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Pu S, Zhuang Z, Liu N, Luo Q, Zhang D. Research progress on the relationship between Helicobacter pylori infection and iron deficiency anemia. Front Microbiol 2025; 16:1552630. [PMID: 40201441 PMCID: PMC11975960 DOI: 10.3389/fmicb.2025.1552630] [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: 12/28/2024] [Accepted: 03/11/2025] [Indexed: 04/10/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection affects around half of the global population and is a globally highly prevalent pathogen that is closely linked not only to gastrointestinal diseases such as chronic atrophic gastritis, functional dyspepsia and peptic ulcer but also to the development and progression of a variety of extra-gastrointestinal diseases. Numerous studies have shown the correlation between H. pylori infection and iron-deficiency anemia (IDA). The prevalence of H. pylori infection is higher in individuals with IDA, and the hemoglobin level of patients with IDA can be increased to different degrees or even returned to normal following active H. pylori eradication. However, this conclusion is still controversial. In this paper, a comprehensive literature search was conducted using the PubMed/MEDLINE/Web of Science database, combining the following terms: "Helicobacter pylori," "Helicobacter pylori infection," "iron deficiency anemia," "iron deficiency," "iron absorption," "iron malabsorption," "serum iron," "hemoglobin," "pathogenesis," "mechanism," and "eradication therapy." Through extensive literature searches, the correlation between H. pylori infection and IDA, its potential mechanism, and the efficacy of H. pylori eradication therapy in IDA patients have been comprehensively discussed. We conclude that the majority of existing studies have confirmed the correlation between H. pylori infection and IDA, indicating that patients with H. pylori infection are more likely to develop IDA and that the prevalence of H. pylori infection is higher in individuals with IDA. Compared with iron supplementation alone, combining H. pylori eradication with iron supplementation is more effective in treating IDA, particularly in unexplained or refractory IDA cases. These findings provide valuable insights for clinicians managing patients with unexplained or refractory IDA.
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Affiliation(s)
- Sugui Pu
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, China
| | - Ze Zhuang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, China
| | - Na Liu
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, China
| | - Qian Luo
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, China
| | - Dekui Zhang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China
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Zhang Y, Yan Z, Jiao Y, Feng Y, Zhang S, Yang A. Innate Immunity in Helicobacter pylori Infection and Gastric Oncogenesis. Helicobacter 2025; 30:e70015. [PMID: 40097330 PMCID: PMC11913635 DOI: 10.1111/hel.70015] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 03/19/2025]
Abstract
Helicobacter pylori is an extremely common cause of gastritis that can lead to gastric adenocarcinoma over time. Approximately half of the world's population is infected with H. pylori, making gastric cancer the fourth leading cause of cancer-related deaths worldwide. Innate immunity significantly contributes to systemic and local immune responses, maintains homeostasis, and serves as the vital link to adaptive immunity, and in doing so, mediates H. pylori infection outcomes and consequent cancer risk and development. The gastric innate immune system, composed of gastric epithelial and myeloid cells, is uniquely challenged by its need to interact simultaneously and precisely with commensal microbiota, exogenous pathogens, ingested substances, and endogenous exfoliated cells. Additionally, innate immunity can be detrimental by promoting chronic infection and fibrosis, creating an environment conducive to tumor development. This review summarizes and discusses the complex role of innate immunity in H. pylori infection and subsequent gastric oncogenesis, and in doing so, provides insights into how these pathways can be exploited to improve prevention and treatment.
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Affiliation(s)
- Yuheng Zhang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Eight‐Year Medical Doctor Program, Peking Union Medical CollegeChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Zhiyu Yan
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Department of Medicine, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yuhao Jiao
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Department of Medicine, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yunlu Feng
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Shengyu Zhang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
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Duan Y, Xu Y, Dou Y, Xu D. Helicobacter pylori and gastric cancer: mechanisms and new perspectives. J Hematol Oncol 2025; 18:10. [PMID: 39849657 PMCID: PMC11756206 DOI: 10.1186/s13045-024-01654-2] [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: 08/20/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world's population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis-key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori's role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.
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Affiliation(s)
- Yantao Duan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yonghu Xu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi Dou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dazhi Xu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Shires CB, Duhon M, Calligas J, Dewan K. The Incidence and Implication of Helicobacter pylori Infection in the Setting of Reinke's Edema. J Voice 2025:S0892-1997(24)00440-5. [PMID: 39848848 DOI: 10.1016/j.jvoice.2024.12.011] [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: 07/11/2024] [Revised: 09/23/2024] [Accepted: 12/04/2024] [Indexed: 01/25/2025]
Abstract
OBJECTIVE(S) To assess the prevalence of Helicobacter pylori in Reinke's edema patients. To evaluate and compare the disease severity of patients who are H. pylori positive with those who are H. pylori negative. METHODS In this prospective study, subjects were recruited at the time of Reinke's edema diagnosis using flexible laryngoscopy between March of 2022 through August of 2022. Participants completed a Voice Handicap Index (VHI-10) survey and then underwent a H. pylori IgG blood test to identify infection. The severity of Reinke's edema, grade, and type were determined by a fellowship trained laryngologist. RESULTS Thirty one patients participated. The cohort was 19% male. 38.7% of the cohort had a positive H. pylori test. Men had significantly greater smoking exposure in pack years than women (P = 0.003). Interestingly, the total VHI-10 score was significantly greater in patients negative for H. pylori (P = 0.05). This was also true for four of the VHI-10 domains. Patients positive for H. pylori had significantly more severe Reinke's edema in terms of type (P = 0.03) and grade (P = 0.01). CONCLUSIONS There is a significant relationship between H. pylori status and the severity of Reinke's edema, with patients H. pylori positive having a greater grade and type of Reinke's edema. There is also a significant inverse relationship between H. pylori status and dysphonia, a subjective Reinke's symptom. LEVEL OF EVIDENCE III.
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Affiliation(s)
| | - Miranda Duhon
- School of Medicine, Louisiana State University, Shreveport, LA 71103
| | - Jason Calligas
- Department of Otolaryngology - Head and Neck Surgery, School of Medicine, Louisiana State University, Shreveport, LA 71103
| | - Karuna Dewan
- Department of Otolaryngology - Head and Neck Surgery, School of Medicine, Louisiana State University, Shreveport, LA 71103
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Hrizat AS, Shahin AA, Mafarjeh BM, Atawneh MA, Gharaibeh K, Rumman N, Sultan M. Association of Helicobacter pylori Infection with Pediatric Asthma in Palestine. Pediatr Gastroenterol Hepatol Nutr 2025; 28:27-37. [PMID: 39839471 PMCID: PMC11745570 DOI: 10.5223/pghn.2025.28.1.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 11/02/2024] [Accepted: 11/08/2024] [Indexed: 01/23/2025] Open
Abstract
Purpose Significant debate exists on the association between Helicobacter pylori infection and childhood asthma. We aimed to explore this association in a cohort of children in Palestine while estimating the prevalence of H. pylori in this population. Methods We conducted a prospective case-control study among children aged 6-15 years in Palestine, including 44 asthma cases diagnosed by pediatric pulmonologists and 99 age-matched healthy controls recruited through cluster sampling from schools. H. pylori status was determined using a stool antigen test. Asthma severity was assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Data on recent antibiotic use, which could affect H. pylori status, were collected for both groups. Multiple logistic regression analyzed the association between H. pylori and asthma, adjusting for age and sex. The chi-square test assessed the impact of antibiotic use on H. pylori status. Results The prevalence of H. pylori infection in the study population was 45%. Children with asthma had a lower prevalence of H. pylori infection compared to healthy controls (32% vs. 51%, adjusted odds ratios, 0.46; 95% confidence interval, 0.22-0.99; p=0.04). Antibiotic use in the past month or year did not significantly impact H. pylori status. Among children with asthma, H. pylori infection rates did not vary by asthma severity (p=0.05). Conclusion H. pylori infection is associated with a reduced risk of asthma in children, suggesting a potential protective role. Further prospective cohort studies are warranted to clarify the mechanisms underlying this association.
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Affiliation(s)
- Alaa S. Hrizat
- Al-Quds University, Faculty of Medicine, Palestine
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | | | - Banan M Mafarjeh
- Al-Quds University, Faculty of Medicine, Palestine
- Pediatric Department, Palestine Medical Complex, Ramallah, Palestine
| | | | - Kamel Gharaibeh
- Al-Quds University, Faculty of Medicine, Palestine
- Division of Pulmonary Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Nisreen Rumman
- Al-Quds University, Faculty of Medicine, Palestine
- Pediatric Department, Makassed Hospital, East Jerusalem, Palestine
| | - Mutaz Sultan
- Al-Quds University, Faculty of Medicine, Palestine
- Pediatric Department, Makassed Hospital, East Jerusalem, Palestine
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Oka S, Higuchi T, Furukawa H, Shimada K, Okamoto A, Fujimori M, Hashimoto A, Komiya A, Saisho K, Yoshikawa N, Katayama M, Matsui T, Fukui N, Migita K, Tohma S. Helicobacter pylori Seroprevalence in Rheumatoid Arthritis Patients with Interstitial Lung Disease. Biomark Insights 2024; 19:11772719241297171. [PMID: 39640205 PMCID: PMC11618895 DOI: 10.1177/11772719241297171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 10/09/2024] [Indexed: 12/07/2024] Open
Abstract
Background Rheumatoid arthritis (RA) is complicated with interstitial lung disease (ILD). Gastroesophageal reflux disease is prevented by Helicobacter pylori infection and is a predisposing factor for idiopathic pulmonary fibrosis. However, the prevalence of H. pylori infection in RA patients with ILD has not been sufficiently investigated. Objective In this study, we analyzed anti-H. pylori antibodies in RA patients with ILD. Design Case-control observational study. Methods Anti-H. pylori antibodies were analyzed in the sera of RA patients using a commercially available enzyme-linked immunosorbent assay kit. Results The positivity of anti-H. pylori antibodies in RA with ILD (n = 30 [18.0%], P = .0227), usual interstitial pneumonia (n = 10 [14.3%], P = .0212), and airway disease (n = 30 [18.0%], P = .0227) was significantly lower than that of RA without chronic lung disease (n = 78 [27.5%]). The positivity of anti-H. pylori antibodies was also lower in RA with chronic lung disease (n = 68 [18.2%], P = .0059). Multiple logistic regression analyses showed that the presence of anti-H. pylori antibodies was independently and protectively associated with chronic lung disease in RA. Conclusion The seroprevalence of H. pylori was lower in RA with ILD. H. pylori infection prevented ILD in patients with RA by protecting them from gastroesophageal reflux disease.
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Affiliation(s)
- Shomi Oka
- Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
| | - Takashi Higuchi
- Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan
| | - Hiroshi Furukawa
- Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
| | - Kota Shimada
- Department of Rheumatology, NHO Sagamihara National Hospital, Minami-ku, Sagamihara, Japan
- Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan
| | - Akira Okamoto
- Department of Rheumatology, NHO Himeji Medical Center, Himeji, Japan
| | - Misuzu Fujimori
- Department of Rheumatology, NHO Himeji Medical Center, Himeji, Japan
| | - Atsushi Hashimoto
- Department of Rheumatology, NHO Sagamihara National Hospital, Minami-ku, Sagamihara, Japan
- Department of Internal Medicine, Sagami Seikyou Hospital, Minami-ku, Sagamihara, Japan
| | - Akiko Komiya
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
- Department of Clinical Laboratory, NHO Sagamihara National Hospital, Minami-ku, Sagamihara, Japan
| | - Koichiro Saisho
- Department of Orthopedics/Rheumatology, NHO Miyakonojo Medical Center, Miyakonojo, Japan
- Tanimura Hospital, Nobeoka, Japan
| | | | - Masao Katayama
- Department of Internal Medicine, NHO Nagoya Medical Center, Naka-ku, Nagoya, Japan
| | - Toshihiro Matsui
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
- Department of Rheumatology, NHO Sagamihara National Hospital, Minami-ku, Sagamihara, Japan
| | - Naoshi Fukui
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro-ku, Tokyo, Japan
| | - Kiyoshi Migita
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shigeto Tohma
- Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
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Islam MZ, Jozipovic D, Lopez PA, Krych L, Correia BSB, Bertram HC, Hansen AK, Hansen CHF. Wild-Mouse-Derived Gut Microbiome Transplantation in Laboratory Mice Partly Alleviates House-Dust-Mite-Induced Allergic Airway Inflammation. Microorganisms 2024; 12:2499. [PMID: 39770703 PMCID: PMC11728220 DOI: 10.3390/microorganisms12122499] [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: 11/20/2024] [Revised: 11/26/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025] Open
Abstract
Laboratory mice are instrumental for preclinical research but there are serious concerns that the use of a clean standardized environment for specific-pathogen-free (SPF) mice results in poor bench-to-bedside translation due to their immature immune system. The aim of the present study was to test the importance of the gut microbiota in wild vs. SPF mice for evaluating host immune responses in a house-dust-mite-induced allergic airway inflammation model without the influence of pathogens. The wild mouse microbiome reduced histopathological changes and TNF-α in the lungs and serum when transplanted to microbiota-depleted mice compared to mice transplanted with the microbiome from SPF mice. Moreover, the colonic gene expression of Gata3 was significantly lower in the wild microbiome-associated mice, whereas Muc1 was more highly expressed in both the ileum and colon. Intestinal microbiome and metabolomic analyses revealed distinct profiles associated with the wild-derived microbiome. The wild-mouse microbiome thus partly reduced sensitivity to house-dust-mite-induced allergic airway inflammation compared to the SPF mouse microbiome, and preclinical studies using this model should consider using both 'dirty' rewilded and SPF mice for testing new therapeutic compounds due to the significant effects of their respective microbiomes and derived metabolites on host immune responses.
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Affiliation(s)
- Md Zohorul Islam
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark (A.K.H.)
- Section on Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
- CSIRO Health & Biosecurity, Australian Centre for Disease Preparedness, Geelong, VIC 3220, Australia
| | - Danica Jozipovic
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark (A.K.H.)
| | - Pablo Atienza Lopez
- Department of Food Science, Faculty of Science, University of Copenhagen, 1958 Frederiksberg, Denmark
| | - Lukasz Krych
- Department of Food Science, Faculty of Science, University of Copenhagen, 1958 Frederiksberg, Denmark
| | | | | | - Axel Kornerup Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark (A.K.H.)
| | - Camilla Hartmann Friis Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark (A.K.H.)
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Wade TJ, Mistry JH, Augustine SAJ, Griffin SM, Kobylanski J, Styles J, Sams E, Hudgens E, Kowalcyk M, Cochran W, Ward H, Egorov A. Salivary Antibody Responses to Potentially Waterborne and Environmentally Transmitted Infections Among Two Tribal Nations in the Southwest United States. J Epidemiol Glob Health 2024; 14:1619-1632. [PMID: 39495475 PMCID: PMC11652455 DOI: 10.1007/s44197-024-00315-4] [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: 07/24/2024] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
PURPOSE Tribal Nations disproportionately lack access to safe drinking water and can be adversely affected by other water quality and environmental concerns. Such conditions could lead to an increase in the transmission of waterborne, environmental and hygiene related infections. We collected saliva samples from attendees at two Tribal Nation annual festivals and tested them for salivary immunoglobulin G (IgG) responses to selected common infections using an in-house multiplex immunoassay. Antibody responses were compared to responses from a previously conducted study in the midwestern United States. METHODS We collected and tested 531 samples from Tribal Nation sites and used data on 453 previously analyzed samples from the Midwest site. Logistic and linear regression models were used to model a binary classification of seropositivity and the intensity of the antibody response, respectively. RESULTS Seroprevalence of chronic infections (Helicobacter pylori and Toxoplasma gondii) were generally consistent with estimates from population-based studies. Compared to the Midwest site, one of the Tribal Nation sites had consistently higher median antibody responses to several noroviruses. The Tribal Nation sites had a lower seroprevalence of hepatitis E virus antibodies. At the Tribal Nation sites, farm residents had higher antibody responses to Cryptosporidium spp., bottled water consumption was associated with lower responses to Cryptosporidium spp., animal contact was associated with T. gondii seropositivity, and recent diarrhea was associated with higher norovirus antibody responses. Helicobacter pylori seropositivity was associated with reduced odds of reporting allergies. CONCLUSION This study demonstrated the application of a multiplex salivary immunoassay in Tribal Nations to provide insights regarding selected common pathogens which are transmitted through different transmission pathways including person-to-person contacts, contaminated food, soil and drinking water.
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Affiliation(s)
- Timothy J Wade
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA.
| | - Jatin H Mistry
- Region 6, United States Environmental Protection Agency, Dallas, TX, USA
| | - Swinburne A J Augustine
- Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA
| | - Shannon M Griffin
- Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA
| | - Jason Kobylanski
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Jennifer Styles
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pediatrics, Division of Allergy and Immunology, Food Allergy Initiative, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA
| | - Elizabeth Sams
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Edward Hudgens
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Megan Kowalcyk
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Wesley Cochran
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | | | - Andrey Egorov
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
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Hasanzadeh Haghighi F, Menbari S, Mohammadzadeh R, Pishdadian A, Farsiani H. Developing a potent vaccine against Helicobacter pylori: critical considerations and challenges. Expert Rev Mol Med 2024; 27:e12. [PMID: 39584502 PMCID: PMC11964096 DOI: 10.1017/erm.2024.19] [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: 06/27/2023] [Revised: 01/13/2024] [Accepted: 08/07/2024] [Indexed: 11/26/2024]
Abstract
Helicobacter pylori (H. pylori) is closely associated with gastric cancer and peptic ulcers. The effectiveness of antibiotic treatment against H. pylori is diminished by the emergence of drug-resistant strains, side effects, high cost and reinfections. Given the circumstances, it is imperative to develop a potent vaccination targeting H. pylori. Understanding H. pylori's pathogenicity and the host's immune response is essential to developing a vaccine. Furthermore, vaccine evaluation necessitates the careful selection of design formulation. This review article aims to provide a concise overview of the considerations involved in selecting the optimal antigen, adjuvant, vaccine delivery system and laboratory animal model for vaccine formulation. Furthermore, we will discuss some significant obstacles in the realm of developing a potent vaccination against H. pylori.
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Affiliation(s)
- Faria Hasanzadeh Haghighi
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaho Menbari
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Roghayeh Mohammadzadeh
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Pishdadian
- Department of Immunology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Hadi Farsiani
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Liang Z, Zhang C, Liu X, Yang K, Xiong Z, Liang B, Mai J, Xiao X, Liu J, Yang P, Xu D, Zhou Z. Neutrophil-activating protein in Bacillus spores inhibits casein allergy via TLR2 signaling. Front Immunol 2024; 15:1428079. [PMID: 39564136 PMCID: PMC11574345 DOI: 10.3389/fimmu.2024.1428079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 10/10/2024] [Indexed: 11/21/2024] Open
Abstract
Background Milk allergy commonly occurs in children, mainly caused by bovine-derived casein (CAS) protein. Neutrophil-activating protein (NAP) of Helicobacter pylori plays an immunomodulatory role with potential to suppress Th2-type immune responses. Bacillus subtilis (B. subtilis) spores are commonly used as oral vectors for drug delivery. Objective To investigate whether recombinantly expressed NAP on B. subtilis spores could be an effective treatment for CAS allergy in mouse. Methods After CAS sensitization, mice were orally administered B. subtilis spores expressing recombinant NAP for 6 weeks. Allergic symptoms and parameters were evaluated after CAS challenge oral gavage, including allergic inflammation, splenic cytokines, and serum-specific antibodies. Protein levels of Toll-like receptor 2 (TLR2) and c-JUN in the jejunum tissue were measured by western blot. Bone marrow-derived macrophages (BMDMs) were stimulated with inactivated NAP spores to measure the influence on cytokine profiles in vitro. Results NAP recombinant spore treatment significantly reduced allergic symptoms and intestinal inflammation. Interleukin-12 and interferon-gamma levels increased, whereas serum CAS-specific IgG1 and IgE levels decreased. TLR2 and c-JUN expression levels were elevated in the jejunal tissue. Inactivated NAP spores polarized BMDMs to the M1 phenotype and enhanced cytokine expression, which were inhibited by a TLR2 neutralizing antibody. Conclusion NAP offers a new strategy in the treatment of CAS allergy by inhibiting the Th2 response, while eliciting macrophages to promote Th1 immune responses.
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Affiliation(s)
- Zhuwei Liang
- Clinical Laboratory, Longgang Maternity and Child Institute of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City), Shenzhen, Guangdong, China
- Clinical Laboratory, Guangdong Provincial Second Hospital of Traditional Chinese Medicine (Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine), Guangzhou, Guangdong, China
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Chao Zhang
- National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
| | - Xiaoyu Liu
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Kaiyue Yang
- Clinical Laboratory, Longgang Maternity and Child Institute of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City), Shenzhen, Guangdong, China
| | - Zhile Xiong
- Clinical Laboratory, Longgang Maternity and Child Institute of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City), Shenzhen, Guangdong, China
- Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Bingshao Liang
- Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jialiang Mai
- Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
- Clinical Laboratory, Foshan Maternity and Child Health Hospital, Foshan, Guangdong, China
| | - Xiaojun Xiao
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Jie Liu
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Pingchang Yang
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Damo Xu
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
- Department of Respiratory & Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Zhenwen Zhou
- Clinical Laboratory, Longgang Maternity and Child Institute of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City), Shenzhen, Guangdong, China
- The State Key Laboratory of Respiratory Disease for Allergy, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, Guangdong, China
- Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
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11
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Kløve S, Stinson SE, Romme FO, Butt J, Graversen KB, Lund MAV, Fonvig CE, Waterboer T, Perez-Perez GI, Hansen T, Holm JC, Andersen SB. Helicobacter pylori seropositivity associates with hyperglycemia, but not obesity, in Danish children and adolescents. BMC Med 2024; 22:379. [PMID: 39256870 PMCID: PMC11389555 DOI: 10.1186/s12916-024-03591-w] [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: 03/01/2024] [Accepted: 08/27/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Helicobacter pylori colonizes the human stomach and may affect the inflammatory response, hormone production related to energy regulation, and gastrointestinal microbiota composition. Previous studies have explored a potential association between H. pylori infection and pediatric obesity with varying results. Considering the immunomodulatory effects of early-life infection with H. pylori that can confer beneficial effects, we hypothesized that we would find an inverse relationship between H. pylori seropositivity and obesity among Danish children and adolescents. METHODS We assessed H. pylori seroprevalence in 713 subjects from an obesity clinic cohort and 990 subjects from a population-based cohort, aged 6 to 19 years, and examined its association with obesity and other cardiometabolic risk factors. RESULTS No association was found between H. pylori and body mass index standard deviation score (BMI SDS). H. pylori seropositivity was, however, significantly associated with higher fasting plasma glucose levels and the prevalence of hyperglycemia. CONCLUSION While we did not find an association between H. pylori seropositivity and BMI SDS, we observed a significant association with higher fasting plasma glucose levels and increased prevalence of hyperglycemia, suggesting that H. pylori infection may contribute to impaired glucose regulation in Danish children and adolescents.
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Affiliation(s)
- Sigri Kløve
- Center for Evolutionary Hologenomics, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1353, Denmark.
| | - Sara E Stinson
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Fie O Romme
- Center for Evolutionary Hologenomics, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1353, Denmark
| | - Julia Butt
- Infections and Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Katrine B Graversen
- Center for Evolutionary Hologenomics, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1353, Denmark
| | - Morten A V Lund
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
- The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Pediatrics, Holbæk Hospital, Holbæk, 4300, Denmark
| | - Cilius E Fonvig
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
- The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Pediatrics, Holbæk Hospital, Holbæk, 4300, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | | | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Jens-Christian Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
- The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Pediatrics, Holbæk Hospital, Holbæk, 4300, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Sandra B Andersen
- Center for Evolutionary Hologenomics, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1353, Denmark.
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12
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Hu X, Li Y, Cao Y, Shi F, Shang L. The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity. Biochim Biophys Acta Rev Cancer 2024; 1879:189156. [PMID: 39032540 DOI: 10.1016/j.bbcan.2024.189156] [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: 12/01/2023] [Revised: 07/11/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.
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Affiliation(s)
- Xudong Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Li Shang
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China.
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13
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Rook GAW. Evolution and the critical role of the microbiota in the reduced mental and physical health associated with low socioeconomic status (SES). Neurosci Biobehav Rev 2024; 161:105653. [PMID: 38582194 DOI: 10.1016/j.neubiorev.2024.105653] [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: 11/28/2023] [Accepted: 04/03/2024] [Indexed: 04/08/2024]
Abstract
The evolution of the gut-microbiota-brain axis in animals reveals that microbial inputs influence metabolism, the regulation of inflammation and the development of organs, including the brain. Inflammatory, neurodegenerative and psychiatric disorders are more prevalent in people of low socioeconomic status (SES). Many aspects of low SES reduce exposure to the microbial inputs on which we are in a state of evolved dependence, whereas the lifestyle of wealthy citizens maintains these exposures. This partially explains the health deficit of low SES, so focussing on our evolutionary history and on environmental and lifestyle factors that distort microbial exposures might help to mitigate that deficit. But the human microbiota is complex and we have poor understanding of its functions at the microbial and mechanistic levels, and in the brain. Perhaps its composition is more flexible than the microbiota of animals that have restricted habitats and less diverse diets? These uncertainties are discussed in relation to the encouraging but frustrating results of attempts to treat psychiatric disorders by modulating the microbiota.
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Affiliation(s)
- Graham A W Rook
- Centre for Clinical Microbiology, Department of infection, UCL (University College London), London, UK.
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14
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Siegel NA, Jimenez MT, Rocha CS, Rolston M, Dandekar S, Solnick JV, Miller LA. Helicobacter pylori infection in infant rhesus macaque monkeys is associated with an altered lung and oral microbiome. Sci Rep 2024; 14:9998. [PMID: 38693196 PMCID: PMC11063185 DOI: 10.1038/s41598-024-59514-5] [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: 08/24/2023] [Accepted: 04/11/2024] [Indexed: 05/03/2024] Open
Abstract
It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. From a cohort of 4-7 month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In order of relative abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. In comparison to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.
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Affiliation(s)
- Noah A Siegel
- California National Primate Research Center, University of California Davis, Davis, CA, USA
| | - Monica T Jimenez
- California National Primate Research Center, University of California Davis, Davis, CA, USA
| | - Clarissa Santos Rocha
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA
| | - Matthew Rolston
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA
| | - Satya Dandekar
- California National Primate Research Center, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA
| | - Jay V Solnick
- California National Primate Research Center, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA
| | - Lisa A Miller
- California National Primate Research Center, University of California Davis, Davis, CA, USA.
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
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15
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Elghannam MT, Hassanien MH, Ameen YA, Turky EA, ELattar GM, ELRay AA, ELTalkawy MD. Helicobacter pylori and oral-gut microbiome: clinical implications. Infection 2024; 52:289-300. [PMID: 37917397 PMCID: PMC10954935 DOI: 10.1007/s15010-023-02115-7] [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: 07/06/2023] [Accepted: 10/09/2023] [Indexed: 11/04/2023]
Abstract
More than half of the world's population are colonized with H. pylori; however, the prevalence varies geographically with the highest incidence in Africa. H. pylori is probably a commensal organism that has been associated with the development of gastritis, ulcers, and gastric cancer. H. pylori alone is most probably not enough for the development of gastric carcinoma, but evidence for its association with the disease is high and has, therefore, been classified by the International Agency for Research on Cancer as a Class 1 carcinogen. Bacteroidetes and Fusobacteria positively coexisted during H. pylori infection along the oral-gut axis. The eradication therapy required to treat H. pylori infection can also have detrimental consequences for the gut microbiota, leading to a decreased alpha diversity. Therefore, therapy regimens integrated with probiotics may abolish the negative effects of antibiotic therapy on the gut microbiota. These eradication therapies combined with probiotics have also higher rates of eradication, when compared to standard treatments, and are associated with reduced side effects, improving the patient's compliance. The eradication therapy not only affects gut microbiome but also affects the oral microbiome with robust predominance of harmful bacteria. However, there have been reports of a protective role of H. pylori in Barrett's esophagus, esophageal adenocarcinoma, eosinophilic esophagitis, IBD, asthma, and even multiple sclerosis. Therefore, eradication therapy should be carefully considered, and test to treat policy should be tailored to specific communities especially in highly endemic areas. Supplementation of probiotics, prebiotics, herbals, and microbial metabolites to reduce the negative effects of eradication therapy should be considered. After failure of many eradication attempts, the benefits of H. pylori eradication should be carefully balanced against the risk of adverse effects especially in the elderly, persons with frailty, and intolerance to antibiotics.
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Affiliation(s)
- Maged T Elghannam
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Moataz H Hassanien
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Yosry A Ameen
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Emad A Turky
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Gamal M ELattar
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Ahmed A ELRay
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mohammed D ELTalkawy
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt
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16
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Malfertheiner P, Schulz C, Hunt RH. Helicobacter pylori Infection: A 40-Year Journey through Shifting the Paradigm to Transforming the Management. Dig Dis 2024; 42:299-308. [PMID: 38447558 DOI: 10.1159/000538079] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 02/26/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) was discovered 40 years ago and has set a milestone in human medicine. The discovery led to rejection of the dogma of the acidic stomach as a sterile organ and requested to rewrite the chapters on gastric pathophysiology and gastroduodenal diseases. SUMMARY Over a period of 40 years following the discovery, more than 50,000 articles can be retrieved in PubMed as of today and illustrate the amount and the intensity of research around the role of this bacterium. H. pylori emerged as cause of chronic gastritis and principal cause of peptic ulcer disease (PUD). Eradication of H. pylori became standard of care in management in PUD. The importance of this was highlighted in 2005 with the Nobel Prize in Medicine awarded to Barry Marshall and Robin Warren. H. pylori became eventually recognized for its oncogenic potential in the stomach and as the main risk factor for gastric cancer development. KEY MESSAGES H. pylori gastritis is defined as infectious disease and requires therapy in all infected individuals. Strategies of gastric cancer prevention and development of therapies to overcome the increasing antibiotic resistance are main targets in clinical research of today.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Medical Department 2, LMU, Munich, Germany
| | - Christian Schulz
- Medical Department 2, LMU, Munich, Germany,
- Partner Site Munich, DZIF, Braunschweig, Germany,
| | - Richard H Hunt
- Farncombe Family Digestive Health Research Institute and Division of Gastroenterology, Department of Medicine, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
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17
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Reuter S, Raspe J, Taube C. Microbes little helpers and suppliers for therapeutic asthma approaches. Respir Res 2024; 25:29. [PMID: 38218816 PMCID: PMC10787474 DOI: 10.1186/s12931-023-02660-7] [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: 10/20/2023] [Accepted: 12/28/2023] [Indexed: 01/15/2024] Open
Abstract
Bronchial asthma is a prevalent and increasingly chronic inflammatory lung disease affecting over 300 million people globally. Initially considered an allergic disorder driven by mast cells and eosinophils, asthma is now recognized as a complex syndrome with various clinical phenotypes and immunological endotypes. These encompass type 2 inflammatory endotypes characterized by interleukin (IL)-4, IL-5, and IL-13 dominance, alongside others featuring mixed or non-eosinophilic inflammation. Therapeutic success varies significantly based on asthma phenotypes, with inhaled corticosteroids and beta-2 agonists effective for milder forms, but limited in severe cases. Novel antibody-based therapies have shown promise, primarily for severe allergic and type 2-high asthma. To address this gap, novel treatment strategies are essential for better control of asthma pathology, prevention, and exacerbation reduction. One promising approach involves stimulating endogenous anti-inflammatory responses through regulatory T cells (Tregs). Tregs play a vital role in maintaining immune homeostasis, preventing autoimmunity, and mitigating excessive inflammation after pathogenic encounters. Tregs have demonstrated their ability to control both type 2-high and type 2-low inflammation in murine models and dampen human cell-dependent allergic airway inflammation. Furthermore, microbes, typically associated with disease development, have shown immune-dampening properties that could be harnessed for therapeutic benefits. Both commensal microbiota and pathogenic microbes have demonstrated potential in bacterial-host interactions for therapeutic purposes. This review explores microbe-associated approaches as potential treatments for inflammatory diseases, shedding light on current and future therapeutics.
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Affiliation(s)
- Sebastian Reuter
- Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany.
| | - Jonas Raspe
- Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany
| | - Christian Taube
- Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany
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18
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Rook GAW. The old friends hypothesis: evolution, immunoregulation and essential microbial inputs. FRONTIERS IN ALLERGY 2023; 4:1220481. [PMID: 37772259 PMCID: PMC10524266 DOI: 10.3389/falgy.2023.1220481] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/18/2023] [Indexed: 09/30/2023] Open
Abstract
In wealthy urbanised societies there have been striking increases in chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel diseases. There has also been an increase in the prevalence of individuals with systemically raised levels of inflammatory biomarkers correlating with increased risk of metabolic, cardiovascular and psychiatric problems. These changing disease patterns indicate a broad failure of the mechanisms that should stop the immune system from attacking harmless allergens, components of self or gut contents, and that should terminate inappropriate inflammation. The Old Friends Hypothesis postulates that this broad failure of immunoregulation is due to inadequate exposures to the microorganisms that drive development of the immune system, and drive the expansion of components such as regulatory T cells (Treg) that mediate immunoregulatory mechanisms. An evolutionary approach helps us to identify the organisms on which we are in a state of evolved dependence for this function (Old Friends). The bottom line is that most of the organisms that drive the regulatory arm of the immune system come from our mothers and family and from the natural environment (including animals) and many of these organisms are symbiotic components of a healthy microbiota. Lifestyle changes that are interrupting our exposure to these organisms can now be identified, and many are closely associated with low socioeconomic status (SES) in wealthy countries. These insights will facilitate the development of education, diets and urban planning that can correct the immunoregulatory deficit, while simultaneously reducing other contributory factors such as epithelial damage.
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Affiliation(s)
- Graham A. W. Rook
- Centre for Clinical Microbiology, Department of Infection, UCL (University College London), London, United Kingdom
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19
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Ansari KK, Wagh V, Saifi AI, Saifi I, Chaurasia S. Advancements in Understanding Gastric Cancer: A Comprehensive Review. Cureus 2023; 15:e46046. [PMID: 37900456 PMCID: PMC10611549 DOI: 10.7759/cureus.46046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/22/2023] [Indexed: 10/31/2023] Open
Abstract
As a complex and difficult condition, gastric cancer (GC) continues to have a big impact on the world's health. The goal of this review article is to give a thorough summary of the most recent developments and research discoveries in the field of stomach cancer. The review discusses a wide range of topics, such as the epidemiology and risk factors for GC, molecular insights into its pathogenesis, the use of biomarkers in diagnosis and prognosis, current and novel therapeutic approaches, and the intriguing potential of immunotherapy. In addition, procedures for surgery, therapy strategies, and imaging modalities for diagnosis and staging are examined. The paper emphasizes how crucial it is to comprehend the tumor microenvironment and how it affects the course of the disease. Overall, this review provides a comprehensive assessment of the current body of knowledge, highlights research gaps, and suggests future lines of inquiry to enhance the treatment of GC.
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Affiliation(s)
- Khizer K Ansari
- Medicine and Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Vasant Wagh
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Azeem I Saifi
- Microbiology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Iram Saifi
- Radiology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sharad Chaurasia
- Medicine and Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
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20
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Siegel NA, Jimenez MT, Rocha CS, Rolston M, Dandekar S, Solnick JV, Miller LA. Helicobacter pylori Infection in Infant Rhesus Macaque Monkeys is Associated with an Altered Lung and Oral Microbiome. RESEARCH SQUARE 2023:rs.3.rs-3225953. [PMID: 37609264 PMCID: PMC10441512 DOI: 10.21203/rs.3.rs-3225953/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Background It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. Results From a cohort of 4-7-month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In relative order of abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. Relative to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. Conclusions We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.
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21
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Shi L, Zhang D. Association of Dietary Inflammation Index and Helicobacter pylori Immunoglobulin G Seropositivity in US Adults: A Population-Based Study. Mediators Inflamm 2023; 2023:8880428. [PMID: 37545737 PMCID: PMC10403320 DOI: 10.1155/2023/8880428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 08/08/2023] Open
Abstract
Background Dietary patterns play important role in Helicobacter pylori (H. pylori) infection. We aimed to investigate the potential relationship between Dietary Inflammation Index (DII) and H. pylori infection in US adults. Methods This cross-sectional study was based on National Health and Nutrition Examination Survey (1999-2000). Individuals aged ≥20 years who provided a 24 hr dietary intake history and underwent H. pylori testing were included in the analysis. Multivariate weighted logistic regression analysis, smooth curve fitting, and subgroup analysis were used to investigate the relationship between DII and H. pylori infection. Subgroup analyses were based on demographic and clinical variables. Results There were 4,000 individuals enrolled in our final analysis. The overall mean age was 45.92 years and 46.77% were males. The overall prevalence of H. pylori infection in the study population was 45.9%. The smooth curve fitting analysis indicated a near-linear relationship between DII and H. pylori. In multivariate weighted logistic regression analysis, the odds ratio (OR) of DII is 1.17 (95% confidence interval (CI), 1.09-1.27) for H. pylori infection. In subgroup analysis, DII still increased the risk of H. pylori infection independently. Conclusions The increased DII levels were associated with an increased risk of H. pylori infection among US adults. Further studies are needed to elucidate the exact mechanisms of DII and H. pylori infection.
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Affiliation(s)
- Lin Shi
- Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dan Zhang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, 99 West Huai-hai Road, Xuzhou 221002, Jiangsu, China
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Raspe J, Schmitz MS, Barbet K, Caso GC, Cover TL, Müller A, Taube C, Reuter S. Therapeutic properties of Helicobacter pylori-derived vacuolating cytotoxin A in an animal model of chronic allergic airway disease. Respir Res 2023; 24:178. [PMID: 37415170 PMCID: PMC10324189 DOI: 10.1186/s12931-023-02484-5] [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] [Received: 05/05/2023] [Accepted: 06/26/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND It has previously been shown that the Helicobacter pylori (H. pylori)-derived molecule vacuolating cytotoxin A (VacA) could be suitable for the treatment of allergic airway disease. The therapeutic activity of the protein, which acts through modulation of dendritic cells (DC) and regulatory T cells (Tregs), was demonstrated in murine short-term acute models. The aim of this study is to further evaluate the therapeutic potential of VacA by determining the effectiveness of different application routes and the suitability of the protein for treating the chronic phase of allergic airway disease. METHODS VacA was administered by the intraperitoneal (i.p.), oral (p.o.) or intratracheal (i.t.) routes, and long-term therapeutic effectiveness, allergic airway disease hallmarks, and immune phenotype were analyzed in murine models of acute and chronic allergic airway disease. RESULTS Administration of VacA via the i.p., p.o or i.t. routes was associated with a reduction in airway inflammation. The i.p. route showed the most consistent effect in reducing airway inflammation and i.p. treatment with VacA was the only treatment that significantly reduced mucus cell hyperplasia. In a murine model of chronic allergic airway disease, both short- and long-term treatment with VacA showed a therapeutic effect, with a reduction in a variety of asthma hallmarks, including bronchoalveolar lavage eosinophilia, lung inflammation and goblet cell metaplasia. Short-term treatment was associated with induction of Tregs, while repetitive long-term administration of VacA influenced immunological memory in the lung. CONCLUSIONS In addition to showing therapeutic efficacy in short-term models, treatment with VacA also appeared to be effective in suppressing inflammation in a chronic airway disease model. The observation that treatment was effective after administration via several different routes highlights the potential of VacA as a therapeutic agent with different routes of administration in humans.
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Affiliation(s)
- Jonas Raspe
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen - Ruhrlandklinik, Tueschener Weg 40, Essen, 45239, Germany.
| | - Mona S Schmitz
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen - Ruhrlandklinik, Tueschener Weg 40, Essen, 45239, Germany
| | - Kimberly Barbet
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen - Ruhrlandklinik, Tueschener Weg 40, Essen, 45239, Germany
| | - Georgia C Caso
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Timothy L Cover
- Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System Nashville, Nashville, TN, USA
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Christian Taube
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen - Ruhrlandklinik, Tueschener Weg 40, Essen, 45239, Germany
| | - Sebastian Reuter
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen - Ruhrlandklinik, Tueschener Weg 40, Essen, 45239, Germany
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Ravikumara M. Helicobacter pylori in children: think before you kill the bug! Therap Adv Gastroenterol 2023; 16:17562848231177610. [PMID: 37361453 PMCID: PMC10285598 DOI: 10.1177/17562848231177610] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/06/2023] [Indexed: 06/28/2023] Open
Abstract
Since the discovery of Helicobacter pylori (H. pylori) as the causative organism for gastric and duodenal ulcers four decades ago and subsequent recognition as class 1 gastric carcinogen, countless numbers of studies have been conducted and papers published, on the efficacy of various management strategies to eradicate the infection. In adults, a global consensus by the experts in the field concluded that H. pylori gastritis is an infectious disease and requires treatment irrespective of the presence or absence of symptoms due to the potential for serious complication like peptic ulcer disease and gastric neoplasia. However, although more than half the world's population harbors H. pylori, these serious complications occur only in a small minority of the infected population, even less so in childhood. More importantly, there is accumulating evidence for beneficial role of H. pylori against many chronic health conditions, from several epidemiological and laboratory studies. No doubt, eradication therapy is indicated in children with H. pylori-related peptic ulcer disease. Even though the pediatric guidelines from various learned societies recommend against a "test and treat" strategy, this is not always adhered to. With the accumulating evidence of the possible beneficial role of H. pylori, it is time to pause and think, are we causing more harm than good by eradicating H. pylori in every child who has this bug?
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Adejumo AC, Labonte P, Bukong TN. Relationship Between Recreational Cannabis Use and Helicobacter pylori Infection. Cannabis Cannabinoid Res 2023; 8:537-546. [PMID: 34748370 PMCID: PMC10249739 DOI: 10.1089/can.2021.0139] [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] [Indexed: 11/13/2022] Open
Abstract
Background: Cannabis plant extracts suppress gastric acid secretion and inflammation, and promote gastroduodenal ulcer healing, all of which are triggered by Helicobacter Pylori infection (HPI). Here, we evaluate the association between cannabis use and HPI among a representative community sample. Materials and Methods: We identified respondents who completed cannabis use questions and were tested for HPI (H. pylori IgG antibody seropositivity) from the National Health and Nutrition Examination Survey III dataset (n=4556). Cannabis usage was categorized as ever-use (ever, never), cumulative lifetime use (>10-times, 1-10-times, never), or recent use (>31-days-ago, within-31-days, never). We calculated the crude and adjusted risk (prevalence rate ratio, cPRR and aPRR) of having HPI with cannabis use using generalized Poisson models (SAS 9.4). The models were adjusted for demographics and risk factors for HPI. Results: The prevalence of HPI was lower among ever versus never cannabis users (18.6% vs. 33%, p<0.0001). Cannabis use was associated with a decreased risk of HPI (cPRR: 0.56 confidence interval [95% CI: 0.47-0.67]; p<0.0001), which persisted after adjusting for demographics (aPRR: 0.75 [95% CI: 0.63-0.90]; p=0.0016) and comorbidities (aPRR: 0.79 [95% CI: 0.66-0.95]; p=0.0145). Further, individuals with >10-times lifetime cannabis use had a decreased risk of HPI compared with those with 1-10-times lifetime use (aPRR: 0.70 [95% CI: 0.55-0.89]; p=0.0011) and never-users (aPRR: 0.65 [95% CI: 0.50-0.84]; p=0.0002). Conclusion: Recreational cannabis use is associated with diminished risk of HPI. These observations suggest the need for additional research assessing the effects of medical cannabis formulations on HPI.
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Affiliation(s)
- Adeyinka Charles Adejumo
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrick Labonte
- Armand-Frappier Santé Biotechnologie Research Centre-INRS, Laval, Québec, Canada
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Alashkar Alhamwe B, López JF, Zhernov Y, von Strandmann EP, Karaulov A, Kolahian S, Geßner R, Renz H. Impact of local human microbiota on the allergic diseases: Organ-organ interaction. Pediatr Allergy Immunol 2023; 34:e13976. [PMID: 37366206 DOI: 10.1111/pai.13976] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 05/22/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023]
Abstract
The homogeneous impact of local dysbiosis on the development of allergic diseases in the same organ has been thoroughly studied. However, much less is known about the heterogeneous influence of dysbiosis within one organ on allergic diseases in other organs. A comprehensive analysis of the current scientific literature revealed that most of the relevant publications focus on only three organs: gut, airways, and skin. Moreover, the interactions appear to be mainly unidirectional, that is, dysbiotic conditions of the gut being associated with allergic diseases of the airways and the skin. Similar to homogeneous interactions, early life appears to be not only a crucial period for the formation of the microbiota in one organ but also for the later development of allergic diseases in other organs. In particular, we were able to identify a number of specific bacterial and fungal species/genera in the intestine that were repeatedly associated in the literature with either increased or decreased allergic diseases of the skin, like atopic dermatitis, or the airways, like allergic rhinitis and asthma. The reported studies indicate that in addition to the composition of the microbiome, also the relative abundance of certain microbial species and the overall diversity are associated with allergic diseases of the corresponding organs. As anticipated for human association studies, the underlying mechanisms of the organ-organ crosstalk could not be clearly resolved yet. Thus, further work, in particular experimental animal studies are required to elucidate the mechanisms linking dysbiotic conditions of one organ to allergic diseases in other organs.
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Affiliation(s)
- Bilal Alashkar Alhamwe
- Institute of Laboratory Medicine, Member of the German Center for Lung Research (DZL), and the Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany
- College of Pharmacy, International University for Science and Technology (IUST), Daraa, Syria
| | - Juan-Felipe López
- Institute for Immunological Research, University of Cartagena, Cartagena, Colombia
| | - Yury Zhernov
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - Elke Pogge von Strandmann
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany
| | - Alexander Karaulov
- Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Saeed Kolahian
- Institute of Laboratory Medicine, Member of the German Center for Lung Research (DZL), and the Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Reinhard Geßner
- Institute of Laboratory Medicine, Member of the German Center for Lung Research (DZL), and the Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Harald Renz
- Institute of Laboratory Medicine, Member of the German Center for Lung Research (DZL), and the Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
- Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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Reyes VE. Helicobacter pylori and Its Role in Gastric Cancer. Microorganisms 2023; 11:1312. [PMID: 37317287 PMCID: PMC10220541 DOI: 10.3390/microorganisms11051312] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/08/2023] [Accepted: 05/15/2023] [Indexed: 06/16/2023] Open
Abstract
Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and the promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities, and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and mitigating the burden of this life-threatening disease. This review aims to provide an overview of our current understanding of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection.
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Affiliation(s)
- Victor E Reyes
- Department of Pediatrics and Microbiology & Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0372, USA
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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: 50] [Impact Index Per Article: 25.0] [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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Reuter S, Raspe J, Uebner H, Contoyannis A, Pastille E, Westendorf AM, Caso GC, Cover TL, Müller A, Taube C. Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease. Front Immunol 2023; 14:1092801. [PMID: 36761723 PMCID: PMC9902502 DOI: 10.3389/fimmu.2023.1092801] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/03/2023] [Indexed: 01/26/2023] Open
Abstract
Background Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions. Methods Murine models of allergic airway diseases, and murine and human in vitro models were used. Results In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo. Conclusion H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease.
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Affiliation(s)
- Sebastian Reuter
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen- Ruhrlandklinik, Essen, Germany
| | - Jonas Raspe
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen- Ruhrlandklinik, Essen, Germany
| | - Hendrik Uebner
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen- Ruhrlandklinik, Essen, Germany
| | - Alexandros Contoyannis
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen- Ruhrlandklinik, Essen, Germany
| | - Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Georgia C. Caso
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Timothy L. Cover
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
- Veterans Affairs Tennessee Valley Healthcare System Nashville, Nashville, TN, United States
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Christian Taube
- Department of Pulmonary Medicine, Experimental Pneumology, University Hospital Essen- Ruhrlandklinik, Essen, Germany
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Reyes VE. Helicobacter pylori Immune Response in Children Versus Adults. MEDICAL RESEARCH ARCHIVES 2022; 10:3370. [PMID: 37936946 PMCID: PMC10629867 DOI: 10.18103/mra.v10i12.3370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
H. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.
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Affiliation(s)
- Victor E. Reyes
- Department of Pediatrics, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555-0372 USA
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Belén LH, Beltrán JF, Pessoa A, Castillo RL, de Oliveira Rangel-Yagui C, Farías JG. Helicobacter pyloril-asparaginase: a study of immunogenicity from an in silico approach. 3 Biotech 2022; 12:286. [PMID: 36276451 PMCID: PMC9489821 DOI: 10.1007/s13205-022-03359-0] [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: 05/06/2022] [Accepted: 09/12/2022] [Indexed: 11/27/2022] Open
Abstract
Helicobacter pylori has become the causal agent of multiple forms of gastric disease worldwide, including gastric cancer. The enzyme l-asparaginase (ASNase) has been studied as a virulence factor. In this work, we performed an in silico investigation to characterize the immunological profile of H. pylori ASNase (HpASNase) to ascertain the possible implication of HpASNase immunogenicity in the H. pylori virulence mechanism. We applied a workflow based on bioinformatics tools, which, by calculating the relative frequency of immunogenic T-cell and B-cell epitopes, allowed us to predict the immunogenicity and allergenicity of HpASNase in silico. We also visualized the epitopes by mapping them into the native structure of the enzyme. We report for the first time the T-cell and B-cell epitope composition that contributes to the immunogenicity of this HpASNase, as well as the regions that could generate a hypersensitivity response in humans. ASNase from H. pylori resulted in highly immunogenic and allergenic. The high immunogenicity of HpASNase could imply the pathogenic mechanisms of H. pylori. This knowledge could be important for the development of new drugs against H. pylori infections. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-022-03359-0.
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Affiliation(s)
- Lisandra Herrera Belén
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomas, Santiago, Chile
- Department of Chemical Engineering, Faculty of Engineering and Science, Universidad de La Frontera, Avda. Francisco Salazar 01145, P.O. Box: 54-D, Temuco, Chile
| | - Jorge F. Beltrán
- Department of Chemical Engineering, Faculty of Engineering and Science, Universidad de La Frontera, Avda. Francisco Salazar 01145, P.O. Box: 54-D, Temuco, Chile
| | - Adalberto Pessoa
- Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences, Universidad de Sao Paulo, São Paulo, Brazil
| | - Rodrigo L. Castillo
- Department of Internal Medicine East, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Carlota de Oliveira Rangel-Yagui
- Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences, Universidad de Sao Paulo, São Paulo, Brazil
| | - Jorge G. Farías
- Department of Chemical Engineering, Faculty of Engineering and Science, Universidad de La Frontera, Avda. Francisco Salazar 01145, P.O. Box: 54-D, Temuco, Chile
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Wang D, Chen Y, Ding Y, Tu J. Inverse association between Helicobacter pylori infection and childhood asthma in a physical examination population: a cross-sectional study in Chongqing, China. BMC Pediatr 2022; 22:615. [PMID: 36289457 PMCID: PMC9597970 DOI: 10.1186/s12887-022-03682-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/30/2022] [Indexed: 01/06/2023] Open
Abstract
Background Childhood asthma has substantial effects on children's health. It is important to identify factors in early life that influence childhood asthma. Accumulating evidence indicates that Helicobacter pylori may protect against allergic diseases. This study aimed to evaluate the relationship between H. pylori infection and pediatric asthma in Chongqing, China. Materials and methods This cross-sectional study included healthy children aged 4–18 years who underwent a 13C urea breath test during medical checkups in 2021. All medical information was extracted from electronic medical records and a big data system. Logistic regression was used to evaluate the association between H. pylori infection and pediatric asthma, and multivariate regression models were adjusted for covariates. Results In our study, 2241 participants, including 1240 boys (55.33%) and 1001 girls (44.67%), underwent urea breath testing (average age: 8.67 ± 2.70 years). Among them, 292 (13.03%) were positive for H. pylori and 152 (6.78%) had asthma. The rates of asthma diagnosis in H. pylori-negative and -positive children were 7.23% and 3.77%, respectively (odds ratio = 1.995; 95% confidence interval: 1.003–3.968; P < .05). Furthermore, family history of asthma and the percentage of eosinophils in routine blood examination were associated with childhood asthma; however, the body mass index, platelet count, and serum vitamin D level were not. Conclusions We demonstrated a significant inverse association between H. pylori infection and pediatric asthma in Chongqing, China. Further studies are required to determine the causal association and underlying mechanisms to prevent and control childhood asthma.
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Affiliation(s)
- Donghai Wang
- grid.488412.3Department of Respiratory Disease, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Yuxia Chen
- grid.488412.3Department of Gastroenterology, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Ding
- grid.488412.3Department of Child Health Care, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Jinwei Tu
- grid.488412.3Department of Child Health Care, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
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Civelek Z, Urgancı N, Usta M, Özgüven MB. Prevalence of <i>Helicobacter pylori</i> Infection in Pediatric Patients With Celiac Disease. CYPRUS JOURNAL OF MEDICAL SCIENCES 2022. [DOI: 10.4274/cjms.2021.2021-50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Old but New: Group IIA Phospholipase A 2 as a Modulator of Gut Microbiota. Metabolites 2022; 12:metabo12040352. [PMID: 35448539 PMCID: PMC9029192 DOI: 10.3390/metabo12040352] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/15/2022] Open
Abstract
Among the phospholipase A2 (PLA2) superfamily, the secreted PLA2 (sPLA2) family contains 11 mammalian isoforms that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using sPLA2-deficient or -overexpressed mouse strains, along with mass spectrometric lipidomics to determine sPLA2-driven lipid pathways, have revealed the diverse pathophysiological roles of sPLA2s in various biological events. In general, individual sPLA2s exert their specific functions within tissue microenvironments, where they are intrinsically expressed through hydrolysis of extracellular phospholipids. Recent studies have uncovered a new aspect of group IIA sPLA2 (sPLA2-IIA), a prototypic sPLA2 with the oldest research history among the mammalian PLA2s, as a modulator of the gut microbiota. In the intestine, Paneth cell-derived sPLA2-IIA acts as an antimicrobial protein to shape the gut microbiota, thereby secondarily affecting inflammation, allergy, and cancer in proximal and distal tissues. Knockout of intestinal sPLA2-IIA in BALB/c mice leads to alterations in skin cancer, psoriasis, and anaphylaxis, while overexpression of sPLA2-IIA in Pla2g2a-null C57BL/6 mice induces systemic inflammation and exacerbates arthritis. These phenotypes are associated with notable changes in gut microbiota and fecal metabolites, are variable in different animal facilities, and are abrogated after antibiotic treatment, co-housing, or fecal transfer. These studies open a new mechanistic action of this old sPLA2 and add the sPLA2 family to the growing list of endogenous factors capable of affecting the microbe–host interaction and thereby systemic homeostasis and diseases.
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Meier HCS, Sandler DP, Wilkerson J, Miller FW, Dinse GE, Parks CG. Hygiene Hypothesis Indicators and Prevalence of Antinuclear Antibodies in US Adolescents. Front Immunol 2022; 13:789379. [PMID: 35154106 PMCID: PMC8832391 DOI: 10.3389/fimmu.2022.789379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/07/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmunity prevalence, as measured by antinuclear antibodies (ANA), is increasing in U.S. adolescents. Improved hygiene and cleaner environments in childhood may reduce exposure to infections and other immune challenges, resulting in improper immune responses to later-life exposures. We examined associations of hygiene hypothesis indicators, including asthma, allergies, and antibodies to infectious agents, with ANA prevalence, measured by HEp-2 immunofluorescence, in adolescents (aged 12-19 years) over a 25-year time span in the National Health and Nutrition Examination Survey (NHANES) (N=2,709), adjusting for age, sex, race/ethnicity, body mass index, education and survey cycle, overall and within individual time periods, using logistic regression. Prevalence of ANA in adolescents increased from 5.0% in 1988-1991 to 12.8% in 2011-2012. ANA were positively associated with diagnosis of asthma in early childhood (OR: 2.07, CI: 1.09-3.99) and the effect estimate for current hay fever was elevated but not statistically significant (OR: 1.55, CI: 0.85-2.84). Fewer than 2% of those with ANA in 1988-1991 had been diagnosed with asthma, compared with 18% in 1999-2000, and 27% in 2003-2004 and 2011-2012. ANA trended negatively with Helicobacter pylori antibodies (OR: 0.49, CI: 0.24-0.99). ANA may be useful as an additional indicator of inadequate immune education in adolescence, a critical period of growth and development.
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Affiliation(s)
- Helen C S Meier
- Population, Neurodevelopment and Genetics Program, Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
| | - Dale P Sandler
- Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
| | - Jesse Wilkerson
- Public Health & Scientific Research, Social and Scientific Systems, Durham, NC, United States
| | - Frederick W Miller
- Environmental Autoimmunity Group, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
| | - Gregg E Dinse
- Public Health & Scientific Research, Social and Scientific Systems, Durham, NC, United States
| | - Christine G Parks
- Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
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Abstract
Healthy development and function of essentially all physiological systems and organs, including the brain, require exposure to the microbiota of our mothers and of the natural environment, especially in early life. We also know that some infections, if we survive them, modulate the immune system in relevant ways. If we study the evolution of the immune and metabolic systems, we can understand how these requirements developed and the nature of the organisms that we need to encounter. We can then begin to identify the mechanisms of the beneficial effects of these exposures. Against this evolutionary background, we can analyze the ways in which the modern urban lifestyle, particularly for individuals experiencing low socioeconomic status (SES), results in deficient or distorted microbial exposures and microbiomes. Thus, an evolutionary approach facilitates the identification of practical solutions to the growing scandal of health disparities linked to inequality.
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Oster P, Vaillant L, Riva E, McMillan B, Begka C, Truntzer C, Richard C, Leblond MM, Messaoudene M, Machremi E, Limagne E, Ghiringhelli F, Routy B, Verdeil G, Velin D. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut 2022; 71:457-466. [PMID: 34253574 PMCID: PMC8862014 DOI: 10.1136/gutjnl-2020-323392] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 06/24/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE In this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies. DESIGN Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of H. pylori-infected mice. In humans, we evaluated the correlation between H. pylori seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC). RESULTS In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8+ T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8+ T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for H. pylori seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, H. pylori seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy. CONCLUSION Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that H. pylori serology would be a powerful tool to personalize cancer immunotherapy treatment.
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Affiliation(s)
- Paul Oster
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Laurie Vaillant
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Erika Riva
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Brynn McMillan
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Christina Begka
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Caroline Truntzer
- Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France
| | - Corentin Richard
- Research Centre for the University of Montréal (CRCHUM), Hematology-Oncology Division, Department of Medicine, University of Montreal Healthcare Centre (CHUM), Montreal, Quebec, Canada
| | - Marine M Leblond
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Meriem Messaoudene
- Research Centre for the University of Montréal (CRCHUM), Hematology-Oncology Division, Department of Medicine, University of Montreal Healthcare Centre (CHUM), Montreal, Quebec, Canada
| | - Elisavet Machremi
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Emeric Limagne
- Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France
| | | | - Bertrand Routy
- Research Centre for the University of Montréal (CRCHUM), Hematology-Oncology Division, Department of Medicine, University of Montreal Healthcare Centre (CHUM), Montreal, Quebec, Canada
| | - Gregory Verdeil
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Dominique Velin
- Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Miki Y, Taketomi Y, Kidoguchi Y, Yamamoto K, Muramatsu K, Nishito Y, Park J, Hosomi K, Mizuguchi K, Kunisawa J, Soga T, Boilard E, B. Gowda SG, Ikeda K, Arita M, Murakami M. Group IIA secreted phospholipase A2 controls skin carcinogenesis and psoriasis by shaping the gut microbiota. JCI Insight 2022; 7:152611. [PMID: 35076024 PMCID: PMC8855835 DOI: 10.1172/jci.insight.152611] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 12/01/2021] [Indexed: 12/22/2022] Open
Abstract
Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A2 (sPLA2-IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA2-IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA2-IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota. Metagenome, transcriptome, and metabolome analyses have revealed that sPLA2-IIA deficiency alters the gut microbiota, accompanied by notable changes in the intestinal expression of genes related to immunity and metabolism, as well as in the levels of various blood metabolites and fecal bacterial lipids, suggesting that sPLA2-IIA contributes to shaping of the gut microbiota. The skin phenotypes in Pla2g2a–/– mice are lost (a) when they are cohoused with littermate WT mice, resulting in the mixing of the microbiota between the genotypes, or (b) when they are housed in a more stringent pathogen-free facility, where Pla2g2a expression in WT mice is low and the gut microbial compositions in both genotypes are nearly identical. Thus, our results highlight a potentially new aspect of sPLA2-IIA as a modulator of gut microbiota, perturbation of which affects distal skin responses.
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Affiliation(s)
- Yoshimi Miki
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo (UTokyo), Tokyo, Japan
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science (TMIMS), Tokyo, Japan
| | - Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo (UTokyo), Tokyo, Japan
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science (TMIMS), Tokyo, Japan
| | - Yuh Kidoguchi
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science (TMIMS), Tokyo, Japan
- School of Science and Engineering, Tokyo Denki University, Saitama, Japan
| | - Kei Yamamoto
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science (TMIMS), Tokyo, Japan
- Division of Bioscience and Bioindustry, Tokushima University, Tokushima, Japan
| | - Kazuaki Muramatsu
- School of Science and Engineering, Tokyo Denki University, Saitama, Japan
| | | | - Jonguk Park
- Artificial Intelligence Center for Health and Biomedical Research and
| | - Koji Hosomi
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Osaka, Japan
| | - Kenji Mizuguchi
- Artificial Intelligence Center for Health and Biomedical Research and
- Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Jun Kunisawa
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Osaka, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Eric Boilard
- Centre de Recherche du CHU de Québec, Centre de Recherche Arthrite de l’Université Laval, Department of Microbiology and Immunology, Québec, Canada
| | | | - Kazutaka Ikeda
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo (UTokyo), Tokyo, Japan
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science (TMIMS), Tokyo, Japan
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Altamimi E, Ahmad B, Abu-Aqoulah A, Rawabdeh N. Clinico-pathological characteristics of eosinophilic esophagitis in Jordanian children. PRZEGLAD GASTROENTEROLOGICZNY 2021; 17:207-212. [PMID: 36127947 PMCID: PMC9475479 DOI: 10.5114/pg.2021.109975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 07/28/2021] [Indexed: 12/02/2022]
Abstract
Introduction Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disorder manifested by symptoms of impaired esophageal function and hypereosinophilic esophageal inflammation. It is believed that the number of patients being diagnosed globally is increasing. Aim To describe the frequency and clinicopathological features of EoE in Jordanian children. Material and methods A retrospective review of all paediatric patients with eosinophilic esophagitis diagnosed and followed up at our paediatric gastroenterology service at King Abdullah University Hospital between January 2015 and January 2020. Results During the study period, 21 patients were diagnosed with EoE out of 700 diagnostic endoscopic procedures. Only 1 (4.8%) female was diagnosed. The average age at presentation was 9.5 years (age range: 1-16 years). The most common manifestation was solid food dysphagia (15, 71.4%), followed by food impaction and vomiting (11, 52.4% and 6, 28.6%, respectively). Atopy was diagnosed in 10 (47.6%) patients. Four (19.0%) had food allergy, 3 (14.3%) had respiratory allergy, and 3 (14.3%) had combined. Linear furrows and circular rings were the most common endoscopic features - 17 (81.0%) and 10 (47.6%), respectively, while papillary elongation, basal zone hyperplasia, and eosinophilic infiltrate were the most common reported histopathological features. Almost all patients received proton pump inhibitors (19, 90.5%). Steroids were used in 18 (85.7%) patients; local steroids in 11 (52.4%), and oral steroids in 7 (33.3%). Out of the 4 (19%) patients with esophageal strictures, 2 (9.5%) required pneumatic dilatation. Conclusions Eosinophilic esophagitis is not uncommon in our community. Clinical and histological parameters point to delayed referral and diagnosis. Increasing awareness of this problem will lead to early diagnosis and will decrease complications.
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Affiliation(s)
- Eyad Altamimi
- Paediatric Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Bayan Ahmad
- Paediatric Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Abdullah Abu-Aqoulah
- Paediatric Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Naif Rawabdeh
- Paediatric Department, King Abdullah University Hospital, Irbid, Jordan
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Miller AK, Williams SM. Helicobacter pylori infection causes both protective and deleterious effects in human health and disease. Genes Immun 2021; 22:218-226. [PMID: 34244666 PMCID: PMC8390445 DOI: 10.1038/s41435-021-00146-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023]
Abstract
Infection with Helicobacter pylori (H. pylori) is necessary but not sufficient for the development of gastric cancer, the third leading cause of cancer death globally. H. pylori infection affects over half of people globally; however, it does not affect populations uniformly. H. pylori infection rates are declining in western industrialized countries but are plateauing in developing and newly industrialized countries where gastric cancer is most prevalent. Despite H. pylori infection being the primary causative agent for gastric cancer, H. pylori infection can also cause other effects, detrimental or beneficial, throughout an individual's life, with the beneficial effects often being seen in childhood and the deleterious effects in adulthood. H. pylori is an ancient bacterium and its likelihood of affecting disease or health is dependent on both human and bacterial genetics that have co-evolved over millennia. In this review, we focus on the impact of infection and its genetic bases in different populations and diseases throughout an individual's lifespan, highlighting the benefits of individualized treatment and argue that universal eradication of H. pylori in its host may cause more harm than good for those infected with H. pylori.
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Affiliation(s)
- Anna K Miller
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH
| | - Scott M Williams
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH,Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
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Microbial exposures that establish immunoregulation are compatible with targeted hygiene. J Allergy Clin Immunol 2021; 148:33-39. [PMID: 34033844 DOI: 10.1016/j.jaci.2021.05.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/30/2021] [Accepted: 05/18/2021] [Indexed: 01/22/2023]
Abstract
It is often suggested that hygiene is not compatible with the microbial exposures that are necessary for establishment of the immune system in early life. However, when we analyze the microbial exposures of modern humans in the context of human evolution and history, it becomes evident that whereas children need exposure to the microbiotas of their mothers, other family members, and the natural environment, exposure to the unnatural microbiota of the modern home is less relevant. In addition, any benefits of exposure to the infections of childhood within their household setting are at least partly replaced by the recently revealed nonspecific effects of vaccines. This article shows how targeting hygiene practices at key risk moments and sites can maximize protection against infection while minimizing any impact on essential microbial exposures. Moreover, this targeting must aim to reduce direct exposure of children to cleaning agents because those agents probably exert TH2-adjuvant effects that trigger allergic responses to normally innocuous antigens. Finally, we need to halt the flow of publications in the scientific literature and the media that blame hygiene for the increases in immunoregulatory disorders. Appropriately targeted hygiene behavior is compatible with a healthy lifestyle that promotes exposure to essential microorganisms.
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41
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de Souza MPC, de Camargo BAF, Spósito L, Fortunato GC, Carvalho GC, Marena GD, Meneguin AB, Bauab TM, Chorilli M. Highlighting the use of micro and nanoparticles based-drug delivery systems for the treatment of Helicobacter pylori infections. Crit Rev Microbiol 2021; 47:435-460. [PMID: 33725462 DOI: 10.1080/1040841x.2021.1895721] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Due to the high adaptability of Helicobacter pylori and the low targeting specificity of the drugs normally used in pharmacological therapy, the strains are becoming increasingly resistant to these drugs, making it difficult to eradicate the infection. Thus, the search for new therapeutic approaches has been considered urgent. The incorporation of drugs in advanced drug delivery systems, such as nano and microparticles, would allow the improvement of the retention time in the stomach and the prolongation of drug release rates at the target site. Because of this, the present review article aims to highlight the use of micro and nanoparticles as important technological tools for the treatment of H. pylori infections, focussing on the main nanotechnological systems, including nanostructured lipid carriers, liposomes, nanoemulsion, metallic nanoparticles, and polymeric nanoparticles, as well as microtechnological systems such as gastroretentive dosage forms, among them mucoadhesive, magnetic and floating systems were highlighted.
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Affiliation(s)
| | | | - Larissa Spósito
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil São Paulo
| | | | - Gabriela Corrêa Carvalho
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil São Paulo
| | - Gabriel Davi Marena
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil São Paulo
| | | | - Taís Maria Bauab
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil São Paulo
| | - Marlus Chorilli
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil São Paulo
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Chen Y, Zhan X, Wang D. Association between Helicobacter pylori and risk of childhood asthma: a meta-analysis of 18 observational studies. J Asthma 2021; 59:890-900. [PMID: 33630702 DOI: 10.1080/02770903.2021.1892752] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Objective: The association between Helicobacter pylori (H. pylori) and childhood asthma is unclear. Thus, the aim of this study was to explore the association between H. pylori and childhood asthma.Methods: A literature search, study selection, and data extraction were performed independently and in duplicate. Data were analyzed using STATA software.Results: Eighteen studies enrolling 17,196 children were analyzed. All studies were of moderate-to-high quality. Four studies subcategorized H. pylori infection according to CagA status. Overall, there was a significant negative association between H. pylori and risk for childhood asthma (OR = 0.68; 95% CI, 0.54-0.87; P = 0.002), with no/marginal publication bias identified by the Egger's test and the Begg's test (P = 0.162 and P = 0.198, respectively). The observed inverse association persisted for CagA(+) strains of H. pylori (OR = 0.58; 95% CI, 0.35-0.96; P = 0.034) but not for CagA(-) strains (OR = 0.52; 95% CI, 0.12-2.28; P = 0.387). There was no significant difference between studies with respect to study design, participant age, geographical region, and method of measuring H. pylori.Conclusion: The evidence suggests that H. pylori infection, particularly CagA(+) H. pylori infection, is inversely associated with the risk of childhood asthma. Supplemental data for this article can be accessed at publisher's website.
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Affiliation(s)
- Yuxia Chen
- Department of Gastroenterology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xue Zhan
- Department of Gastroenterology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Donghai Wang
- Department of Respiratory Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
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Reshetnyak VI, Burmistrov AI, Maev IV. Helicobacter pylori: Commensal, symbiont or pathogen? World J Gastroenterol 2021; 27:545-560. [PMID: 33642828 PMCID: PMC7901052 DOI: 10.3748/wjg.v27.i7.545] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 12/28/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
This review considers the data on Helicobacter pylori (H. pylori), which have been accumulated over 40 years since its description as an etiological factor in gastrointestinal diseases. The majority of modern publications are devoted to the study of the pathogenic properties of the microorganism in the development of chronic gastritis, peptic ulcer disease, and gastric cancer, as well as methods for its eradication. However, in recent years, there have been more and more studies which have suggested that H. pylori has a beneficial, or potentially positive, effect on the human body. The authors have attempted to objectively analyze the information accumulated in the literature on H. pylori. Some studies consider it as one of the recently identified human bacterial pathogens, and special attention is paid to the evidence suggesting that it is probably part of the composition of the human microbiome as a commensal (commensal from French to English is a table companion) or even a symbiont. The presented data discussing the presence or absence of the effect of H. pylori on human health suggest that there is an apparent ambiguity of the problem. The re-assessment of the data available on H. pylori infection is important in order to answer the question of whether it is necessary to create a program of mass H. pylori eradication or to apply a more personalized approach to treating patients with H. pylori-associated gastrointestinal diseases and to perform eradication therapy.
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Affiliation(s)
- Vasiliy Ivanovich Reshetnyak
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Alexandr Igorevich Burmistrov
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Igor Veniaminovich Maev
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
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Chen CC, Liou JM, Lee YC, Hong TC, El-Omar EM, Wu MS. The interplay between Helicobacter pylori and gastrointestinal microbiota. Gut Microbes 2021; 13:1-22. [PMID: 33938378 PMCID: PMC8096336 DOI: 10.1080/19490976.2021.1909459] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 03/10/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023] Open
Abstract
The complex population of microbes in the human gastrointestinal (GI) tract interacts with itself and with the host, exerting a deep influence on health and disease development. The development of modern sequencing technology has enabled us to gain insight into GI microbes. Helicobacter pylori colonization significantly affects the gastric microenvironment, which in turn affects gastric microbiota and may be correlated with colonic microbiota changes. Crosstalk between H. pylori and GI commensal flora may play a role in H. pylori-related carcinogenicity and extragastric manifestations. We review current knowledge on how H. pylori shapes GI microbiota with a specific focus on its impact on the stomach and colon. We also review current evidence on colonic microbiota changes attributed to eradication therapy based on the clinical studies performed to date.
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Affiliation(s)
- Chieh-Chang Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jyh-Ming Liou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medicine, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Chia Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Tzu-Chan Hong
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Emad M El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Ming-Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Varga MG, Wood CR, Butt J, Ryan ME, You WC, Pan K, Waterboer T, Epplein M, Shaffer CL. Immunostimulatory membrane proteins potentiate H. pylori-induced carcinogenesis by enabling CagA translocation. Gut Microbes 2021; 13:1-13. [PMID: 33382363 PMCID: PMC7781638 DOI: 10.1080/19490976.2020.1862613] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/04/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023] Open
Abstract
Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations.
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Affiliation(s)
- Matthew G. Varga
- Department of Epidemiology, Lineberger Comprehensive Cancer Center and Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Cecily R. Wood
- Department of Veterinary Science, University of Kentucky, Lexington, KY, USA
| | - Julia Butt
- Infections and Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Mackenzie E. Ryan
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA
| | - Wei-Cheng You
- Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Kaifeng Pan
- Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Meira Epplein
- Department of Population Health Sciences and Duke Cancer Institute, Cancer Control and Population Sciences Program, Duke University, Durham, NC, USA
| | - Carrie L. Shaffer
- Department of Veterinary Science, University of Kentucky, Lexington, KY, USA
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA
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Abstract
Since the description of Helicobacter pylori (HP) as the most common cause of gastritis and its neoplastic complications, numerous articles have been written about the epidemiology, clinical features, diagnostic methods, histopathology, pathogenesis, molecular biology and treatment of this infection. This review focuses on those aspects of the infection that challenge the universality of the medical implications through the lens of evolutionary science applied to medicine. The divergent epidemiological and clinical outcomes observed in different populations and the possible beneficial aspects of the infection are discussed. Also reviewed are Correa's seminal contributions to our understanding of gastric cancer in particular and postinflammatory tumours in general, and the renewed interest in intestinal metaplasia and its clinical implications.
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Affiliation(s)
- Jose Jessurun
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
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Owyang SY, Zhang M, El-Zaatari M, Eaton KA, Bishu S, Hou G, Grasberger H, Kao JY. Dendritic cell-derived TGF-β mediates the induction of mucosal regulatory T-cell response to Helicobacter infection essential for maintenance of immune tolerance in mice. Helicobacter 2020; 25:e12763. [PMID: 33025641 PMCID: PMC7885176 DOI: 10.1111/hel.12763] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/04/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori infection leads to regulatory T-cell (Treg) induction in infected mice, which contributes to H. pylori immune escape. However, the mechanisms responsible for H. pylori induction of Treg and immune tolerance remain unclear. We hypothesized DC-produced TGF-β may be responsible for Treg induction and immune tolerance. MATERIALS AND METHODS To test this hypothesis, we generated TGF-β∆DC mice (CD11c+ DC-specific TGF-β deletion) and assessed the impact of DC-specific TGF-β deletion on DC function during Helicobacter infection in vitro and in vivo. To examine the T cell-independent DC function, we crossed TGF-β∆DC mice onto Rag1KO background to generate TGF-β∆DC xRag1KO mice. RESULTS When stimulated with H. pylori, TGF-β∆DC BMDC/splenocyte cocultures showed increased levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines compared to control, indicating a proinflammatory DC phenotype. Following 6 months of H. felis infection, TGF-β∆DC mice developed more severe gastritis and a trend toward more metaplasia compared to TGF-βfl/fl with increased levels of inflammatory Th1 cytokine mRNA and lower gastric H. felis colonization compared to infected TGF-βfl/fl mice. In a T cell-deficient background using TGF-β∆DC xRag1KO mice, H. felis colonization was significantly lower when DC-derived TGF-β was absent, revealing a direct, innate function of DC in controlling H. felis infection independent of Treg induction. CONCLUSIONS Our findings indicate that DC-derived TGF-β mediates Helicobacter-induced Treg response and attenuates the inflammatory Th1 response. We also demonstrated a previously unrecognized innate role of DC controlling Helicobacter colonization via a Treg-independent mechanism. DC TGF-β signaling may represent an important target in the management of H. pylori.
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Affiliation(s)
- Stephanie Y. Owyang
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Min Zhang
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Mohamad El-Zaatari
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Kathryn A. Eaton
- Unit for Laboratory Animal Medicine and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, 48109 USA
| | - Shrinivas Bishu
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Guoqing Hou
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Helmut Grasberger
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - John Y. Kao
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
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Robinson K, Atherton JC. The Spectrum of Helicobacter-Mediated Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:123-144. [PMID: 33197219 DOI: 10.1146/annurev-pathol-032520-024949] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Helicobacter pylori is the leading cause of peptic ulcer disease. The infection has been implicated in more than 75% of duodenal ulcer cases and 17% of gastric ulcer cases. H. pylori has been classified as a human carcinogen, since it is the main cause of distal gastric adenocarcinoma and B cell mucosa-associated lymphoid tissue lymphoma. Evidence also links H. pylori with extragastric conditions including iron deficiency anemia, idiopathic thrombocytopenic purpura, and vitamin B12 deficiency. Studies indicate that H. pylori may be protective against other conditions of the gastrointestinal tract (e.g., reflux esophagitis and related pathologies) and elsewhere in the body (e.g., asthma). The infection is asymptomatic in the vast majority of cases; more serious outcomes occur in only 10-15% of infected individuals. Despite extensive research over the past 3 decades, there is no effective vaccine, and the circumstances leading to disease development remain unclear. In addition, there is now a growing prevalence of antimicrobial resistance in H. pylori. This review discusses these important issues.
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Affiliation(s)
- Karen Robinson
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
| | - John C Atherton
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
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Roszczenko-Jasińska P, Wojtyś MI, Jagusztyn-Krynicka EK. Helicobacter pylori treatment in the post-antibiotics era-searching for new drug targets. Appl Microbiol Biotechnol 2020; 104:9891-9905. [PMID: 33052519 PMCID: PMC7666284 DOI: 10.1007/s00253-020-10945-w] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 12/14/2022]
Abstract
Abstract Helicobacter pylori, a member of Epsilonproteobacteria, is a Gram-negative microaerophilic bacterium that colonizes gastric mucosa of about 50% of the human population. Although most infections caused by H. pylori are asymptomatic, the microorganism is strongly associated with serious diseases of the upper gastrointestinal tract such as chronic gastritis, peptic ulcer, duodenal ulcer, and gastric cancer, and it is classified as a group I carcinogen. The prevalence of H. pylori infections varies worldwide. The H. pylori genotype, host gene polymorphisms, and environmental factors determine the type of induced disease. Currently, the most common therapy to treat H. pylori is the first line clarithromycin–based triple therapy or a quadruple therapy replacing clarithromycin with new antibiotics. Despite the enormous recent effort to introduce new therapeutic regimens to combat this pathogen, treatment for H. pylori still fails in more than 20% of patients, mainly due to the increased prevalence of antibiotic resistant strains. In this review we present recent progress aimed at designing new anti-H. pylori strategies to combat this pathogen. Some novel therapeutic regimens will potentially be used as an extra constituent of antibiotic therapy, and others may replace current antibiotic treatments. Key points • Attempts to improve eradication rate of H. pylori infection. • Searching for new drug targets in anti-Helicobacter therapies.
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Affiliation(s)
- Paula Roszczenko-Jasińska
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland
| | - Marta Ilona Wojtyś
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland.,Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, Univeristy of Warsaw, Pasteura 5, 02-093, Warszawa, Poland
| | - Elżbieta K Jagusztyn-Krynicka
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland.
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