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Zhao H, Catarino J, Stack G, Albizu AK, Lara-Tejero M, Horvath TL, Galán JE. Typhoid toxin causes neuropathology by disrupting the blood-brain barrier. Nat Microbiol 2025:10.1038/s41564-025-02000-z. [PMID: 40341334 DOI: 10.1038/s41564-025-02000-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 03/31/2025] [Indexed: 05/10/2025]
Abstract
Typhoid fever, primarily caused by Salmonella Typhi, can result in severe life-threatening complications such as encephalopathy. Here we elucidate the mechanisms by which typhoid toxin, a unique virulence factor of S. Typhi, mediates the neuropathology associated with typhoid fever. Utilizing mice engineered to have specific tissues protected from toxin action and an in vitro model of the blood-brain barrier (BBB), we demonstrate that, rather than direct action on neuronal or glial cells, typhoid toxin causes neuropathology by disrupting the BBB. Intravenous tracer studies confirmed significant BBB permeability changes following toxin exposure, an effect we found to be mediated by typhoid toxin's CdtB catalytic subunit. We demonstrate that corticosteroids are effective at mitigating BBB disruption in vivo, supporting their use for managing typhoid fever neurological complications. Our data reveal mechanistic insight into how typhoid toxin causes encephalopathy and suggest targeted therapeutic interventions to alleviate the severe neurological manifestations of typhoid fever.
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Affiliation(s)
- Heng Zhao
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA
| | - Jonatas Catarino
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Max Plank Institute for Metabolic Research, Cologne, Germany
| | - Gabrielle Stack
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA
- Elly Lilly and Company, Cork, Ireland
| | - Ashley Kristant Albizu
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Maria Lara-Tejero
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA
| | - Tamas L Horvath
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary
| | - Jorge E Galán
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
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Dey S, Ghosh M, Dev A. Signalling and molecular pathways, overexpressed receptors of colorectal cancer and effective therapeutic targeting using biogenic silver nanoparticles. Gene 2025; 936:149099. [PMID: 39557372 DOI: 10.1016/j.gene.2024.149099] [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: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Increasing morbidity and mortality in CRC is a potential threat to human health. The major challenges for better treatment outcomes are the heterogeneity of CRC cases, complicated molecular pathway cross-talks, the influence of gut dysbiosis in CRC, and the lack of multimodal target-specific drug delivery. The overexpression of many receptors in CRC cells may pave the path for targeting them with multiple ligands. The design of a more target-specific drug-delivery device with multiple ligand-functionalized, green-synthesized silver nanoparticles is highly promising and may also deliver other approved chemotherapeutic agents. This review presents the various aspects of colorectal cancer and over-expressed receptors that can be targeted with appropriate ligands to enhance the specific drug delivery potency of green synthesised silver nanoparticles. This review aims to broaden further research into this multi-ligand functionalised, safer and effective silver nano drug delivery system.
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Affiliation(s)
- Sandip Dey
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Manik Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India.
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Al-Matouq J, Al-Ghafli H, Alibrahim NN, Alsaffar N, Radwan Z, Ali MD. Unveiling the Interplay Between the Human Microbiome and Gastric Cancer: A Review of the Complex Relationships and Therapeutic Avenues. Cancers (Basel) 2025; 17:226. [PMID: 39858007 PMCID: PMC11763844 DOI: 10.3390/cancers17020226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/23/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human microbiota plays a crucial role in maintaining overall health and well-being. The gut microbiota has been implicated in developing and progressing various diseases, including cancer. This review highlights the related mechanisms and the compositions that influence cancer pathogenesis with a highlight on gastric cancer. We provide a comprehensive overview of the mechanisms by which the microbiome influences cancer development, progression, and response to treatment, with a focus on identifying potential biomarkers for early detection, prevention strategies, and novel therapeutic interventions that leverage microbiome modulation. This comprehensive review can guide future research and clinical practices in understanding and harnessing the microbiome to optimize gastric cancer therapies.
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Affiliation(s)
- Jenan Al-Matouq
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Hawra Al-Ghafli
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Noura N. Alibrahim
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Nida Alsaffar
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Zaheda Radwan
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Mohammad Daud Ali
- Department of Pharmacy, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia;
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Veronese P, Dodi I. Campylobacter jejuni/ coli Infection: Is It Still a Concern? Microorganisms 2024; 12:2669. [PMID: 39770871 PMCID: PMC11728820 DOI: 10.3390/microorganisms12122669] [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: 12/04/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Campylobacteriosis is a leading cause of infectious diarrhea and foodborne illness worldwide. Campylobacter infection is primarily transmitted through the consumption of contaminated food, especially uncooked meat, or untreated water; contact with infected animals or contaminated environments; poultry is the primary reservoir and source of human transmission. The clinical spectrum of Campylobacter jejuni/coli infection can be classified into two distinct categories: gastrointestinal and extraintestinal manifestations. Late complications are reactive arthritis, Guillain-Barré syndrome, and Miller Fisher syndrome. In the pediatric population, the 0-4 age group has the highest incidence of campylobacteriosis. Regarding the use of specific antimicrobial therapy, international guidelines agree in recommending it for severe intestinal infections. Host factors, including malnutrition, immunodeficiency, and malignancy, can also influence the decision to treat. The Centers for Disease Control and Prevention (CDC) has identified antibiotic resistance in Campylobacter as a 'significant public health threat' due to increasing resistance to FQs or macrolides. Although numerous vaccines have been proposed in recent years to reduce the intestinal colonization of poultry, none have shown sufficient efficacy to provide a definitive solution.
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Affiliation(s)
- Piero Veronese
- Pediatric Infectious Disease Unit, Barilla Children’s Hospital of Parma, 43126 Parma, Italy;
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He Z, Yu J, Gong J, Wu J, Zong X, Luo Z, He X, Cheng WM, Liu Y, Liu C, Zhang Q, Dai L, Ding T, Gao B, Gharaibeh RZ, Huang J, Jobin C, Lan P. Campylobacter jejuni-derived cytolethal distending toxin promotes colorectal cancer metastasis. Cell Host Microbe 2024; 32:2080-2091.e6. [PMID: 39626677 DOI: 10.1016/j.chom.2024.11.006] [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: 01/02/2024] [Revised: 09/13/2024] [Accepted: 11/07/2024] [Indexed: 12/14/2024]
Abstract
Various forms of solid tumors harbor intracellular bacteria, but the physiological consequences of these microorganisms are poorly understood. We show that Campylobacter is significantly enriched in primary colorectal cancer (CRC) lesions from patients with metastasis. Campylobacter jejuni-derived cytolethal distending toxin (CDT) promotes CRC metastasis through JAK2-STAT3-MMP9 signaling in liver or pulmonary metastatic mice models, as confirmed in C. jejuni-infected human colonic tissue and CDT-treated colonic tumoroids from patients. Genetic deletion of cdtB (ΔcdtB) or purified CdtB protein demonstrates that the genotoxin is essential for C. jejuni's pro-metastatic property. In C.-jejuni-colonized mice, increased translocation of CDT-producing C. jejuni to extraintestinal implanted tumors potentially leads to accelerated metastasis of these tumors. Overall, these findings demonstrate that an intratumor-bacteria-derived genotoxin accelerates tumor metastasis, potentially opening a new diagnostic and therapeutic avenue for cancer management.
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Affiliation(s)
- Zhen He
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China
| | - Jing Yu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China
| | - Junli Gong
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China
| | - Jinjie Wu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China
| | - Xuan Zong
- Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| | - Zhanhao Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiaowen He
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Wai Ming Cheng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yugeng Liu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Chen Liu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Qiang Zhang
- School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Lei Dai
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Tao Ding
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Beile Gao
- CAS Key Laboratory of Tropical Marine Bio Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, Guangdong 510301, China
| | - Raad Z Gharaibeh
- Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Jinlin Huang
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-Food Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Christian Jobin
- Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610, USA; Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA.
| | - Ping Lan
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
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Magyar LB, Ábrahám E, Lipinszki Z, Tarnopol RL, Whiteman NK, Varga V, Hultmark D, Andó I, Cinege G. Pore-Forming Toxin-Like Proteins in the Anti-Parasitoid Immune Response of Drosophila. J Innate Immun 2024; 17:10-28. [PMID: 39626640 PMCID: PMC11731912 DOI: 10.1159/000542583] [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: 07/25/2024] [Accepted: 11/10/2024] [Indexed: 12/08/2024] Open
Abstract
INTRODUCTION Species of the ananassae subgroup of Drosophilidae are highly resistant to parasitoid wasp infections. We have previously shown that the genes encoding cytolethal distending toxin B (CdtB) and the apoptosis inducing protein of 56 kDa (AIP56) were horizontally transferred to these fly species from prokaryotes and are now instrumental in the anti-parasitoid immune defense of Drosophila ananassae. Here we describe a new family of genes, which encode proteins with hemolysin E domains, heretofore only identified in prokaryotes. Hemolysin E proteins are pore-forming toxins, important virulence factors of bacteria. METHODS Bioinformatical, transcriptional, and protein expressional studies were used. RESULTS The hemolysin E-like genes have a scattered distribution among the genomes of species belonging to several different monophyletic lineages in the family Drosophilidae. We detected structural homology with the bacterial Hemolysin E toxins and showed that the origin of the D. ananassae hemolysin E-like genes (hl1-38) is consistent with prokaryotic horizontal gene transfer. These genes encode humoral factors, secreted into the hemolymph by the fat body and hemocytes. Their expression is induced solely by parasitoid infection and the proteins bind to the developing parasitoids. CONCLUSIONS Hemolysin E-like proteins acquired by horizontal gene transfer and expressed by the primary immune organs may contribute to the elimination of parasitoids, as novel humoral factors in Drosophila innate immunity.
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Affiliation(s)
- Lilla B. Magyar
- Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
- Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Edit Ábrahám
- Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
- National Laboratory for Biotechnology, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Zoltán Lipinszki
- Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
- National Laboratory for Biotechnology, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Rebecca L. Tarnopol
- Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA
| | - Noah K. Whiteman
- Department of Integrative Biology, University of California, Berkeley, CA, USA
- Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
| | - Viktória Varga
- Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Dan Hultmark
- Department of Molecular Biology, Umea University, Umea, Sweden
| | - István Andó
- Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Gyöngyi Cinege
- Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
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Omole Z, Dorrell N, Elmi A, Nasher F, Gundogdu O, Wren BW. Pathogenicity and virulence of Campylobacter jejuni: What do we really know? Virulence 2024; 15:2436060. [PMID: 39648291 PMCID: PMC11633169 DOI: 10.1080/21505594.2024.2436060] [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: 06/14/2024] [Revised: 10/08/2024] [Accepted: 10/31/2024] [Indexed: 12/10/2024] Open
Abstract
Campylobacter jejuni is the leading cause of bacterial gastroenteritis and is a major public health concern worldwide. Despite its importance, our understanding of how C. jejuni causes diarrhoea and interacts with its hosts is limited due to the absence of appropriate infection models and established virulence factors found in other enteric pathogens. Additionally, despite its genetic diversity, non-pathogenic C. jejuni strains are unknown. Regardless of these limitations, significant progress has been made in understanding how C. jejuni uses a complex array of factors which aid the bacterium to survive and respond to host defences. This review provides an update on fitness and virulence determinants of this important pathogen and questions our knowledge on these determinants that are often based on inferred genomics knowledge and surrogate infection models.
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Affiliation(s)
- Zahra Omole
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Nick Dorrell
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Abdi Elmi
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Fauzy Nasher
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Ozan Gundogdu
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Brendan W. Wren
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
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Ma Y, Chen T, Sun T, Dilimulati D, Xiao Y. The oncomicrobiome: New insights into microorganisms in cancer. Microb Pathog 2024; 197:107091. [PMID: 39481695 DOI: 10.1016/j.micpath.2024.107091] [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: 07/10/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
The discoveries of the oncomicrobiome (intratumoral microbiome) and oncomicrobiota (intratumoral microbiota) represent significant advances in tumor research and have rapidly become of key interest to the field. Within tumors, microorganisms such as bacteria, fungi, viruses, and archaea form the oncomicrobiota and are primarily found within tumor cells, immunocytes, and the intercellular matrix. The oncomicrobiome exhibits marked heterogeneity and is associated with tumor initiation, progression, metastasis, and treatment response. Interactions between the oncomicrobiome and the immune system can modulate host antitumor immunity, influencing the efficacy of immunotherapies. Oncomicrobiome research also faces numerous challenges, including overcoming methodological issues such as low target abundance, susceptibility to contamination, and biases in sample handling and analysis methods across different studies. Furthermore, studies of the oncomicrobiome may be confounded by baseline differences in microbiomes among populations driven by both environmental and genetic factors. Most studies to date have revealed associations between the oncomicrobiome and tumors, but very few have established mechanistic links between the two. This review introduces the relevant concepts, detection methods, sources, and characteristics of the oncomicrobiome. We then describe the composition of the oncomicrobiome in common tumors and its role in shaping the tumor microenvironment. We also discuss the current problems and challenges to be overcome in this rapidly progressing field.
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Affiliation(s)
- Yingying Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingting Sun
- Department of Structure and Morphology, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China; Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, China
| | - Dilinuer Dilimulati
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yonghong Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Structure and Morphology, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China; Peking Union Medical College & Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, China.
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Singhal S, Bhadana R, Jain BP, Gautam A, Pandey S, Rani V. Role of gut microbiota in tumorigenesis and antitumoral therapies: an updated review. Biotechnol Genet Eng Rev 2024; 40:3716-3742. [PMID: 36632709 DOI: 10.1080/02648725.2023.2166268] [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: 05/31/2022] [Indexed: 01/13/2023]
Abstract
Gut microbiota plays a prominent role in regulation of host nutrientmetabolism, drug and xenobiotics metabolism, immunomodulation and defense against pathogens. It synthesizes numerous metabolites thatmaintain the homeostasis of host. Any disbalance in the normalmicrobiota of gut can lead to pathological conditions includinginflammation and tumorigenesis. In the past few decades, theimportance of gut microbiota and its implication in various diseases, including cancer has been a prime focus in the field of research. Itplays a dual role in tumorigenesis, where it can accelerate as wellas inhibit the process. Various evidences validate the effects of gutmicrobiota in development and progression of malignancies, wheremanipulation of gut microbiota by probiotics, prebiotics, dietarymodifications and faecal microbiota transfer play a significant role.In this review, we focus on the current understanding of theinterrelationship between gut microbiota, immune system and cancer,the mechanisms by which they play dual role in promotion andinhibition of tumorigenesis. We have also discussed the role ofcertain bacteria with probiotic characteristics which can be used tomodulate the outcome of the various anti-cancer therapies under theinfluence of the alteration in the composition of gut microbiota.Future research primarily focusing on the microbiota as a communitywhich affect and modulate the treatment for cancer would benoteworthy in the field of oncology. This necessitates acomprehensive knowledge of the roles of individual as well asconsortium of microbiota in relation to physiology and response ofthe host.
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Affiliation(s)
- Shivani Singhal
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Renu Bhadana
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Buddhi Prakash Jain
- Department of Zoology, Mahatma Gandhi Central University, Motihari, Bihar, India
| | - Akash Gautam
- Centre for Neural and Cognitive Sciences, School of Medical Sciences, University of Hyderabad, Hyderabad, India
| | - Shweta Pandey
- Department of Biotechnology, Govt Vishwanath Yadav Tamaskar Post-Graduate Autonomous College Durg, Chhattisgarh, India
| | - Vibha Rani
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
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Jehanne Q, Bénéjat L, Azzi Martin L, Korolik V, Ducournau A, Aptel J, Ménard A, Jauvain M, Aguilera C, Doreille A, Mesnard L, Eckert C, Lehours P. First isolation of Campylobacter vicugnae sp. nov. in humans suffering from gastroenteritis. Microbiol Spectr 2024; 12:e0152324. [PMID: 39365090 PMCID: PMC11537083 DOI: 10.1128/spectrum.01523-24] [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: 06/26/2024] [Accepted: 08/01/2024] [Indexed: 10/05/2024] Open
Abstract
The present study describes the first isolation of a recently described Campylobacter species, Campylobacter vicugnae, in humans. The isolates were recovered by two independent French laboratories in 2020 and 2022 from a man and a woman suffering from gastroenteritis. Biochemical and growth characteristics, and electron microscopy for these two strains indicated that they belong to Campylobacter genus. 16S rDNA and GyrA-based phylogeny, as well as average nucleotide identity and in silico DNA-DNA Hybridization analyses revealed that both strains belong to the Campylobacter vicugnae species. Both isolates possess a complete cytolethal distending toxin (CDT) locus with cdtA, cdtB, and cdtC, and features of CDT activity were demonstrated in vitro with Caco-2 intestinal epithelial cells. Our data suggest that these two isolates of C. vicugnae were associated with gastroenteritis in humans and induced major cytopathogenic effects in vitro. C. vicugnae is likely to be a novel human pathogen, with a source of foodborne infection that needs to be determined.IMPORTANCECampylobacter species that display toxicity features are a worldwide public health issue. In clinical contexts, it is crucial to identify which isolate could be an urgent threat to a patient. Actual and widely used laboratory methods such as mass spectrometry or PCR may be flawed in the field of species identification. In contrast, the present study shows that next-generation sequencing allows to precisely identify isolates to species level that may have been omitted otherwise. Moreover, it helps to identify emerging species before they become a threat to human health. Recovery of a new Campylobacter species in human sample, such as the new species "Campylobacter vicugnae," is an important step for the identification of emerging pathogens posing threat to global health.
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Affiliation(s)
- Quentin Jehanne
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
| | - Lucie Bénéjat
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
| | - Lamia Azzi Martin
- University of Bordeaux, Inserm, UMR 1312, Bordeaux Institute of Oncology (BRIC), Bordeaux, France
| | - Victoria Korolik
- Institute for Glycomics, Griffith University, Gold Coast, Australia
| | - Astrid Ducournau
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
| | - Johanna Aptel
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
| | - Armelle Ménard
- University of Bordeaux, Inserm, UMR 1312, Bordeaux Institute of Oncology (BRIC), Bordeaux, France
| | - Marine Jauvain
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
- University of Bordeaux, Inserm, UMR 1312, Bordeaux Institute of Oncology (BRIC), Bordeaux, France
| | | | - Alice Doreille
- Sorbonne Université, Inserm, U1135, Centre d’Immunologie et des Maladies Infectieuses, Paris, France
- AP-HP, Soins Intensifs Néphrologique et Rein Aigu, Hôpital Tenon, Paris, France
| | - Laurent Mesnard
- Sorbonne Université, Inserm, U1135, Centre d’Immunologie et des Maladies Infectieuses, Paris, France
- AP-HP, Soins Intensifs Néphrologique et Rein Aigu, Hôpital Tenon, Paris, France
| | - Catherine Eckert
- Sorbonne Université, Inserm, U1135, Centre d’Immunologie et des Maladies Infectieuses, Paris, France
- Département de Bactériologie, AP-HP, Sorbonne-Université, Hôpital Saint-Antoine, Paris, France
| | - Philippe Lehours
- National Reference Centre for Campylobacters and Helicobacters, Bordeaux, France
- University of Bordeaux, Inserm, UMR 1312, Bordeaux Institute of Oncology (BRIC), Bordeaux, France
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11
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Malet-Villemagne J, Vidic J. Extracellular vesicles in the pathogenesis of Campylobacter jejuni. Microbes Infect 2024; 26:105377. [PMID: 38866352 DOI: 10.1016/j.micinf.2024.105377] [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: 02/29/2024] [Revised: 06/05/2024] [Accepted: 06/06/2024] [Indexed: 06/14/2024]
Abstract
Bacteria in genus Campylobacter are the leading cause of foodborne infections worldwide. Here we describe the roles of extracellular vesicles in the pathogenesis of these bacteria and current knowledge of vesicle biogenesis. We also discuss the advantages of this alternative secretion pathway for bacterial virulence.
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Affiliation(s)
- Jeanne Malet-Villemagne
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78350, Jouy en Josas, France.
| | - Jasmina Vidic
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78350, Jouy en Josas, France.
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12
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Halawa M, Newman PM, Aderibigbe T, Carabetta VJ. Conjugated therapeutic proteins as a treatment for bacteria which trigger cancer development. iScience 2024; 27:111029. [PMID: 39635133 PMCID: PMC11615139 DOI: 10.1016/j.isci.2024.111029] [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] [Indexed: 12/07/2024] Open
Abstract
In recent years, an increasing amount of research has focused on the intricate and complex correlation between bacterial infections and the development of cancer. Some studies even identified specific bacterial species as potential culprits in the initiation of carcinogenesis, which generated a great deal of interest in the creation of innovative therapeutic strategies aimed at addressing both the infection and the subsequent risk of cancer. Among these strategies, there has been a recent emergence of the use of conjugated therapeutic proteins, which represent a highly promising avenue in the field of cancer therapeutics. These proteins offer a dual-targeting approach that seeks to effectively combat both the bacterial infection and the resulting malignancies that may arise because of such infections. This review delves into the landscape of conjugated therapeutic proteins that have been intricately designed with the purpose of specifically targeting bacteria that have been implicated in the induction of cancer.
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Affiliation(s)
- Mohamed Halawa
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Precious M. Newman
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Tope Aderibigbe
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Valerie J. Carabetta
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
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13
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Chang YF, Huang YP, Chou CH, Ho MW, Lin HJ, Chen CY, Wu HY, Lai YR, Lee YH, Chiu CH, Lai CH. RAGE participates in the intracellular transport of Campylobacter jejuni cytolethal distending toxin. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2024; 57:709-719. [PMID: 39160115 DOI: 10.1016/j.jmii.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 06/06/2024] [Accepted: 07/08/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Cytolethal distending toxin (CDT) belongs to the genotoxin family and is closely related to Campylobacter jejuni-associated gastroenteritis. We recently reported that CDT triggers the danger-associated molecular pattern (DAMP) signaling to exert deleterious effects on host cells. However, how CDT traffics in cells and the mechanism of CDT intoxication remain to be elucidated. METHODS Recombinant CDT subunits (CdtA, CdtB, and CdtC) were purified, and their activity was characterized in gastrointestinal cells. Molecular approaches and image tracking were employed to analyze the delivery of CDT in host cells. RESULTS In this study, we found that CDT interacts with the receptor of advanced glycation end products (RAGE) and high mobility group box 1 (HMGB1) to enter the cells. Our results further showed that CdtB transport in cells through the dynamin-dependent endocytic pathway and lysosome is involved in this process. Conversely, blockage of RAGE signaling resulted in a reduction in CDT-arrested cell cycles, indicating that RAGE is involved in CDT intracellular transport and its subsequent pathogenesis. CONCLUSION Our results demonstrate that RAGE is important for CDT trafficking in the cells. These findings expand our understanding of important issues related to host cell intoxication by C. jejuni CDT.
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Affiliation(s)
- Yu-Fang Chang
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Ping Huang
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chia-Huei Chou
- Departments of Infectious Disease, School of Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Mao-Wang Ho
- Departments of Infectious Disease, School of Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Hwai-Jeng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho Hospital, New Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Ya Chen
- Department of Laboratory Medicine, Taichung Veterans General Hospital Chiayi Branch, Chiayi, Taiwan
| | - Hui-Yu Wu
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Ru Lai
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yuan-Haw Lee
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Hsun Chiu
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan; Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chih-Ho Lai
- Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan; Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Nursing, Asia University, Taichung, Taiwan; Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan.
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14
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Zhou Y, Meyle J, Groeger S. Periodontal pathogens and cancer development. Periodontol 2000 2024; 96:112-149. [PMID: 38965193 PMCID: PMC11579836 DOI: 10.1111/prd.12590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/03/2024] [Accepted: 06/11/2024] [Indexed: 07/06/2024]
Abstract
Increasing evidence suggests a significant association between periodontal disease and the occurrence of various cancers. The carcinogenic potential of several periodontal pathogens has been substantiated in vitro and in vivo. This review provides a comprehensive overview of the diverse mechanisms employed by different periodontal pathogens in the development of cancer. These mechanisms induce chronic inflammation, inhibit the host's immune system, activate cell invasion and proliferation, possess anti-apoptotic activity, and produce carcinogenic substances. Elucidating these mechanisms might provide new insights for developing novel approaches for tumor prevention, therapeutic purposes, and survival improvement.
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Affiliation(s)
- Yuxi Zhou
- Department of PeriodontologyJustus‐Liebig‐University of GiessenGiessenGermany
| | - Joerg Meyle
- Department of PeriodontologyJustus‐Liebig‐University of GiessenGiessenGermany
| | - Sabine Groeger
- Department of PeriodontologyJustus‐Liebig‐University of GiessenGiessenGermany
- Department of OrthodonticsJustus‐Liebig‐University of GiessenGiessenGermany
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15
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Nakano S, Kasai M, Nakamura K, Akasaka T, Yoshida Y, Suzuki S, Ohiro Y, Hasebe A. Epithelial-mesenchymal transition in oral cancer cells induced by prolonged and persistent Fusobacterium nucleatum stimulation. J Oral Biosci 2024; 66:594-604. [PMID: 38782256 DOI: 10.1016/j.job.2024.05.006] [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: 02/05/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVES Several studies have reported the effects of Fusobacterium nucleatum stimulation on oral cancer cells. However, given that these studies typically span a stimulation period of three days to eight days, the in vitro studies conducted to date may not fully mimic the oral cancer environment, which involves constant exposure to oral commensal bacteria. This study aimed to elucidate the effects of prolonged and persistent Fusobacterium nucleatum infection on oral cancer cells. METHODS Human tongue squamous cell carcinoma (SCC) cells were continuously stimulated with Fusobacterium nucleatum for two or four weeks, then experimentally evaluated. RESULTS Prolonged, persistent Fusobacterium nucleatum stimulation increased the cells' proliferative, invasive, and migratory capacities, decreased their expression of epithelial markers, and increased their expression of mesenchymal markers progressively with time. The cells also adopted a spindle-shaped morphology and cell-to-cell contact dependence was progressively lost, suggesting time-dependent occurrence of epithelial-mesenchymal transition. Furthermore, mRNA levels of CD44, a cancer stem cell marker, were time-dependently upregulated. When SCC cells were stimulated with Fusobacterium nucleatum for four weeks in the presence of dexamethasone, Fusobacterium nucleatum induced epithelial-mesenchymal transition was inhibited. CONCLUSIONS Epithelial-mesenchymal transition in human tongue SCC cells was time-dependently induced by prolonged, persistent Fusobacterium nucleatum stimulation and inhibited by dexamethasone. Routine decontamination of the oral cavity may be crucial for controlling tumor invasion and metastasis.
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Affiliation(s)
- Shintaro Nakano
- Oral and Maxillofacial Surgery, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan; Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Machiko Kasai
- Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan; Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Keisuke Nakamura
- Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan; Oral Diagnosis and Medicine, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tsukasa Akasaka
- Biomaterials and Bioengineering, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Yasuhiro Yoshida
- Biomaterials and Bioengineering, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Shiho Suzuki
- Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Yoichi Ohiro
- Oral and Maxillofacial Surgery, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Akira Hasebe
- Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
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16
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Azzi-Martin L, Touffait-Calvez V, Everaert M, Jia R, Sifré E, Seeneevassen L, Varon C, Dubus P, Ménard A. Cytolethal Distending Toxin Modulates Cell Differentiation and Elicits Epithelial to Mesenchymal Transition. J Infect Dis 2024; 229:1688-1701. [PMID: 38416880 DOI: 10.1093/infdis/jiae105] [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: 08/07/2023] [Revised: 01/29/2024] [Accepted: 02/27/2024] [Indexed: 03/01/2024] Open
Abstract
BACKGROUND The bacterial genotoxin, cytolethal distending toxin (CDT), causes DNA damage in host cells, a risk factor for carcinogenesis. Previous studies have shown that CDT induces phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process involved in cancer initiation and progression. METHODS We investigated different steps of EMT in response to Helicobacter hepaticus CDT and its active CdtB subunit using in vivo and in vitro models. RESULTS Most of the steps of the EMT process were induced by CDT/CdtB and observed throughout the study in murine and epithelial cell culture models. CdtB induced cell-cell junction disassembly, causing individualization of cells and acquisition of a spindle-like morphology. The key transcriptional regulators of EMT (SNAIL and ZEB1) and some EMT markers were upregulated at both RNA and protein levels in response to CDT/CdtB. CdtB increased the expression and proteolytic activity of matrix metalloproteinases, as well as cell migration. A range of these results were confirmed in Helicobacter hepaticus-infected and xenograft murine models. In addition, colibactin, a genotoxic metabolite produced by Escherichia coli, induced EMT-like effects in cell culture. CONCLUSIONS Overall, these data show that infection with genotoxin-producing bacteria elicits EMT process activation, supporting their role in tumorigenesis.
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Affiliation(s)
- Lamia Azzi-Martin
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
- Unité de Formation et de Recherche des Sciences Médicales, University of Bordeaux, Bordeaux, France
| | | | - Maude Everaert
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Ruxue Jia
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Elodie Sifré
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Lornella Seeneevassen
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Christine Varon
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
- Unité de Formation et de Recherche des Sciences Médicales, University of Bordeaux, Bordeaux, France
| | - Pierre Dubus
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
- Unité de Formation et de Recherche des Sciences Médicales, University of Bordeaux, Bordeaux, France
- Institut de Pathologie et de Biologie du Cancer, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Armelle Ménard
- Bordeaux Institute of Oncology, UMR1312, INSERM, University of Bordeaux, Bordeaux, France
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17
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Mascaretti F, Haider S, Amoroso C, Caprioli F, Ramai D, Ghidini M. Role of the Microbiome in the Diagnosis and Management of Gastroesophageal Cancers. J Gastrointest Cancer 2024; 55:662-678. [PMID: 38411876 DOI: 10.1007/s12029-024-01021-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE Stomach and esophageal cancers are among the highest mortality from cancers worldwide. Microbiota has an interplaying role within the human gastrointestinal (GI) tract. Dysbiosis occurs when a disruption of the balance between the microbiota and the host happens. With this narrative review, we discuss the main alterations in the microbiome of gastroesophageal cancer, revealing its potential role in the pathogenesis, early detection, and treatment. RESULTS Helicobacter pylori plays a major role the development of a cascade of preneoplastic conditions ranging from atrophic gastritis to metaplasia and dysplasia, ultimately culminating in gastric cancer, while other pathogenic agents are Fusobacterium nucleatum, Bacteroides fragilis, Escherichia coli, and Lactobacillus. Campylobacter species (spp.)'s role in the progression of esophageal adenocarcinoma may parallel that of Helicobacter pylori in the context of gastric cancer, with other esophageal carcinogenic agents being Escherichia coli, Bacteroides fragilis, and Fusobacterium nucleatum. Moreover, gut microbiome could significantly alter the outcomes of chemotherapy and immunotherapy. The gut microbiome can be modulated through interventions such as antibiotics, probiotics, or prebiotics intake. Fecal microbiota transplantation has emerged as a therapeutic strategy as well. CONCLUSIONS Nowadays, it is widely accepted that changes in the normal gut microbiome causing dysbiosis and immune dysregulation play a role gastroesophageal cancer. Different interventions, including probiotics and prebiotics intake are being developed to improve therapeutic outcomes and mitigate toxicities associated with anticancer treatment. Further studies are required in order to introduce the microbiome among the available tools of precision medicine in the field of anticancer treatment.
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Affiliation(s)
- Federica Mascaretti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Salman Haider
- Department of Internal Medicine, Brooklyn Hospital Center, Brooklyn, New York, NY, USA
| | - Chiara Amoroso
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Daryl Ramai
- Division of Gastroenterology and Hepatology, University of Utah Health, Salt Lake City, UT, USA
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Via Sforza 28, Milan, Italy.
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18
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Lieu DJ, Crowder MK, Kryza JR, Tamilselvam B, Kaminski PJ, Kim IJ, Li Y, Jeong E, Enkhbaatar M, Chen H, Son SB, Mok H, Bradley KA, Phillips H, Blanke SR. Autophagy suppression in DNA damaged cells occurs through a newly identified p53-proteasome-LC3 axis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.21.595139. [PMID: 38826216 PMCID: PMC11142043 DOI: 10.1101/2024.05.21.595139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that suppression of autophagy, through a newly identified p53-proteasome-LC3 axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could potentially be important for realigning proteostasis in cells undergoing DNA damage repair.
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19
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Liu S, Li W, Chen J, Li M, Geng Y, Liu Y, Wu W. The footprint of gut microbiota in gallbladder cancer: a mechanistic review. Front Cell Infect Microbiol 2024; 14:1374238. [PMID: 38774627 PMCID: PMC11106419 DOI: 10.3389/fcimb.2024.1374238] [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: 01/21/2024] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.
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Affiliation(s)
- Shujie Liu
- Joint Program of Nanchang University and Queen Mary University of London, Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi, China
| | - Weijian Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Jun Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yajun Geng
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Wenguang Wu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
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20
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Tikhomirova A, McNabb ER, Petterlin L, Bellamy GL, Lin KH, Santoso CA, Daye ES, Alhaddad FM, Lee KP, Roujeinikova A. Campylobacter jejuni virulence factors: update on emerging issues and trends. J Biomed Sci 2024; 31:45. [PMID: 38693534 PMCID: PMC11064354 DOI: 10.1186/s12929-024-01033-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/22/2024] [Indexed: 05/03/2024] Open
Abstract
Campylobacter jejuni is a very common cause of gastroenteritis, and is frequently transmitted to humans through contaminated food products or water. Importantly, C. jejuni infections have a range of short- and long-term sequelae such as irritable bowel syndrome and Guillain Barre syndrome. C. jejuni triggers disease by employing a range of molecular strategies which enable it to colonise the gut, invade the epithelium, persist intracellularly and avoid detection by the host immune response. The objective of this review is to explore and summarise recent advances in the understanding of the C. jejuni molecular factors involved in colonisation, invasion of cells, collective quorum sensing-mediated behaviours and persistence. Understanding the mechanisms that underpin the pathogenicity of C. jejuni will enable future development of effective preventative approaches and vaccines against this pathogen.
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Affiliation(s)
- Alexandra Tikhomirova
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Emmylee R McNabb
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Luca Petterlin
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Georgia L Bellamy
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Kyaw H Lin
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Christopher A Santoso
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Ella S Daye
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Fatimah M Alhaddad
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Kah Peng Lee
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia
| | - Anna Roujeinikova
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, 3800, Australia.
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia.
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Le LHM, Elgamoudi B, Colon N, Cramond A, Poly F, Ying L, Korolik V, Ferrero RL. Campylobacter jejuni extracellular vesicles harboring cytolethal distending toxin bind host cell glycans and induce cell cycle arrest in host cells. Microbiol Spectr 2024; 12:e0323223. [PMID: 38319111 PMCID: PMC10913475 DOI: 10.1128/spectrum.03232-23] [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: 08/30/2023] [Accepted: 12/20/2023] [Indexed: 02/07/2024] Open
Abstract
Cytolethal distending toxins (CDTs) are released by Gram-negative pathogens into the extracellular medium as free toxin or associated with extracellular vesicles (EVs), commonly known as outer membrane vesicles (OMVs). CDT production by the gastrointestinal pathogen Campylobacter jejuni has been implicated in colorectal tumorigenesis. Despite CDT being a major virulence factor for C. jejuni, little is known about the EV-associated form of this toxin. To address this point, C. jejuni mutants lacking each of the three CDT subunits (A, B, and C) were generated. C. jejuni cdtA, cdtB, and cdtC bacteria released EVs in similar numbers and sizes to wild-type bacteria, ranging from 5 to 530 nm (mean ± SEM = 118 ±6.9 nm). As the CdtAC subunits mediate toxin binding to host cells, we performed "surface shearing" experiments, in which EVs were treated with proteinase K and incubated with host cells. These experiments indicated that CDT subunits are internal to EVs and that surface proteins are probably not involved in EV-host cell interactions. Furthermore, glycan array studies demonstrated that EVs bind complex host cell glycans and share receptor binding specificities with C. jejuni bacteria for fucosyl GM1 ganglioside, P1 blood group antigen, sialyl, and sulfated Lewisx. Finally, we show that EVs from C. jejuni WT but not mutant bacteria induce cell cycle arrest in epithelial cells. In conclusion, we propose that EVs are an important mechanism for CDT release by C. jejuni and are likely to play a significant role in toxin delivery to host cells. IMPORTANCE Campylobacter jejuni is the leading cause of foodborne gastroenteritis in humans worldwide and a significant cause of childhood mortality due to diarrheal disease in developing countries. A major factor by which C. jejuni causes disease is a toxin, called cytolethal distending toxin (CDT). The biology of this toxin, however, is poorly understood. In this study, we report that C. jejuni CDT is protected within membrane blebs, known as extracellular vesicles (EVs), released by the bacterium. We showed that proteins on the surfaces of EVs are not required for EV uptake by host cells. Furthermore, we identified several sugar receptors that may be required for EV binding to host cells. By studying the EV-associated form of C. jejuni CDT, we will gain a greater understanding of how C. jejuni intoxicates host cells and how EV-associated CDT may be used in various therapeutic applications, including as anti-tumor therapies.
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Affiliation(s)
- Lena Hoang My Le
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia
| | - Bassam Elgamoudi
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
| | - Nina Colon
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
| | - Angus Cramond
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
| | - Frederic Poly
- Enteric Diseases Department, Naval Medical Research Centre, Silver Spring, Maryland, USA
| | - Le Ying
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
- Department of Molecular and Translational Sciences, Monash University, Victoria, Australia
| | - Victoria Korolik
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
| | - Richard L. Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia
- Department of Molecular and Translational Sciences, Monash University, Victoria, Australia
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22
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Lopez Chiloeches M, Bergonzini A, Martin OCB, Bergstein N, Erttmann SF, Aung KM, Gekara NO, Avila Cariño JF, Pateras IS, Frisan T. Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes. Front Immunol 2024; 14:1270449. [PMID: 38274797 PMCID: PMC10808668 DOI: 10.3389/fimmu.2023.1270449] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/22/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain. Methods In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis. Result The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage. Conclusions Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.
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Affiliation(s)
- Maria Lopez Chiloeches
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
| | - Anna Bergonzini
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
| | - Océane C. B. Martin
- Biological and Medical Sciences Department, University Bordeaux, Centre National de la Recherche Scientifique (CNRS), Institut de Biochimie et Génétique Cellulaires (IBGC), Unité Mixte de Recherche (UMR) 5095, Bordeaux, France
| | - Nicole Bergstein
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
| | - Saskia F. Erttmann
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
- Infection Oncology Unit, Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Kyaw Min Aung
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Nelson O. Gekara
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Institute of Medical Microbiology and Hygiene, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Javier F. Avila Cariño
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
| | - Ioannis S. Pateras
- Second Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR) Umeå University, Umeå, Sweden
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23
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Shayya NW, Bandick R, Busmann LV, Mousavi S, Bereswill S, Heimesaat MM. Metabolomic signatures of intestinal colonization resistance against Campylobacter jejuni in mice. Front Microbiol 2023; 14:1331114. [PMID: 38164399 PMCID: PMC10757985 DOI: 10.3389/fmicb.2023.1331114] [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: 10/31/2023] [Accepted: 11/24/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Campylobacter jejuni stands out as one of the leading causes of bacterial enteritis. In contrast to humans, specific pathogen-free (SPF) laboratory mice display strict intestinal colonization resistance (CR) against C. jejuni, orchestrated by the specific murine intestinal microbiota, as shown by fecal microbiota transplantation (FMT) earlier. Methods Murine infection models, comprising SPF, SAB, hma, and mma mice were employed. FMT and microbiota depletion were confirmed by culture and culture-independent analyses. Targeted metabolome analyses of fecal samples provided insights into the associated metabolomic signatures. Results In comparison to hma mice, the murine intestinal microbiota of mma and SPF mice (with CR against C. jejuni) contained significantly elevated numbers of lactobacilli, and Mouse Intestinal Bacteroides, whereas numbers of enterobacteria, enterococci, and Clostridium coccoides group were reduced. Targeted metabolome analysis revealed that fecal samples from mice with CR contained increased levels of secondary bile acids and fatty acids with known antimicrobial activities, but reduced concentrations of amino acids essential for C. jejuni growth as compared to control animals without CR. Discussion The findings highlight the role of microbiota-mediated nutrient competition and antibacterial activities of intestinal metabolites in driving murine CR against C. jejuni. The study underscores the complex dynamics of host-microbiota-pathogen interactions and sets the stage for further investigations into the mechanisms driving CR against enteric infections.
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24
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Patel V, Lynn-Bell N, Chevignon G, Kucuk RA, Higashi CHV, Carpenter M, Russell JA, Oliver KM. Mobile elements create strain-level variation in the services conferred by an aphid symbiont. Environ Microbiol 2023; 25:3333-3348. [PMID: 37864320 DOI: 10.1111/1462-2920.16520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/27/2023] [Indexed: 10/22/2023]
Abstract
Heritable, facultative symbionts are common in arthropods, often functioning in host defence. Despite moderately reduced genomes, facultative symbionts retain evolutionary potential through mobile genetic elements (MGEs). MGEs form the primary basis of strain-level variation in genome content and architecture, and often correlate with variability in symbiont-mediated phenotypes. In pea aphids (Acyrthosiphon pisum), strain-level variation in the type of toxin-encoding bacteriophages (APSEs) carried by the bacterium Hamiltonella defensa correlates with strength of defence against parasitoids. However, co-inheritance creates difficulties for partitioning their relative contributions to aphid defence. Here we identified isolates of H. defensa that were nearly identical except for APSE type. When holding H. defensa genotype constant, protection levels corresponded to APSE virulence module type. Results further indicated that APSEs move repeatedly within some H. defensa clades providing a mechanism for rapid evolution in anti-parasitoid defences. Strain variation in H. defensa also correlates with the presence of a second symbiont Fukatsuia symbiotica. Predictions that nutritional interactions structured this coinfection were not supported by comparative genomics, but bacteriocin-containing plasmids unique to co-infecting strains may contribute to their common pairing. In conclusion, strain diversity, and joint capacities for horizontal transfer of MGEs and symbionts, are emergent players in the rapid evolution of arthropods.
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Affiliation(s)
- Vilas Patel
- Department of Entomology, University of Georgia, Athens, Georgia, USA
| | - Nicole Lynn-Bell
- Department of Entomology, University of Georgia, Athens, Georgia, USA
| | - Germain Chevignon
- Laboratoire de Génétique et Pathologie des Mollusques Marins, IFREMER, La Tremblade, France
| | - Roy A Kucuk
- Department of Entomology, University of Georgia, Athens, Georgia, USA
| | | | - Melissa Carpenter
- Department of Biodiversity, Earth, and Environmental Science, Drexel University, Philadelphia, Pennsylvania, USA
| | - Jacob A Russell
- Department of Biology, Drexel University, Philadelphia, Pennsylvania, USA
| | - Kerry M Oliver
- Department of Entomology, University of Georgia, Athens, Georgia, USA
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25
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Chen Z, Guan D, Wang Z, Li X, Dong S, Huang J, Zhou W. Microbiota in cancer: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e417. [PMID: 37937304 PMCID: PMC10626288 DOI: 10.1002/mco2.417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/09/2023] Open
Abstract
The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Defeng Guan
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Zhengfeng Wang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Xin Li
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Shi Dong
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Junjun Huang
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Wence Zhou
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
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26
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Brown PI, Ojiakor A, Chemello AJ, Fowler CC. The diverse landscape of AB5-type toxins. ENGINEERING MICROBIOLOGY 2023; 3:100104. [PMID: 39628907 PMCID: PMC11610972 DOI: 10.1016/j.engmic.2023.100104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/25/2023] [Accepted: 06/17/2023] [Indexed: 12/06/2024]
Abstract
AB5-type toxins are a group of secreted protein toxins that are central virulence factors for bacterial pathogens such as Shigella dysenteriae, Vibrio cholerae, Bordetella pertussis, and certain lineages of pathogenic Escherichia coli and Salmonella enterica. AB5 toxins are composed of an active (A) subunit that manipulates host cell biology in complex with a pentameric binding/delivery (B) subunit that mediates the toxin's entry into host cells and its subsequent intracellular trafficking. Broadly speaking, all known AB5-type toxins adopt similar structural architectures and employ similar mechanisms of binding, entering and trafficking within host cells. Despite this, there is a remarkable amount of diversity amongst AB5-type toxins; this includes different toxin families with unrelated activities, as well as variation within families that can have profound functional consequences. In this review, we discuss the diversity that exists amongst characterized AB5-type toxins, with an emphasis on the genetic and functional variability within AB5 toxin families, how this may have evolved, and its impact on human disease.
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Affiliation(s)
- Paris I. Brown
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G2E9, Canada
| | - Adaobi Ojiakor
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G2E9, Canada
| | - Antonio J. Chemello
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G2E9, Canada
| | - Casey C. Fowler
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G2E9, Canada
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27
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Archer EW, Chisnall T, Tano-Debrah K, Card RM, Duodu S, Kunadu APH. Prevalence and genomic characterization of Salmonella isolates from commercial chicken eggs retailed in traditional markets in Ghana. Front Microbiol 2023; 14:1283835. [PMID: 38029182 PMCID: PMC10646427 DOI: 10.3389/fmicb.2023.1283835] [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: 08/27/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Salmonella enterica are important foodborne bacterial pathogens globally associated with poultry. Exposure to Salmonella-contaminated eggs and egg-related products is a major risk for human salmonellosis. Presently, there is a huge data gap regarding the prevalence and circulating serovars of Salmonella in chicken eggs sold in Ghana. In this study, 2,304 eggs (pools of six per sample unit) collected from informal markets in Accra, Kumasi and Tamale, representing the three ecological belts across Ghana, were tested for Salmonella. Antimicrobial susceptibility testing and Whole Genome Sequencing (WGS) of the isolates were performed using standard microdilution protocols and the Illumina NextSeq platform, respectively. The total prevalence of Salmonella was 5.5% with a higher rate of contamination in eggshell (4.9%) over egg content (1.8%). The serovars identified were S. Ajiobo (n = 1), S. Chester (n = 6), S. Hader (n = 7), S. enteritidis (n = 2); and S. I 4:b:- (n = 8). WGS analysis revealed varied sequence types (STs) that were serovar specific. The S. I 4:b:- isolates had a novel ST (ST8938), suggesting a local origin. The two S. enteritidis isolates belonged to ST11 and were identified with an invasive lineage of a global epidemic clade. All isolates were susceptible to ampicillin, azithromycin, cefotaxime, ceftazidime, gentamicin, meropenem, and tigecycline. The phenotypic resistance profiles to seven antimicrobials: chloramphenicol (13%), ciprofloxacin (94%), and nalidixic acid (94%), colistin (13%), trimethoprim (50%) sulfamethoxazole (50%) and tetracycline (50%) corresponded with the presence of antimicrobial resistance (AMR) determinants including quinolones (gyrA (D87N), qnrB81), aminoglycosides (aadA1), (aph(3")-Ib aph(6)-Id), tetracyclines (tet(A)), phenicols (catA1), trimethoprim (dfrA14 and dfrA1). The S. enteritidis and S. Chester isolates were multidrug resistant (MDR). Several virulence factors were identified, notably cytolethal distending toxin (cdtB gene), rck, pef and spv that may promote host invasion and disease progression in humans. The findings from this study indicate the presence of multidrug resistant and virulent strains of Salmonella serovars in Ghanaian chicken eggs, with the potential to cause human infections. This is a critical baseline information that could be used for Salmonella risk assessment in the egg food chain to mitigate potential future outbreaks.
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Affiliation(s)
- Edward W. Archer
- Nutrition and Food Science Department, University of Ghana, Accra, Ghana
- Food and Drug Authority, Food Safety Management Department, Accra, Ghana
| | - Tom Chisnall
- Animal and Plant Health Agency, Addlestone, United Kingdom
| | - Kwaku Tano-Debrah
- Nutrition and Food Science Department, University of Ghana, Accra, Ghana
| | | | - Samuel Duodu
- Biochemistry Cell and Molecular Biology Department, University of Ghana, Accra, Ghana
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana
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28
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Simons ME, Narindoshvili T, Raushel FM. Biosynthesis of UDP-β-l-Arabinofuranoside for the Capsular Polysaccharides of Campylobacter jejuni. Biochemistry 2023; 62:3012-3019. [PMID: 37737649 PMCID: PMC10615251 DOI: 10.1021/acs.biochem.3c00298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/05/2023] [Indexed: 09/23/2023]
Abstract
Campylobacter jejuni is the leading cause of food poisoning in North America and Europe. The exterior surface of this bacterium is coated with a capsular polysaccharide (CPS) which enables adherence to the host epithelial cells and evasion of the host immune system. Many strains of C. jejuni can be differentiated from one another by changes in the sequence of the carbohydrates found within the CPS. The CPS structures of serotypes HS:15 and HS:41 of C. jejuni were chemically characterized and found to contain an l-arabinofuranoside moiety in the repeating CPS sequence. Sequence similarity and genome neighborhood networks were used to identify the putative gene cluster within the HS:15 serotype for the biosynthesis of the l-arabinofuranoside fragment. The first enzyme (HS:15.18) in the pathway was found to catalyze the NAD+-dependent oxidation of UDP-α-d-glucose to UDP-α-d-glucuronate, while the second enzyme (HS:15.19) catalyzes the NAD+-dependent decarboxylation of this product to form UDP-α-d-xylose. The UDP-α-d-xylose is then epimerized at C4 by the third enzyme (HS:15.17) to produce UDP-β-l-arabinopyranoside. In the last step, HS:15.16 catalyzes the FADH2-dependent conversion of UDP-β-l-arabinopyranoside into UDP-β-l-arabinofuranoside. The UDP-β-l-arabinopyranoside mutase catalyzed reaction was further interrogated by measurement of a positional isotope exchange reaction within [18O]-UDP-β-l-arabinopyranoside.
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Affiliation(s)
- Max Errickson Simons
- Department
of Biochemistry & Biophysics, Texas
A&M University, College
Station, Texas 77842, United States
| | - Tamari Narindoshvili
- Department
of Chemistry, Texas A&M University, College Station, Texas 77842, United States
| | - Frank M. Raushel
- Department
of Biochemistry & Biophysics, Texas
A&M University, College
Station, Texas 77842, United States
- Department
of Chemistry, Texas A&M University, College Station, Texas 77842, United States
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Zulpa AK, Barathan M, Iyadorai T, Mariappan V, Vadivelu J, Teh CSJ, Vellasamy KM. Selective pks+ Escherichia coli strains induce cell cycle arrest and apoptosis in colon cancer cell line. World J Microbiol Biotechnol 2023; 39:333. [PMID: 37801157 DOI: 10.1007/s11274-023-03767-1] [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: 07/13/2023] [Accepted: 09/15/2023] [Indexed: 10/07/2023]
Abstract
pks+ Escherichia coli (E. coli) triggers genomic instability in normal colon cells which leads to colorectal cancer (CRC) tumorigenesis. Previously, we reported a significant presentation of pks+ E. coli strains in CRC patients' biopsies as compared to healthy cohorts. In this work, using an in vitro infection model, we further explored the ability of these strains in modulating cell cycle arrest and activation of apoptotic mediators in both primary colon epithelial cells (PCE) and CRC cells (HCT-116). Sixteen strains, of which eight tumours and the matching non-malignant tissues, respectively, from eight pks+ E. coli CRC patients were subjected to BrDU staining and cell cycle analysis via flow cytometry, while a subset of these strains underwent analysis of apoptotic mediators including caspase proteins, cellular reactive oxygen species (cROS) and mitochondrial membrane potential (MMP) via spectrophotometry as well as proinflammatory cytokines via flow cytometry. Data revealed that all strains exerted S-phase cell cycle blockade in both cells and G2/M phase in PCE cells only. Moreover, more significant upregulation of Caspase 9, cROS, proinflammatory cytokines and prominent downregulation of MMP were detected in HCT-116 cells indicating the potential role of pks related bacterial toxin as anticancer agent as compared to PCE cells which undergo cellular senescence leading to cell death without apparent upregulation of apoptotic mediators. These findings suggest the existence of discrepancies underlying the mechanism of action of pks+ E. coli on both cancer and normal cell lines. This work propounds the rationale to further understand the mechanism underlying pks+ E. coli-mediated CRC tumorigenesis and cancer killing.
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Affiliation(s)
- A K Zulpa
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - M Barathan
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - T Iyadorai
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - V Mariappan
- Center of Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - J Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - C S J Teh
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - K M Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
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30
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Zhang Y, Huang R, Jiang Y, Shen W, Pei H, Wang G, Pei P, Yang K. The role of bacteria and its derived biomaterials in cancer radiotherapy. Acta Pharm Sin B 2023; 13:4149-4171. [PMID: 37799393 PMCID: PMC10547917 DOI: 10.1016/j.apsb.2022.10.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/02/2022] [Accepted: 08/16/2022] [Indexed: 11/21/2022] Open
Abstract
Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics. It has made significant progress in breaking the limitations of monotherapy and effectively eradicating tumors, especially when combined with traditional therapy, such as radiotherapy. According to their different biological characteristics, bacteria and their derivatives can not only improve the sensitivity of tumor radiotherapy but also protect normal tissues. Moreover, genetically engineered bacteria and bacteria-based biomaterials have further expanded the scope of their applications in radiotherapy. In this review, we have summarized relevant researches on the application of bacteria and its derivatives in radiotherapy in recent years, expounding that the bacteria, bacterial derivatives and bacteria-based biomaterials can not only directly enhance radiotherapy but also improve the anti-tumor effect by improving the tumor microenvironment (TME) and immune effects. Furthermore, some probiotics can also protect normal tissues and organs such as intestines from radiation via anti-inflammatory, anti-oxidation and apoptosis inhibition. In conclusion, the prospect of bacteria in radiotherapy will be very extensive, but its biological safety and mechanism need to be further evaluated and studied.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Ruizhe Huang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Yunchun Jiang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Wenhao Shen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Hailong Pei
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Guanglin Wang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Pei Pei
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Kai Yang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
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Yi J, Lin P, Li Q, Zhang A, Kong X. A new strategy for treating colorectal cancer: Regulating the influence of intestinal flora and oncolytic virus on interferon. Mol Ther Oncolytics 2023; 30:254-274. [PMID: 37701850 PMCID: PMC10493895 DOI: 10.1016/j.omto.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
Colorectal cancer (CRC) has the third highest incidence and the second highest mortality in the world, which seriously affects human health, while current treatments methods for CRC, including systemic therapy, preoperative radiotherapy, and surgical local excision, still have poor survival rates for patients with metastatic disease, making it critical to develop new strategies for treating CRC. In this article, we found that the gut microbiota can modulate the signaling pathways of cancer cells through direct contact with tumor cells, generate inflammatory responses and oxidative stress through interactions between the innate and adaptive immune systems, and produce diverse metabolic combinations to trigger specific immune responses and promote the initiation of systemic type I interferon (IFN-I) and anti-viral immunity. In addition, oncolytic virus-mediated immunotherapy for regulating oncolytic virus can directly lyse tumor cells, induce the immune activity of the body, interact with interferon, inhibit the anti-viral effect of IFN-I, and enhance the anti-tumor effect of IFN-II. Interferon plays an important role in the anti-tumor process. We put forward that exploring the effects of intestinal flora and oncolytic virus on interferon to treat CRC is a promising therapeutic option.
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Affiliation(s)
- Jia Yi
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Peizhe Lin
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Qingbo Li
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ao Zhang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xianbin Kong
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
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Gong Y, Huang X, Wang M, Liang X. Intratumor microbiota: a novel tumor component. J Cancer Res Clin Oncol 2023; 149:6675-6691. [PMID: 36639531 DOI: 10.1007/s00432-023-04576-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023]
Abstract
Bacteria have been found in tumors for over 100 years, but the irreproducibility of experiments on bacteria, the limitations of science and technology, and the contamination of the host environment have severely hampered most research into the role of bacteria in carcinogenesis and cancer treatment. With the development of molecular tools and techniques (e.g., macrogenomics, metabolomics, lipidomics, and macrotranscriptomics), the complex relationships between hosts and different microorganisms are gradually being deciphered. In the past, attention has been focused on the impact of the gut microbiota, the site where the body's microbes gather most, on tumors. However, little is known about the role of microbes from other sites, particularly the intratumor microbiota, in cancer. In recent years, an increasing number of studies have identified the presence of symbiotic microbiota within a large number of tumors, bringing the intratumor microbiota into the limelight. In this review, we aim to provide a better understanding of the role of the intratumor microbiota in cancer, to provide direction for future experimental and translational research, and to offer new approaches to the treatment of cancer and the improvement of patient prognosis.
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Affiliation(s)
- Yanyu Gong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xinqi Huang
- Excellent Class, Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Minhui Wang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoqiu Liang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Hassan J, Awasthi SP, Hatanaka N, Hoang PH, Nagita A, Hinenoya A, Faruque SM, Yamasaki S. Presence of Functionally Active Cytolethal Distending Toxin Genes on a Conjugative Plasmid in a Clinical Isolate of Providencia rustigianii. Infect Immun 2023; 91:e0012122. [PMID: 37158737 PMCID: PMC10269090 DOI: 10.1128/iai.00121-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/14/2023] [Indexed: 05/10/2023] Open
Abstract
Providencia rustigianii is potentially enteropathogenic in humans. Recently, we identified a P. rustigianii strain carrying a part of the cdtB gene homologous to that of Providencia alcalifacines that produces an exotoxin called cytolethal distending toxin (CDT), encoded by three subunit genes (cdtA, cdtB, and cdtC). In this study, we analyzed the P. rustigianii strain for possible presence of the entire cdt gene cluster and its organization, location, and mobility, as well as expression of the toxin as a putative virulence factor of P. rustigianii. Nucleotide sequence analysis revealed the presence of the three cdt subunit genes in tandem, and over 94% homology to the corresponding genes carried by P. alcalifaciens both at nucleotide and amino acid sequence levels. The P. rustigianii strain produced biologically active CDT, which caused distension of eukaryotic cell lines with characteristic tropism of CHO and Caco-2 cells but not of Vero cells. S1-nuclease digested pulsed-field gel electrophoresis followed by Southern hybridization analysis demonstrated that the cdt genes in both P. rustigianii and P. alcalifaciens strains are located on large plasmids (140 to 170 kb). Subsequently, conjugation assays using a genetically marked derivative of the P. rustigianii strain showed that the plasmid carrying cdt genes in the P. rustigianii was transferable to cdt gene-negative recipient strains of P. rustigianii, Providencia rettgeri, and Escherichia coli. Our results demonstrated the presence of cdt genes in P. rustigianii for the first time, and further showed that the genes are located on a transferable plasmid, which can potentially spread to other bacterial species.
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Affiliation(s)
- Jayedul Hassan
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Sharda Prasad Awasthi
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
- Graduate School of Veterinary Science, Osaka Metropolitan University, Osaka, Japan
- Asian Health Science Research Institute, Osaka Metropolitan University, Osaka, Japan
- Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Japan
| | - Noritoshi Hatanaka
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
- Graduate School of Veterinary Science, Osaka Metropolitan University, Osaka, Japan
- Asian Health Science Research Institute, Osaka Metropolitan University, Osaka, Japan
- Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Japan
| | - Phuong Hoai Hoang
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Akira Nagita
- Department of Pediatrics, Mizushima Central Hospital, Okayama, Japan
| | - Atsushi Hinenoya
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
- Graduate School of Veterinary Science, Osaka Metropolitan University, Osaka, Japan
- Asian Health Science Research Institute, Osaka Metropolitan University, Osaka, Japan
- Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Japan
| | - Shah M. Faruque
- School of Environment and Life Sciences, Independent University Bangladesh (IUB), Bashundhara, Dhaka, Bangladesh
| | - Shinji Yamasaki
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
- Graduate School of Veterinary Science, Osaka Metropolitan University, Osaka, Japan
- Asian Health Science Research Institute, Osaka Metropolitan University, Osaka, Japan
- Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Japan
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Asseri AH, Bakhsh T, Abuzahrah SS, Ali S, Rather IA. The gut dysbiosis-cancer axis: illuminating novel insights and implications for clinical practice. Front Pharmacol 2023; 14:1208044. [PMID: 37361202 PMCID: PMC10288883 DOI: 10.3389/fphar.2023.1208044] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/31/2023] [Indexed: 06/28/2023] Open
Abstract
The human intestinal microbiota, also known as the gut microbiota, comprises more than 100 trillion organisms, mainly bacteria. This number exceeds the host body cells by a factor of ten. The gastrointestinal tract, which houses 60%-80% of the host's immune cells, is one of the largest immune organs. It maintains systemic immune homeostasis in the face of constant bacterial challenges. The gut microbiota has evolved with the host, and its symbiotic state with the host's gut epithelium is a testament to this co-evolution. However, certain microbial subpopulations may expand during pathological interventions, disrupting the delicate species-level microbial equilibrium and triggering inflammation and tumorigenesis. This review highlights the impact of gut microbiota dysbiosis on the development and progression of certain types of cancers and discusses the potential for developing new therapeutic strategies against cancer by manipulating the gut microbiota. By interacting with the host microbiota, we may be able to enhance the effectiveness of anticancer therapies and open new avenues for improving patient outcomes.
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Affiliation(s)
- Amer H. Asseri
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Center for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tahani Bakhsh
- Department of Biology, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | | | - Sajad Ali
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia
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Wang LW, Ruan H, Wang BM, Qin Y, Zhong WL. Microbiota regulation in constipation and colorectal cancer. World J Gastrointest Oncol 2023; 15:776-786. [PMID: 37275451 PMCID: PMC10237018 DOI: 10.4251/wjgo.v15.i5.776] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 04/21/2023] [Indexed: 05/12/2023] Open
Abstract
The relevance of constipation to the development and progression of colorectal cancer (CRC) is currently a controversial issue. Studies have shown that changes in the composition of the gut microbiota, a condition known as ecological imbalance, are correlated with an increasing number of common human diseases, including CRC and constipation. CRC is the second leading cause of cancer-related deaths worldwide, and constipation has been receiving widespread attention as a risk factor for CRC. Early colonoscopy screening of constipated patients, with regular follow-ups and timely intervention, can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC. As an important regulator of the intestinal microenvironment, the gut microbiota plays a critical role in the onset and progression of CRC. An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression, with alterations inducing changes in the expression of host genes, metabolic regulation, and local and systemic immunological responses. Furthermore, constipation greatly affects the composition of the gut microbiota, which in turn influences the susceptibility to intestinal diseases such as CRC. However, the crosstalk between the gut microbiota, constipation, and CRC is still unclear.
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Affiliation(s)
- Li-Wei Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Ruan
- China Resources Biopharmaceutical Company Limited, Beijing 100029, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yuan Qin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Wei-Long Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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36
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Kemper L, Hensel A. Campylobacter jejuni: targeting host cells, adhesion, invasion, and survival. Appl Microbiol Biotechnol 2023; 107:2725-2754. [PMID: 36941439 PMCID: PMC10027602 DOI: 10.1007/s00253-023-12456-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/23/2023]
Abstract
Campylobacter jejuni, causing strong enteritis, is an unusual bacterium with numerous peculiarities. Chemotactically controlled motility in viscous milieu allows targeted navigation to intestinal mucus and colonization. By phase variation, quorum sensing, extensive O-and N-glycosylation and use of the flagellum as type-3-secretion system C. jejuni adapts effectively to environmental conditions. C. jejuni utilizes proteases to open cell-cell junctions and subsequently transmigrates paracellularly. Fibronectin at the basolateral side of polarized epithelial cells serves as binding site for adhesins CadF and FlpA, leading to intracellular signaling, which again triggers membrane ruffling and reduced host cell migration by focal adhesion. Cell contacts of C. jejuni results in its secretion of invasion antigens, which induce membrane ruffling by paxillin-independent pathway. In addition to fibronectin-binding proteins, other adhesins with other target structures and lectins and their corresponding sugar structures are involved in host-pathogen interaction. Invasion into the intestinal epithelial cell depends on host cell structures. Fibronectin, clathrin, and dynein influence cytoskeletal restructuring, endocytosis, and vesicular transport, through different mechanisms. C. jejuni can persist over a 72-h period in the cell. Campylobacter-containing vacuoles, avoid fusion with lysosomes and enter the perinuclear space via dynein, inducing signaling pathways. Secretion of cytolethal distending toxin directs the cell into programmed cell death, including the pyroptotic release of proinflammatory substances from the destroyed cell compartments. The immune system reacts with an inflammatory cascade by participation of numerous immune cells. The development of autoantibodies, directed not only against lipooligosaccharides, but also against endogenous gangliosides, triggers autoimmune diseases. Lesions of the epithelium result in loss of electrolytes, water, and blood, leading to diarrhea, which flushes out mucus containing C. jejuni. Together with the response of the immune system, this limits infection time. Based on the structural interactions between host cell and bacterium, the numerous virulence mechanisms, signaling, and effects that characterize the infection process of C. jejuni, a wide variety of targets for attenuation of the pathogen can be characterized. The review summarizes strategies of C. jejuni for host-pathogen interaction and should stimulate innovative research towards improved definition of targets for future drug development. KEY POINTS: • Bacterial adhesion of Campylobacter to host cells and invasion into host cells are strictly coordinated processes, which can serve as targets to prevent infection. • Reaction and signalling of host cell depend on the cell type. • Campylobacter virulence factors can be used as targets for development of antivirulence drug compounds.
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Affiliation(s)
- Leon Kemper
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Corrensstraße 48, 48149, Münster, Germany
| | - Andreas Hensel
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Corrensstraße 48, 48149, Münster, Germany.
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Molecular Targets in Campylobacter Infections. Biomolecules 2023; 13:biom13030409. [PMID: 36979344 PMCID: PMC10046527 DOI: 10.3390/biom13030409] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/08/2023] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies.
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Genotoxins: The Mechanistic Links between Escherichia coli and Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15041152. [PMID: 36831495 PMCID: PMC9954437 DOI: 10.3390/cancers15041152] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Emerging evidence indicates bacterial infections contribute to the formation of cancers. Bacterial genotoxins are effectors that cause DNA damage by introducing single- and double-strand DNA breaks in the host cells. The first bacterial genotoxin cytolethal distending toxin (CDT) was a protein identified in 1987 in a pathogenic strain in Escherichia coli (E. coli) isolated from a young patient. The peptide-polyketide genotoxin colibactin is produced by the phylogenetic group B2 of E. coli. Recently, a protein produced by attaching/effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) and their murine equivalent Citrobacter rodentium (CR), has been reported as a novel protein genotoxin, being injected via the type III secretion system (T3SS) into host cells and harboring direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. These E. coli-produced genotoxins impair host DNA, which results in senescence or apoptosis of the target cells if the damage is beyond repair. Conversely, host cells can survive and proliferate if the genotoxin-induced DNA damage is not severe enough to kill them. The surviving cells may accumulate genomic instability and acquire malignant traits. This review presents the cellular responses of infection with the genotoxins-producing E. coli and discusses the current knowledge of the tumorigenic potential of these toxins.
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Xu S, Xiong Y, Fu B, Guo D, Sha Z, Lin X, Wu H. Bacteria and macrophages in the tumor microenvironment. Front Microbiol 2023; 14:1115556. [PMID: 36825088 PMCID: PMC9941202 DOI: 10.3389/fmicb.2023.1115556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 01/12/2023] [Indexed: 02/10/2023] Open
Abstract
Cancer and microbial infections are significant worldwide health challenges. Numerous studies have demonstrated that bacteria may contribute to the emergence of cancer. In this review, we assemble bacterial species discovered in various cancers to describe their variety and specificity. The relationship between bacteria and macrophages in cancer is also highlighted, and we look for ample proof to establish a biological basis for bacterial-induced macrophage polarization. Finally, we quickly go over the potential roles of metabolites, cytokines, and microRNAs in the regulation of the tumor microenvironment by bacterially activated macrophages. The complexity of bacteria and macrophages in cancer will be revealed as we gain a better understanding of their pathogenic mechanisms, which will lead to new therapeutic approaches for both inflammatory illnesses and cancer.
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Affiliation(s)
| | | | - Beibei Fu
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Dong Guo
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Zhou Sha
- School of Life Sciences, Chongqing University, Chongqing, China
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Abstract
The major function of the mammalian immune system is to prevent and control infections caused by enteropathogens that collectively have altered human destiny. In fact, as the gastrointestinal tissues are the major interface of mammals with the environment, up to 70% of the human immune system is dedicated to patrolling them The defenses are multi-tiered and include the endogenous microflora that mediate colonization resistance as well as physical barriers intended to compartmentalize infections. The gastrointestinal tract and associated lymphoid tissue are also protected by sophisticated interleaved arrays of active innate and adaptive immune defenses. Remarkably, some bacterial enteropathogens have acquired an arsenal of virulence factors with which they neutralize all these formidable barriers to infection, causing disease ranging from mild self-limiting gastroenteritis to in some cases devastating human disease.
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Affiliation(s)
- Micah J. Worley
- Department of Biology, University of Louisville, Louisville, Kentucky, USA,CONTACT Micah J. Worley Department of Biology, University of Louisville, 139 Life Sciences Bldg, Louisville, Kentucky, USA
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Montanari M, Guescini M, Gundogdu O, Luchetti F, Lanuti P, Ciacci C, Burattini S, Campana R, Ortolani C, Papa S, Canonico B. Extracellular Vesicles from Campylobacter jejuni CDT-Treated Caco-2 Cells Inhibit Proliferation of Tumour Intestinal Caco-2 Cells and Myeloid U937 Cells: Detailing the Global Cell Response for Potential Application in Anti-Tumour Strategies. Int J Mol Sci 2022; 24:ijms24010487. [PMID: 36613943 PMCID: PMC9820799 DOI: 10.3390/ijms24010487] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/15/2022] [Accepted: 12/23/2022] [Indexed: 12/30/2022] Open
Abstract
Cytolethal distending toxin (CDT) is produced by a range of Gram-negative pathogenic bacteria such as Campylobacter jejuni. CDT represents an important virulence factor that is a heterotrimeric complex composed of CdtA, CdtB, and CdtC. CdtA and CdtC constitute regulatory subunits whilst CdtB acts as the catalytic subunit exhibiting phosphatase and DNase activities, resulting in cell cycle arrest and cell death. Extracellular vesicle (EV) secretion is an evolutionarily conserved process that is present throughout all kingdoms. Mammalian EVs play important roles in regular cell-to-cell communications but can also spread pathogen- and host-derived molecules during infections to alter immune responses. Here, we demonstrate that CDT targets the endo-lysosomal compartment, partially evading lysosomal degradation and exploiting unconventional secretion (EV release), which is largely involved in bacterial infections. CDT-like effects are transferred by Caco-2 cells to uninfected heterologous U937 and homologous Caco-2 cells. The journey of EVs derived from CDT-treated Caco-2 cells is associated with both intestinal and myeloid tumour cells. EV release represents the primary route of CDT dissemination, revealing an active toxin as part of the cargo. We demonstrated that bacterial toxins could represent suitable tools in cancer therapy, highlighting both the benefits and limitations. The global cell response involves a moderate induction of apoptosis and autophagic features may play a protective role against toxin-induced cell death. EVs from CDT-treated Caco-2 cells represent reliable CDT carriers, potentially suitable in colorectal cancer treatments. Our data present a potential bacterial-related biotherapeutic supporting a multidrug anticancer protocol.
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Affiliation(s)
- Mariele Montanari
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Michele Guescini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Ozan Gundogdu
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK
| | - Francesca Luchetti
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Paola Lanuti
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Caterina Ciacci
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Sabrina Burattini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Raffaella Campana
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Claudio Ortolani
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Stefano Papa
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
- Correspondence:
| | - Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
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Oey O, Liu YY, Sunjaya AF, Simadibrata DM, Khattak MA, Gray E. Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients: A systematic review. World J Clin Oncol 2022; 13:929-942. [PMID: 36483977 PMCID: PMC9724183 DOI: 10.5306/wjco.v13.i11.929] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 10/30/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Gut microbiome (GM) composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy (ICB) and of ICB-related colitis.
AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.
METHODS The review protocol was registered in PROSPERO: CRD42021228018. From a total of 300 studies, nine studies met inclusion criteria. Two studies were phase I clinical trials, while the remainder were prospective observational studies. All but one study has moderate risk of bias. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com).
RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB, whereas the Bacteroidales family was associated with poor response to ICB. Samples with greater GM diversity were associated with more favorable response to ICB [hazard ratio (HR) = 3.57, 95% confidence interval = 1.02-12.52, P < 0.05]. Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis (P < 0.01) whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis (P < 0.05). Overall, there was limited concordance in the organisms in the GM identified to be associated with response to ICB, and studies evaluating GM diversity showed conflicting results.
CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.
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Affiliation(s)
- Oliver Oey
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland, Perth 6004, WA, Australia
- School of Medicine, University of Western Australia, Perth 6009, WA, Australia
| | - Yu-Yang Liu
- School of Medicine, University of Queensland, Brisbane 4072, QLD, Australia
| | | | | | - Muhammad Adnan Khattak
- Department of Medical Oncology, Fiona Stanley Hospital, Perth 6150, WA, Australia
- School of Medical Sciences, Edith Cowan University, Perth 6027, WA, Australia
- Centre for Precision Health, Edith Cowan University, Perth 6027, WA, Australia
| | - Elin Gray
- School of Medical Sciences, Edith Cowan University, Perth 6027, WA, Australia
- Centre for Precision Health, Edith Cowan University, Perth 6027, WA, Australia
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43
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Abstract
Unexpected members of the gut microbiota produce diverse host cell genotoxins.
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Affiliation(s)
- Jens Puschhof
- Microbiome and Cancer Division, German Cancer Research Center, Heidelberg, Germany
| | - Cynthia L Sears
- Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- TheBloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zhou W, Chen X, Fan Q, Yu H, Jiang W. Using proton pump inhibitors increases the risk of hepato-biliary-pancreatic cancer. A systematic review and meta-analysis. Front Pharmacol 2022; 13:979215. [PMID: 36188583 PMCID: PMC9515471 DOI: 10.3389/fphar.2022.979215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background: More and more studies are focusing on the adverse effects and damage caused by PPI abuse, we carried out a systematic review and meta-analysis for assessing whether the proton pump inhibitor (PPI) leads to hepato-biliary-pancreatic cancer. Methods: PubMed, EMBASE and Web of Science were searched until 1 July 2022, 25 studies (17 case-control and 8 cohort studies; 2741853 individuals) included in this study. Pooled Odd Ratios (ORs) were used for random effect models. Sensitivity analysis and dose-response analysis, subgroup analysis were all conducted. Results: The aggregate OR of the meta-analysis was 1.69 (95% confidence interval (CI): 1.42–2.01, p = 0.01) and heterogeneity (I2 = 98.9%, p < 0.001) was substantial. According to stratified subgroup analyses, the incidence of hepato-biliary-pancreatic cancer was associated, expect for study design, study quality and region. Risk of hepato-biliary-pancreatic cancer is highest when people is treated with normal doses of PPI. The risks decrease and become insignificant when the cumulative defined daily dose (cDDD) increases. Conclusion: The use of PPI may be associated with an increased risk of hepato-biliary-pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of hepato-biliary-pancreatic cancer.
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Affiliation(s)
- Wence Zhou
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, Gansu, China
- *Correspondence: Wence Zhou,
| | - Xinlong Chen
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Qigang Fan
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Haichuan Yu
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Wenkai Jiang
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Abstract
AB toxins are protein virulence factors secreted by many bacterial pathogens, contributing to the pathogenicity of the cognate bacteria. AB toxins consist of two functionally distinct components: the enzymatic "A" component for pathogenicity and the receptor-binding "B" component for toxin delivery. Consistently, unlike other virulence factors such as effectors, AB toxins do not require additional systems to deliver them to the target host cells. Target host cells are located in the infection site and/or located distantly from infected host cells. The first part of this review discusses the structural and functional features of single-peptide and multiprotein AB toxins in the context of host-microbe interactions, using several well-characterized examples. The second part of this review discusses toxin neutralization strategies, as well as applications of AB toxins relevant to developing intervention strategies against diseases.
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Affiliation(s)
- Jeongmin Song
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY, United States.
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Abstract
Bacterial genotoxins are peptide or protein virulence factors produced by several pathogens, which make single-strand breaks (SSBs) and/or double-strand DNA breaks (DSBs) in the target host cells. If host DNA inflictions are not resolved on time, host cell apoptosis, cell senescence, and/or even bacterial pathogen-related cancer may occur. Two multi-protein AB toxins, cytolethal distending toxin (CDT) produced by over 30 bacterial pathogens and typhoid toxin from Salmonella Typhi, as well as small polyketide-peptides named colibactin that causes the DNA interstrand cross-linking and subsequent DSBs is the most well-characterized bacterial genotoxins. Using these three examples, this review discusses the mechanisms by which these toxins deliver themselves into the nucleus of the target host cells and exert their genotoxic functions at the structural and functional levels.
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Affiliation(s)
- Liaoqi Du
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Jeongmin Song
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
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Dey P, Ray Chaudhuri S. Cancer-Associated Microbiota: From Mechanisms of Disease Causation to Microbiota-Centric Anti-Cancer Approaches. BIOLOGY 2022; 11:757. [PMID: 35625485 PMCID: PMC9138768 DOI: 10.3390/biology11050757] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is the only well-established bacterial cause of cancer. However, due to the integral role of tissue-resident commensals in maintaining tissue-specific immunometabolic homeostasis, accumulated evidence suggests that an imbalance of tissue-resident microbiota that are otherwise considered as commensals, can also promote various types of cancers. Therefore, the present review discusses compelling evidence linking tissue-resident microbiota (especially gut bacteria) with cancer initiation and progression. Experimental evidence supporting the cancer-causing role of gut commensal through the modulation of host-specific processes (e.g., bile acid metabolism, hormonal effects) or by direct DNA damage and toxicity has been discussed. The opportunistic role of commensal through pathoadaptive mutation and overcoming colonization resistance is discussed, and how chronic inflammation triggered by microbiota could be an intermediate in cancer-causing infections has been discussed. Finally, we discuss microbiota-centric strategies, including fecal microbiota transplantation, proven to be beneficial in preventing and treating cancers. Collectively, this review provides a comprehensive understanding of the role of tissue-resident microbiota, their cancer-promoting potentials, and how beneficial bacteria can be used against cancers.
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Affiliation(s)
- Priyankar Dey
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, India
| | - Saumya Ray Chaudhuri
- Council of Scientific and Industrial Research (CSIR), Institute of Microbial Technology, Chandigarh 160036, India;
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DiMaio D, Emu B, Goodman AL, Mothes W, Justice A. Cancer Microbiology. J Natl Cancer Inst 2022; 114:651-663. [PMID: 34850062 PMCID: PMC9086797 DOI: 10.1093/jnci/djab212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/18/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health.
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Affiliation(s)
- Daniel DiMaio
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Yale Cancer Center, New Haven, CT, USA
| | - Brinda Emu
- Yale Cancer Center, New Haven, CT, USA
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Andrew L Goodman
- Yale Cancer Center, New Haven, CT, USA
- Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA
| | - Walther Mothes
- Yale Cancer Center, New Haven, CT, USA
- Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA
| | - Amy Justice
- Yale Cancer Center, New Haven, CT, USA
- Department of General Medicine, Yale University, VA Medical Center, New Haven, CT, USA
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Characterization of a universal neutralizing monoclonal antibody against Glaesserella parasuis CdtB. Vet Microbiol 2022; 270:109446. [DOI: 10.1016/j.vetmic.2022.109446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 11/23/2022]
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