disease. However, many individuals infected with Mycobacterium tuberculosis may develop clinical disease in the absence of underlying immunosuppression. It is also possible that unknown conditions may drive the progression to disease. The human microbiota can be an important modulator of the immune system; it can not only trigger inflammatory disorders, but also drive the response to other infectious diseases. In developing countries, chronic mucosal infections with Helicobacter pylori and helminths may be particularly important, as these infections frequently coexist throughout the host's life. However, little is known about the interactions of these pathogens with the immune system and their effects on M. tuberculosis clinical disease, if any. In this review, we discuss the potential effects of H. pylori and helminth co-infections on the immune response to M. tuberculosis. This may contribute to our understanding of host-pathogen interactions and in designing new strategies for the prevention and control of tuberculosis.
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47
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Steiner TM, Lettl C, Schindele F, Goebel W, Haas R, Fischer W, Eisenreich W. Substrate usage determines carbon flux via the citrate cycle in Helicobacter pylori. Mol Microbiol 2021; 116:841-860. [PMID: 34164854 DOI: 10.1111/mmi.14775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/07/2021] [Accepted: 06/19/2021] [Indexed: 12/31/2022]
Abstract
Helicobacter pylori displays a worldwide infection rate of about 50%. The Gram-negative bacterium is the main reason for gastric cancer and other severe diseases. Despite considerable knowledge about the metabolic inventory of H. pylori, carbon fluxes through the citrate cycle (TCA cycle) remained enigmatic. In this study, different 13 C-labeled substrates were supplied as carbon sources to H. pylori during microaerophilic growth in a complex medium. After growth, 13 C-excess and 13 C-distribution were determined in multiple metabolites using GC-MS analysis. [U-13 C6 ]Glucose was efficiently converted into glyceraldehyde but only less into TCA cycle-related metabolites. In contrast, [U-13 C5 ]glutamate, [U-13 C4 ]succinate, and [U-13 C4 ]aspartate were incorporated at high levels into intermediates of the TCA cycle. The comparative analysis of the 13 C-distributions indicated an adaptive TCA cycle fully operating in the closed oxidative direction with rapid equilibrium fluxes between oxaloacetate-succinate and α-ketoglutarate-citrate. 13 C-Profiles of the four-carbon intermediates in the TCA cycle, especially of malate, together with the observation of an isocitrate lyase activity by in vitro assays, suggested carbon fluxes via a glyoxylate bypass. In conjunction with the lack of enzymes for anaplerotic CO2 fixation, the glyoxylate bypass could be relevant to fill up the TCA cycle with carbon atoms derived from acetyl-CoA.
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Affiliation(s)
- Thomas M Steiner
- Bavarian NMR Center-Structural Membrane Biochemistry, Department of Chemistry, Technische Universität München, Garching, Germany
| | - Clara Lettl
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, München, Germany.,German Center for Infection Research (DZIF), Partner Site Munich, München, Germany
| | - Franziska Schindele
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, München, Germany
| | - Werner Goebel
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, München, Germany
| | - Rainer Haas
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, München, Germany.,German Center for Infection Research (DZIF), Partner Site Munich, München, Germany
| | - Wolfgang Fischer
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, München, Germany.,German Center for Infection Research (DZIF), Partner Site Munich, München, Germany
| | - Wolfgang Eisenreich
- Bavarian NMR Center-Structural Membrane Biochemistry, Department of Chemistry, Technische Universität München, Garching, Germany
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Kalani M, Kouhpayeh SA, Shamsdin SA, Jamshidi J, Choopanizadeh M, Keighobadi G, Moravej A. Association of interleukin-17 A gene variants and susceptibility to H. pylori related gastric diseases. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Singh S, Bastos-Amador P, Thompson JA, Truglio M, Yilmaz B, Cardoso S, Sobral D, Soares MP. Glycan-based shaping of the microbiota during primate evolution. eLife 2021; 10:e67450. [PMID: 34009123 PMCID: PMC8133779 DOI: 10.7554/elife.67450] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022] Open
Abstract
Genes encoding glycosyltransferases can be under relatively high selection pressure, likely due to the involvement of the glycans synthesized in host-microbe interactions. Here, we used mice as an experimental model system to investigate whether loss of α-1,3-galactosyltransferase gene (GGTA1) function and Galα1-3Galβ1-4GlcNAcβ1-R (αGal) glycan expression affects host-microbiota interactions, as might have occurred during primate evolution. We found that Ggta1 deletion shaped the composition of the gut microbiota. This occurred via an immunoglobulin (Ig)-dependent mechanism, associated with targeting of αGal-expressing bacteria by IgA. Systemic infection with an Ig-shaped microbiota inoculum elicited a less severe form of sepsis compared to infection with non-Ig-shaped microbiota. This suggests that in the absence of host αGal, antibodies can shape the microbiota towards lower pathogenicity. Given the fitness cost imposed by bacterial sepsis, we infer that the observed reduction in microbiota pathogenicity upon Ggta1 deletion in mice may have contributed to increase the frequency of GGTA1 loss-of-function mutations in ancestral primates that gave rise to humans.
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Roberts-Thomson IC. How did the ancient bacterium, Helicobacter pylori, cause an epidemic of chronic duodenal ulceration? JGH OPEN 2021; 5:636-642. [PMID: 34124378 PMCID: PMC8171156 DOI: 10.1002/jgh3.12560] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
The association of Helicobacter pylori with chronic duodenal ulceration was a seminal observation in the short history of gastroenterology. However, H. pylori is now known to be an ancient bacterium, whereas there is persuasive evidence that the epidemic of duodenal ulceration began in the second half of the 19th century and continued into the second half of the 20th century. Possible explanations for the epidemic include genomic changes in the organism and environmental or other influences on the human host. While genomic changes resulted in the appearance of virulence factors, these seem likely to have appeared thousands of years ago with minimal effects on gastritis because of coexisting suppression of gastric immunity. In contrast, the emergence of duodenal ulceration is best explained by a change in the pattern of gastritis from inflammation involving the antrum and body in most individuals to a significant minority (10-20%) with antral gastritis but with relative sparing of the body of the stomach. In the latter group, the increase in serum gastrin (particularly G17) associated with antral gastritis had trophic effects on gastric parietal cells with an increase in the parietal cell mass and hypersecretion of gastric acid. Hypersecretion of acid is seen as the major risk factor for duodenal ulceration with significant contributions from environmental factors including smoking and use of nonsteroidal, anti-inflammatory drugs. Host factors favoring changes in the pattern of gastritis include delayed acquisition of infection and improved nutrition; both with enhancing effects on mucosal immunity.
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Affiliation(s)
- Ian C Roberts-Thomson
- Faculty of Health and Medical Sciences University of Adelaide Adelaide South Australia Australia
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