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Guan Y, Cheng H, Zhang N, Cai Y, Zhang Q, Jiang X, Wang A, Zeng H, Jia B. The role of the esophageal and intestinal microbiome in gastroesophageal reflux disease: past, present, and future. Front Immunol 2025; 16:1558414. [PMID: 40061946 PMCID: PMC11885504 DOI: 10.3389/fimmu.2025.1558414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/04/2025] [Indexed: 05/13/2025] Open
Abstract
Gastroesophageal reflux disease (GERD) is one of the common diseases of the digestive system, and its incidence is increasing year by year, in addition to its typical symptoms of acid reflux and heartburn affecting the quality of patients' survival. The pathogenesis of GERD has not yet been clarified. With the development of detection technology, microbiome have been studied in depth. Normal microbiome are symbiotic with the host and can assist the host to fulfill the roles of digestion and absorption, and promote the development of the host. Dysbiosis of the microbiome forms a new internal environment, under which it may affect the development of GERD from the perspectives of molecular mechanisms: microbial activation of Toll-like receptors, microbial stimulation of cyclooxygenase-2 expression, microbial stimulation of inducible nitrous oxide synthase, and activation of the NLRP3 inflammatory vesicle; immune mechanisms; and impact on the dynamics of the lower gastrointestinal tract. This review will explore the esophageal microbiome and intestinal microbiome characteristics of GERD and the mechanisms by which dysbiotic microbiome induces GERD.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Boyi Jia
- Department of Spleen and Stomach Diseases, Fangshan Traditional Medical Hospital of Beijing, Beijing, China
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Khan S, Simsek R, Fuentes JDB, Vohra I, Vohra S. Implication of Toll-Like Receptors in growth and management of health and diseases: Special focus as a promising druggable target to Prostate Cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189229. [PMID: 39608622 DOI: 10.1016/j.bbcan.2024.189229] [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: 07/01/2024] [Revised: 11/18/2024] [Accepted: 11/24/2024] [Indexed: 11/30/2024]
Abstract
Toll-like receptors (TLRs) are protein structures belonging to the pattern recognition receptors family. TLRs have the great potential that can directly recognize the specific molecular structures on the surface of pathogens, damaged senescent cells and apoptotic host cells. Available evidence suggests that TLRs have crucial roles in maintaining tissue homeostasis through control of the inflammatory and tissue repair responses during injury. TLRs are the player of first line of defense against different microbes and activate the signaling cascades which help to induce the immune system and inflammatory responses by affecting various signaling pathways, including nuclear factor-κB (NF-κB), interferon regulatory factors, and mitogen-activated protein kinases (MAPKs). TLRs have been identified to be over-expressed in different types of cancers and play an important role in control of health and management of diseases. The current review provides updated knowledge on the implication of TLRs in growth and management of cancers including prostate cancer.
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Affiliation(s)
- Shahanavaj Khan
- Department of Medical Lab Technology, Indian Institute of Health Technology (IIHT), Paramedical and Nursing College, Deoband, 247554 Saharanpur, India; Department of Health Sciences, Novel Global Community Educational Foundation, Australia.
| | - Rahime Simsek
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe Unversity, 06100 Ankara, Turkey
| | - Javier David Benitez Fuentes
- Medical Oncology Department, Hospital General Universitario de Elche, Carrer Almazara, 11, 03203 Elche, Alicante, Spain
| | - Isra Vohra
- University of Houston Clear Lake Graduated with bachelors Physiology, Houston, TX, USA
| | - Saeed Vohra
- Department of Anatomy and Physiology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
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Bonazzi E, Lorenzon G, Maniero D, De Barba C, Bertin L, Barberio B, Salvador R, Valmasoni M, Zingone F, Ghisa M, Savarino EV. The Esophageal Microbiota in Esophageal Health and Disease. GASTROENTEROLOGY INSIGHTS 2024; 15:998-1013. [DOI: 10.3390/gastroent15040069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The esophagus, traditionally viewed as a sterile conduit, is now recognized as a dynamic habitat for diverse microbial communities. The emerging evidence suggests that the esophageal microbiota plays an important role in maintaining esophageal health and contributing to disease. The aim of this systematic review was to synthesize the current knowledge on the esophageal microbiota composition, its variation between healthy individuals and those with esophageal diseases, and the potential mechanisms through which these microorganisms influence esophageal pathology. A systematic literature search was conducted using multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published up to July 2024. The inclusion criteria encompassed original research articles that used molecular techniques to characterize the esophageal microbiota in human subjects, comparing healthy individuals with patients affected by esophageal conditions such as gastroesophageal reflux disease (GERD), Barrett’s esophagus, eosinophilic esophagitis, and esophageal cancer. The primary outcomes were the composition and diversity of the esophageal microbiota, and the secondary outcomes included the correlations between microbial profiles and disease states. The esophageal microbiota of healthy individuals was dominated by Gram-positive bacteria, particularly Streptococcus. Conversely, the esophageal microbiota is considerably altered in disease states, with decreased microbial diversity and specific microbial signatures associated with these conditions, which may serve as biomarkers for disease progression and as targets for therapeutic intervention. However, the heterogeneous study designs, populations, and analytical methods underscore the need for standardized approaches in future research. Understanding the esophageal microbiota’s role in health and disease could guide microbiota-based diagnostics and treatments, offering novel avenues for managing esophageal conditions.
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Affiliation(s)
- Erica Bonazzi
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Greta Lorenzon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Daria Maniero
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Caterina De Barba
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy
| | - Brigida Barberio
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy
| | - Renato Salvador
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Michele Valmasoni
- Department of Surgery, Oncology and Gastroenterology, 3rd Surgical Clinic, University of Padova, 35128 Padua, Italy
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy
| | - Matteo Ghisa
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy
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Ren X, Xin L, Peng L, Xiao Y, Zhou Z, Luo H, Zhu Z, Wei Q, Jiang Y, He H, Xiang L, Wang Y, Tang Y, Gu H. Association between sulfur microbial diet and the risk of esophageal cancer: a prospective cohort study in 101,752 American adults. Nutr J 2024; 23:139. [PMID: 39511614 PMCID: PMC11542201 DOI: 10.1186/s12937-024-01035-y] [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: 06/30/2023] [Accepted: 10/15/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Sulfur microbial diet (SMD) is a dietary pattern closely related to the intestinal load of sulfur-metabolizing microbes in humans. Diet and microbes may play an important role in the carcinogenesis of esophagus. However, epidemiological studies on SMD and esophageal cancer (EC) risk are scarce. Here, we evaluated this association based on a large American cohort. METHODS In the cohort of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a SMD score was calculated to evaluate participants' compliance of SMD pattern, with higher scores presenting greater adherence. Cox hazards regression model was used to explore the association between the SMD score and the incidence of EC, esophageal squamous cell carcinoma (ESCC), and esophageal adenocarcinoma (EA). Subgroup analyses were conducted to figure out potential modifiers interacting with SMD on EC. Sensitivity analyses were used to testify the robustness of our main result. RESULTS Among 101,752 participants, 154 EC cases, consisted of 41 ESCC cases and 97 EA cases, were identified with mean follow-up of 8.9 years. In the fully adjusted model, the highest versus the lowest quartiles of the SMD score were found to be associated with an increased risk of EC and ESCC (EC: HRQ4 vs. Q1: 1.64; 95% CI: 1.05, 2.56; P = 0.016 for trend; ESCC: HRQ4 vs. Q1: 2.37; 95% CI: 1.02, 5.47; P = 0.031 for trend), while not significantly associated with increases risk of EA (HRQ4 vs. Q1: 1.41; P = 0.144 for trend). The main result remained through a series of sensitivity analyses. Subgroup analyses showed a stronger association between SMD and EC in participants with no regular consumption of aspirin (HRQ4 vs. Q1: 1.90; 95% CI: 1.04, 3.47) than in those using aspirin regularly (HRQ4 vs. Q1: 1.37; 95% CI: 0.71, 2.66) (P = 0.008 for interaction). CONCLUSION Adherence to the SMD pattern may be associated with increased risks of EC and ESCC, particularly for EC in individuals who do not regularly consume aspirin.
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Affiliation(s)
- Xiaorui Ren
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Li Xin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Linglong Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Yi Xiao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Zhihang Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haoyun Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Zhiyong Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Qi Wei
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Yahui Jiang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Hongmei He
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Ling Xiang
- Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yaxu Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China
| | - Yunhao Tang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China.
| | - Haitao Gu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing, 400010, China.
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Moe KT, Tan KSW. Mechanistic Insights on Microbiota-Mediated Development and Progression of Esophageal Cancer. Cancers (Basel) 2024; 16:3305. [PMID: 39409925 PMCID: PMC11475040 DOI: 10.3390/cancers16193305] [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: 08/23/2024] [Revised: 09/18/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Esophageal cancer (EC) is one of the most common malignant tumors worldwide, and its two major types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), present a severe global public health problem with an increasing incidence and mortality. Established risk factors include smoking, alcohol consumption, and dietary habits, but recent research has highlighted the substantial role of oral microbiota in EC pathogenesis. This review explores the intricate relationship between the microbiome and esophageal carcinogenesis, focusing on the following eight significant mechanisms: chronic inflammation, microbial dysbiosis, production of carcinogenic metabolites, direct interaction with epithelial cells, epigenetic modifications, interaction with gastroesophageal reflux disease (GERD), metabolic changes, and angiogenesis. Certain harmful bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, are specifically implicated in sustaining irritation and tumor progression through pathways including NF-κB and NLRP3 inflammasome. Additionally, the review explores how microbial byproducts, including short-chain fatty acids (SCFAs) and reactive oxygen species (ROS), contribute to DNA harm and disease advancement. Furthermore, the impact of reflux on microbiota composition and its role in esophageal carcinogenesis is evaluated. By combining epidemiological data with mechanistic understanding, this review underscores the potential to target the microbiota-immune system interplay for novel therapeutic and diagnostic strategies to prevent and treat esophageal cancer.
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Affiliation(s)
- Kyaw Thu Moe
- Biomedical Sciences, Newcastle University Medicine Malaysia, Iskandar Puteri 79200, Johor, Malaysia
| | - Kevin Shyong-Wei Tan
- Laboratory of Molecular and Cellular Parasitology, Health Longevity Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive, Singapore 117545, Singapore
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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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Huang Y, Kang Z, He Y, Qiu Y, Song Y, Liu W. Association between gut microbiota and common overlapping gastrointestinal disorders: a bidirectional two-sample Mendelian randomization study. Front Microbiol 2024; 15:1343564. [PMID: 38855762 PMCID: PMC11157101 DOI: 10.3389/fmicb.2024.1343564] [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: 11/23/2023] [Accepted: 04/29/2024] [Indexed: 06/11/2024] Open
Abstract
Background The main functional gastrointestinal disorders (FGIDs) include functional dyspepsia (FD) and irritable bowel syndrome (IBS), which often present overlapping symptoms with gastroesophageal reflux disease (GERD), posing a challenge for clinical diagnosis and treatment. The gut microbiota is closely associated with FGIDs and GERD, although the causal relationship has not been fully elucidated. Therefore, we aimed to investigate the potential causal relationship using bidirectional two-sample Mendelian randomization (MR) analysis. Materials and methods The genetic data of the 211 gut microbiota were obtained from the MiBioGen consortium (N = 14,306, from phylum to genus level) and species level of gut microbiota were acquired from the Dutch Microbiome Project (N = 7,738). For FD and IBS, we utilized the FinnGen consortium, whereas, for GERD data analysis, we obtained the IEU OpenGWAS project. The inverse-variance weighted (IVW) method was used as the primary method to calculate causal effect values. Sensitivity analyses were also performed to confirm the robustness of the primary findings of the MR analyses. Moreover, a reverse MR analysis was conducted to assess the likelihood of reverse causality. Results Combining the results of the preliminary and sensitivity analyses, we identified that 8 gut microbial taxa were associated with FD. Genus Lachnospiraceae NK4A136 group (p = 3.63 × 10-3) and genus Terrisporobacter (p = 1.13 × 10-3) were strongly associated with FD. At the same time, we found that 8 gut microbial taxa were associated with IBS. Family Prevotellaceae (p = 2.44 × 10-3) and species Clostridium leptum (p = 7.68 × 10-3) display a robust correlation with IBS. In addition, 5 gut microbial taxa were associated with GERD using the IVW approach. In the reverse MR analysis, 2 gut microbial taxa were found to be associated with FD, 5 gut microbial taxa were found to be associated with IBS, and 21 gut microbial taxa were found to be associated with GERD. Conclusion The study reveals the potential causal effects of specific microbial taxa on FD, IBS, and GERD and may offer novel insights into the diagnosis and treatment of these conditions.
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Affiliation(s)
- Yuhan Huang
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhen Kang
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yuhan He
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yi Qiu
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yuhui Song
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Weiai Liu
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- The Second Clinical College of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Li J, Gao X, Sun X, Li H, Wei J, Lv L, Zhu L. Investigating the causal role of the gut microbiota in esophageal cancer and its subtypes: a two-sample Mendelian randomization study. BMC Cancer 2024; 24:416. [PMID: 38575885 PMCID: PMC10996172 DOI: 10.1186/s12885-024-12205-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/29/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Through research on the gut microbiota (GM), increasing evidence has indicated that the GM is associated with esophageal cancer (ESCA). However, the specific cause-and-effect relationship remains unclear. In this study, Mendelian randomization (MR) analysis was applied to investigate the causal relationship between the GM and ESCA, including its subtypes. METHODS We collected information on 211 GMs and acquired data on ESCA and its subtypes through genome-wide association studies (GWASs). The causal relationship was primarily assessed using the inverse variance weighted (IVW) method. Additionally, we applied the weighted median estimator (WME) method, MR-Egger method, weighted mode, and simple mode to provide further assistance. Subsequent to these analyses, sensitivity analysis was conducted using the MR-Egger intercept test, MR-PRESSO global test, and leave-one-out method. RESULT Following our assessment using five methods and sensitivity analysis, we identified seven GMs with potential causal relationships with ESCA and its subtypes. At the genus level, Veillonella and Coprobacter were positively correlated with ESCA, whereas Prevotella9, Eubacterium oxidoreducens group, and Turicibacter were negatively correlated with ESCA. In the case of esophageal adenocarcinoma (EAC), Flavonifractor exhibited a positive correlation, while Actinomyces exhibited a negative correlation. CONCLUSION Our study revealed the potential causal relationship between GM and ESCA and its subtypes, offering novel insights for the advancement of ESCA diagnosis and treatment.
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Affiliation(s)
- Jia Li
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China
| | - Xuedi Gao
- Thoracic Surgery Department, Jinan Mingshui Eye Hospital, Jinan, 250000, China
| | - Xiaoming Sun
- Thoracic Surgery Department, Jinan Central Hospital, Jinan, 250000, China
| | - Hao Li
- Thoracic Surgery Department, Jinan Central Hospital, Shandong First Medical University, Jinan, 250000, China
| | - Jiaheng Wei
- Thoracic Surgery Department, Weifang Medical University, Weifang, 261000, China
| | - Lin Lv
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China
| | - Liangming Zhu
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China.
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Yarahmadi A, Afkhami H. The role of microbiomes in gastrointestinal cancers: new insights. Front Oncol 2024; 13:1344328. [PMID: 38361500 PMCID: PMC10867565 DOI: 10.3389/fonc.2023.1344328] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 12/20/2023] [Indexed: 02/17/2024] Open
Abstract
Gastrointestinal (GI) cancers constitute more than 33% of new cancer cases worldwide and pose a considerable burden on public health. There exists a growing body of evidence that has systematically recorded an upward trajectory in GI malignancies within the last 5 to 10 years, thus presenting a formidable menace to the health of the human population. The perturbations in GI microbiota may have a noteworthy influence on the advancement of GI cancers; however, the precise mechanisms behind this association are still not comprehensively understood. Some bacteria have been observed to support cancer development, while others seem to provide a safeguard against it. Recent studies have indicated that alterations in the composition and abundance of microbiomes could be associated with the progression of various GI cancers, such as colorectal, gastric, hepatic, and esophageal cancers. Within this comprehensive analysis, we examine the significance of microbiomes, particularly those located in the intestines, in GI cancers. Furthermore, we explore the impact of microbiomes on various treatment modalities for GI cancer, including chemotherapy, immunotherapy, and radiotherapy. Additionally, we delve into the intricate mechanisms through which intestinal microbes influence the efficacy of GI cancer treatments.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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Gao X, Wang Z, Liu B, Cheng Y. Causal association of gut microbiota and esophageal cancer: a Mendelian randomization study. Front Microbiol 2023; 14:1286598. [PMID: 38107856 PMCID: PMC10722290 DOI: 10.3389/fmicb.2023.1286598] [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: 08/31/2023] [Accepted: 11/07/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction Despite the growing body of evidence, the link between the gut microbiota and different types of tumors, such as colorectal, gastric, and liver cancer, is becoming more apparent. The gut microbiota can be used as a reference for evaluating various diseases, including cancer, and can also act as risk factors or preventive factors. However, the specific connection between the gut microbiota and the advancement of esophageal cancer has yet to be investigated. Therefore, the aim of this research is to clarify the possible causal influence of intestinal microorganisms on the vulnerability to esophageal cancer through the utilization of Mendelian randomization (MR) studies. Methods In this study, we employed a two-sample Mendelian randomization approach to evaluate the unbiased causal association between 150 different gut microbiota types and the occurrence of esophageal cancer. Following the selection from the IEU GWAS database and SNP filtration, we utilized various MR statistical techniques on the suitable instrumental variables. These included IVW methods, employing inverse variance weighting. Additionally, we performed a range of sensitivity analyses to confirm the heterogeneity and pleiotropy of the instrumental variables, thus ensuring the reliability of the outcomes. Results The increased likelihood of developing esophageal cancer is linked to the genetically predicted high levels of Gordonibacter, Oxalobacter, Coprobacter, Veillonella, Ruminiclostridium 5, Ruminococcus 1, and Senegalimasilia genera. Conversely, a decreased risk of esophageal cancer is associated with the high abundance of Turicibacter, Eubacterium oxidoreducens group, Romboutsia, and Prevotella 9 genera. No heterogeneity and pleiotropy were detected in the sensitivity analysis. Discussion We found that 11 types of gut microbial communities are associated with esophageal cancer, thereby confirming that the gut microbiota plays a significant role in the path.
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Affiliation(s)
- Xiangyu Gao
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
| | - Zhiguo Wang
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bowen Liu
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
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Chandrasekar SA, Palaniyandi T, Parthasarathy U, Surendran H, Viswanathan S, Wahab MRA, Baskar G, Natarajan S, Ranjan K. Implications of Toll-like receptors (TLRs) and their signaling mechanisms in human cancers. Pathol Res Pract 2023; 248:154673. [PMID: 37453359 DOI: 10.1016/j.prp.2023.154673] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Most essential pattern-recognition receptors regulating innate immune functions are toll-like receptors (TLRs). TLRs are characterized by lack of concurrent epithelial markers and are typically identified by their gene expressions. One major mechanism by which TLRs generate their effector functions is by triggering inflammatory responses. Activation of TLRs can impact initiation, advancement, and control of cancers by regulating the inflammatory microenvironment. Several TLRs have been implicated in human cancers and some of them are identified as cancer biomarkers as well; for example, TLRs 2, 3, 5 are expressed more frequently in most cancers. Knowing the upregulation and downregulation of the TLR genes in human cancers will be useful for the development of newer therapeutic targets which can disrupt the pathways associated with such deregulation. We present here the various TLRs and their functions in human lung, gastric, breast, prostate, oral, ovarian, colorectal, cervical, esophageal, bladder and hepatic cancers.
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Affiliation(s)
- Saran Aravinda Chandrasekar
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India; Department of Biomedical, School of Electronics Engineering (SENSE), VIT(Vellore Institute of Technology), Vellore 632014, India
| | - Thirunavukkarasu Palaniyandi
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India; Department of Anatomy, Biomedical Research Unit and Laboratory Animal Centre, Saveetha Dental College and Hospital, SIMATS, Saveetha University, Chennai, India.
| | - Udhayakumar Parthasarathy
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Hemapreethi Surendran
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Sandhiya Viswanathan
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Mugip Rahaman Abdul Wahab
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Gomathy Baskar
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Sudhakar Natarajan
- Department of virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis (NIRT), Chetpet, Chennai 600031, Tamil Nadu, India
| | - Kishu Ranjan
- Department of Pathology, School of Medicine, Yale University, New Haven 06520, USA
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12
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Abbas S, Pich O, Devonshire G, Zamani SA, Katz-Summercorn A, Killcoyne S, Cheah C, Nutzinger B, Grehan N, Lopez-Bigas N, Fitzgerald RC, Secrier M. Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma. Nat Commun 2023; 14:4239. [PMID: 37454136 PMCID: PMC10349863 DOI: 10.1038/s41467-023-39957-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023] Open
Abstract
A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.
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Affiliation(s)
- Sujath Abbas
- Early Cancer Institute, University of Cambridge, Cambridge, UK
| | - Oriol Pich
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ginny Devonshire
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | | | | | - Sarah Killcoyne
- Early Cancer Institute, University of Cambridge, Cambridge, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
| | - Calvin Cheah
- Early Cancer Institute, University of Cambridge, Cambridge, UK
| | | | - Nicola Grehan
- Early Cancer Institute, University of Cambridge, Cambridge, UK
| | - Nuria Lopez-Bigas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Maria Secrier
- UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
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13
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Pandey A, Lieu CH, Kim SS. The Local Microbiome in Esophageal Cancer and Treatment Response: A Review of Emerging Data and Future Directions. Cancers (Basel) 2023; 15:3562. [PMID: 37509225 PMCID: PMC10377659 DOI: 10.3390/cancers15143562] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/28/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
The incidence of esophageal cancer is increasing worldwide, with established risk factors explaining only a small fraction of cases. Currently, there are no established screening protocols in most countries, and treatment options are limited. The human microbiome has been implicated in carcinogenesis and the cancer treatment response. The advent of nucleic acid sequencing technologies has enabled more comprehensive, culture-independent bacterial identification. Across several tumor types, studies of tissue-specific microbiomes have shown associations between the overall microbiome composition, the relative abundance of specific bacteria, and tumorigenesis. Furthermore, in the era of cancer immunotherapy, several studies have demonstrated that the microbiome and specific bacteria may modify treatment responses and the risk of immune-related adverse events. DESIGN peer-reviewed, published studies describing the role of local, gastrointestinal-specific microbiota or the role of the gut microbiome in treatment responses were reviewed. PubMed was searched from 1 September 2022 to 1 November 2022, using the following terms in combination: "microbiome", "tumor microbiome", "esophageal cancer", "cancer", "cancer treatment", and "immunotherapy". Original research articles were considered, and other reviews or editorials were discarded. In total, approximately 250 articles were considered. RESULTS over 70 studies describing microbiome research in either gastrointestinal carcinogenesis or the systemic treatment response were identified and reviewed. CONCLUSIONS a growing body of evidence supports the role of the esophageal microbiome in both esophageal tumorigenesis and the immune checkpoint inhibitor response. More well-designed, comprehensive studies are required to collect the appropriate clinical, microbial, and immunophenotype data that are needed to clarify the precise role of the microbiome in esophageal carcinogenesis and treatment.
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Affiliation(s)
- Abhishek Pandey
- University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Christopher H Lieu
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Sunnie S Kim
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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14
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Ağagündüz D, Cocozza E, Cemali Ö, Bayazıt AD, Nanì MF, Cerqua I, Morgillo F, Saygılı SK, Berni Canani R, Amero P, Capasso R. Understanding the role of the gut microbiome in gastrointestinal cancer: A review. Front Pharmacol 2023; 14:1130562. [PMID: 36762108 PMCID: PMC9903080 DOI: 10.3389/fphar.2023.1130562] [Citation(s) in RCA: 101] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Gastrointestinal cancer represents one of the most diagnosed types of cancer. Cancer is a genetic and multifactorial disease, influenced by the host and environmental factors. It has been stated that 20% of cancer is caused by microorganisms such as Helicobacter pylori, hepatitis B and C virus, and human papillomavirus. In addition to these well-known microorganisms associated with cancer, it has been shown differences in the composition of the microbiota between healthy individuals and cancer patients. Some studies have suggested the existence of the selected microorganisms and their metabolites that can promote or inhibit tumorigenesis via some mechanisms. Recent findings have shown that gut microbiome and their metabolites can act as cancer promotors or inhibitors. It has been shown that gastrointestinal cancer can be caused by a dysregulation of the expression of non-coding RNA (ncRNA) through the gut microbiome. This review will summarize the latest reports regarding the relationship among gut microbiome, ncRNAs, and gastrointestinal cancer. The potential applications of diagnosing and cancer treatments will be discussed.
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Affiliation(s)
- Duygu Ağagündüz
- Department of Nutrition and Dietetics, Gazi University, Emek, Ankara, Turkey
| | | | - Özge Cemali
- Department of Nutrition and Dietetics, Gazi University, Emek, Ankara, Turkey
| | - Ayşe Derya Bayazıt
- Department of Nutrition and Dietetics, Gazi University, Emek, Ankara, Turkey
| | | | - Ida Cerqua
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
| | - Floriana Morgillo
- Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Suna Karadeniz Saygılı
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States,Department of Histology and Embryology, Kütahya Health Sciences University, Kütahya, Turkey
| | - Roberto Berni Canani
- Department of Translational Medical Science and ImmunoNutritionLab at CEINGE Biotechnologies Research Center and Task Force for Microbiome Studies, University of Naples Federico II, Naples, Italy
| | - Paola Amero
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States,*Correspondence: Raffaele Capasso, ; Paola Amero,
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Portici, Italy,*Correspondence: Raffaele Capasso, ; Paola Amero,
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15
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Sun H, Li Y, Zhang P, Xing H, Zhao S, Song Y, Wan D, Yu J. Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives. Biomark Res 2022; 10:89. [PMID: 36476317 PMCID: PMC9727882 DOI: 10.1186/s40364-022-00436-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.
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Affiliation(s)
- Hao Sun
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yingmei Li
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Peng Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Haizhou Xing
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Song Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yongping Song
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Dingming Wan
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jifeng Yu
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004 Henan China
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16
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Li S, Li Q, Lu W. Intratumoral microbiome and gastrointestinal cancers. Front Oncol 2022; 12:1047015. [PMID: 36523986 PMCID: PMC9745085 DOI: 10.3389/fonc.2022.1047015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/11/2022] [Indexed: 12/21/2024] Open
Abstract
Emerging studies have revealed the role of microbiota in regulating tumorigenesis, development, and response to antitumor treatment. However, most studies have focused on gut microbiota, and little is known about the intratumoral microbiome. To date, the latest research has indicated that the intratumoral microbiome is a key component of the tumor microenvironment (TME), and can promote a heterogeneous immune microenvironment, reprogram tumor metabolism to affect tumor invasion and metastasis. In this review, we will summarize existing studies on the intratumoral microbiome of gastrointestinal cancers and reveal their crosstalk. This will provide a better understanding of this emerging field and help to explore new therapeutic approaches for cancer patients by targeting the intratumoral microbiome.
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Affiliation(s)
- Shengnan Li
- Department of Hepatology, Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Qian Li
- Department of Hepatology, Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Wei Lu
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
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17
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Matani H, Sahu D, Paskewicz M, Gorbunova A, Omstead AN, Wegner R, Finley GG, Jobe BA, Kelly RJ, Zaidi AH, Goel A. Prognostic and predictive biomarkers for response to neoadjuvant chemoradiation in esophageal adenocarcinoma. Biomark Res 2022; 10:81. [PMCID: PMC9664643 DOI: 10.1186/s40364-022-00429-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background
Esophageal adenocarcinoma is a lethal disease. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate, therefore establishing the need for new and reliable biomarkers for risk stratification.
Methods
Thirty four patients with locally advanced esophageal adenocarcinoma were analyzed, of which 21 received a CROSS regimen with carboplatin, paclitaxel, and radiation. Capture-based targeted sequencing was performed on the paired baseline and post-treatment samples. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival.
Results
A 3-gene signature, based on mutations in EPHA5, BCL6, and ERBB2, was identified that robustly predicts response to the CROSS regimen. For this model, sensitivity was 84.6% and specificity was 100%. Independently, a 9 gene signature was created using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, PML, and FGF6, which significantly stratifies patients into risk categories, prognosticating for improved relapse-free (p = 4.73E-03) and overall survival (p = 3.325E-06). The sensitivity for this model was 73.33% and the specificity was 94.74%.
Conclusion
We have identified a 3-gene signature (EPHA5, BCL6, and ERBB2) that is predictive of response to neoadjuvant chemoradiotherapy and a separate prognostic 9-gene classifier that predicts survival outcomes. These panels provide significant potential for personalized management of locally advanced esophageal cancer.
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18
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Zaidi AH, Pratama MY, Omstead AN, Gorbonova A, Mansoor R, Melton-Kreft R, Jobe BA, Wagner PL, Kelly RJ, Goel A. A blood-based circulating microbial metagenomic panel for early diagnosis and prognosis of oesophageal adenocarcinoma. Br J Cancer 2022; 127:2016-2024. [PMID: 36097175 PMCID: PMC9681745 DOI: 10.1038/s41416-022-01974-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Emerging evidence indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in oesophageal adenocarcinoma (EAC) patients, particularly as novel non-invasive, early detection, surveillance and prognostic classifiers. METHODS Metagenome sequencing was performed on 81 serum specimens collected across EAC spectrum, with sequencing reads classified using Bracken and MetaPhlAn3. Followed by the Linear Discriminant Analysis effect size (LEfSe) method to identify microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build classifiers. RESULTS A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI: 0.78-0.95; P < 0.001) and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 (95% CI: 0.66-0.92; P = 0.006)). CONCLUSION This study firstly describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC. TRANSLATIONAL RELEVANCE Accumulating data indicates the clinical relevance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in patients with oesophageal adenocarcinoma (EAC). Herein, we performed metagenome sequencing in serum specimens from EAC patients 81 collected across EAC spectrum and observed a significant loss of alpha and beta diversity, with a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 and this panel, in conjunction with the TNM stage, was a robust predictor of overall survival. This study for the first time describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC.
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Affiliation(s)
- Ali H Zaidi
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Muhammad Yogi Pratama
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Ashten N Omstead
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Anastasia Gorbonova
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rubab Mansoor
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rachael Melton-Kreft
- The Allegheny Health Network, Center of Excellence in Biofilm Research, Pittsburgh, PA, USA
| | - Blair A Jobe
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Patrick L Wagner
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Ronan J Kelly
- The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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19
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Song X, Greiner-Tollersrud OK, Zhou H. Oral Microbiota Variation: A Risk Factor for Development and Poor Prognosis of Esophageal Cancer. Dig Dis Sci 2022; 67:3543-3556. [PMID: 34505256 DOI: 10.1007/s10620-021-07245-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/23/2021] [Indexed: 12/24/2022]
Abstract
Recent studies have shown that oral microbiota play an important role in the esophageal cancer (EC) initiation and progression, suggesting that oral microbiota is a new risk factor for EC. The composition of the microbes inhabiting the oral cavity could be perturbed with continuous factors such as smoking, alcohol consumption, and inflammation. The microbial alteration involves the decrease of beneficial species and the increase of pathogenic species. Experimental evidences suggest a significant role of oral commensal organisms in protecting hosts against EC. By contrast, oral pathogens, especially Porphyromonas gingivalis and Fusobacterium nucleatum, give rise to the risk for developing EC through their pro-inflammatory and pro-tumorigenic activities. The presences of oral dysbiosis, microbial biofilm, and periodontitis in EC patients are found to be associated with invasive cancer phenotypes and poor prognosis. The mechanism of oral bacteria in EC progression is complex, which involves a combination of cytokines, chemokines, oncogenic signaling pathways, cell surface receptors, the degradation of extracellular matrix, and cell apoptosis. From a clinical perspective, good oral hygiene, professional oral care, and rational use of antibiotics bring positive impacts on oral microbial balance, thus helping individuals reduce the risk of EC, inhibiting postoperative complications among EC patients, and improving the efficiency of chemoradiotherapy. However, current oral hygiene practices mainly focus on the oral bacteria-based predictive and preventive purposes. It is still far from implementing microbiota-dependent regulation as a therapy for EC. Further explorations are needed to render oral microbiota a potential target for treating EC.
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Affiliation(s)
- Xiaobo Song
- Department of Microbiology, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian, 116044, Liaoning Province, China.,Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037, Tromsø, Norway
| | - Ole K Greiner-Tollersrud
- Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037, Tromsø, Norway
| | - Huimin Zhou
- Department of Microbiology, Dalian Medical University, No.9 West Section Lvshun South Road, Dalian, 116044, Liaoning Province, China.
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20
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Hao Y, Karaoz U, Yang L, Yachimski PS, Tseng W, Nossa CW, Ye W, Tseng M, Poles M, Francois F, Traube M, Brown SM, Chen Y, Torralba M, Peek RM, Brodie EL, Pei Z. Progressive dysbiosis of human orodigestive microbiota along the sequence of gastroesophageal reflux, Barrett's esophagus, and esophageal adenocarcinoma. Int J Cancer 2022; 151:1703-1716. [PMID: 35751398 DOI: 10.1002/ijc.34191] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 11/06/2022]
Abstract
The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE), and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE, and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia, and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway, and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yuhan Hao
- Department of Pathology, NYU School of Medicine, New York, New York, USA.,Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Ulas Karaoz
- Earth and Environmental Sciences, Lawrence Berkeley National Laboratory, Berkeley, California, USA
| | - Liying Yang
- Department of Medicine, NYU School of Medicine, New York, New York, USA
| | - Patrick S Yachimski
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Wenzhi Tseng
- Department of Pathology, NYU School of Medicine, New York, New York, USA.,Amherst College, Amherst, Massachusetts, USA
| | - Carlos W Nossa
- Department of Medicine, NYU School of Medicine, New York, New York, USA
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Mengkao Tseng
- Department of Medicine, NYU School of Medicine, New York, New York, USA
| | - Michael Poles
- Department of Medicine, NYU School of Medicine, New York, New York, USA.,Department of Veterans Affairs New York Harbor Healthcare System, New York, New York, USA
| | - Fritz Francois
- Department of Medicine, NYU School of Medicine, New York, New York, USA
| | - Morris Traube
- Department of Medicine, NYU School of Medicine, New York, New York, USA
| | - Stuart M Brown
- Department of Cell Biology, NYU School of Medicine, New York, New York, USA
| | - Yu Chen
- Department of Population Health and Department of Environmental Medicine, NYU School of Medicine, New York, New York, USA
| | | | - Richard M Peek
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Eoin L Brodie
- Earth and Environmental Sciences, Lawrence Berkeley National Laboratory, Berkeley, California, USA.,Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA
| | - Zhiheng Pei
- Department of Pathology, NYU School of Medicine, New York, New York, USA.,Department of Medicine, NYU School of Medicine, New York, New York, USA.,Department of Veterans Affairs New York Harbor Healthcare System, New York, New York, USA
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21
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Liu Y, Baba Y, Ishimoto T, Gu X, Zhang J, Nomoto D, Okadome K, Baba H, Qiu P. Gut microbiome in gastrointestinal cancer: a friend or foe? Int J Biol Sci 2022; 18:4101-4117. [PMID: 35844804 PMCID: PMC9274484 DOI: 10.7150/ijbs.69331] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 06/04/2022] [Indexed: 12/07/2022] Open
Abstract
The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.
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Affiliation(s)
- Yang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning province, China
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Next-Generation Surgical Therapy Development, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Xi Gu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning province, China
| | - Jun Zhang
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Daichi Nomoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuo Okadome
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
| | - Peng Qiu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
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22
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Sharma T, Gupta A, Chauhan R, Bhat AA, Nisar S, Hashem S, Akhtar S, Ahmad A, Haris M, Singh M, Uddin S. Cross-talk between the microbiome and chronic inflammation in esophageal cancer: potential driver of oncogenesis. Cancer Metastasis Rev 2022; 41:281-299. [PMID: 35511379 PMCID: PMC9363391 DOI: 10.1007/s10555-022-10026-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/12/2022] [Indexed: 12/11/2022]
Abstract
Esophageal cancer (EC) is frequently considered a lethal malignancy and is often identified at a later stage. It is one of the major causes of cancer-related deaths globally. The conventional treatment methods like chemotherapy, radiotherapy, and surgery offer limited efficacy and poor clinical outcome with a less than 25% 5-year survival rate. The poor prognosis of EC persists despite the growth in the development of diagnostic and therapeutic modalities to treat EC. This underlines the need to elucidate the complex molecular mechanisms that drive esophageal oncogenesis. Apart from the role of the tumor microenvironment and its structural and cellular components in tumorigenesis, mounting evidence points towards the involvement of the esophageal microbiome, inflammation, and their cross-talk in promoting esophageal cancer. The current review summarizes recent research that delineates the underlying molecular mechanisms by which the microbiota and inflammation promote the pathophysiology of esophageal cancer, thus unraveling targets for potential therapeutic intervention.
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Affiliation(s)
- Tarang Sharma
- Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India
| | - Ashna Gupta
- Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India
| | - Ravi Chauhan
- Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India
| | - Ajaz A Bhat
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, Qatar
- Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, PA, Philadelphia, USA
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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23
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Balasubramaniam A, Srinivasan S. Dysbiosis Associated With Esophageal Adenocarcinoma-A Novel Method to Detect Tissue-Associated Microbiome. GASTRO HEP ADVANCES 2022; 1:775-776. [PMID: 39131842 PMCID: PMC11307479 DOI: 10.1016/j.gastha.2022.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 08/13/2024]
Affiliation(s)
- Arun Balasubramaniam
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
- Atlanta Veterans Affairs Health Care System, Decatur, Georgia
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
- Atlanta Veterans Affairs Health Care System, Decatur, Georgia
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24
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Upper Gastrointestinal Cancer and Liver Cirrhosis. Cancers (Basel) 2022; 14:cancers14092269. [PMID: 35565397 PMCID: PMC9105927 DOI: 10.3390/cancers14092269] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary There is a higher incidence rate of upper gastrointestinal cancer in those with liver cirrhosis. The contributing factors include gastric ulcers, congestive gastropathy, zinc deficiency, alcohol drinking, tobacco use and gut microbiota. Most of the de novo malignancies that develop after liver transplantation for cirrhotic patients are upper gastrointestinal cancers. The surgical risk of upper gastrointestinal cancers in cirrhotic patients with advanced liver cirrhosis is higher. Abstract The extended scope of upper gastrointestinal cancer can include esophageal cancer, gastric cancer and pancreatic cancer. A higher incidence rate of gastric cancer and esophageal cancer in patients with liver cirrhosis has been reported. It is attributable to four possible causes which exist in cirrhotic patients, including a higher prevalence of gastric ulcers and congestive gastropathy, zinc deficiency, alcohol drinking and tobacco use and coexisting gut microbiota. Helicobacter pylori infection enhances the development of gastric cancer. In addition, Helicobacter pylori, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans also contribute to the development of pancreatic cancer in cirrhotic patients. Cirrhotic patients (especially those with alcoholic liver cirrhosis) who undergo liver transplantation have a higher overall risk of developing de novo malignancies. Most de novo malignancies are upper gastrointestinal malignancies. The prognosis is usually poor. Considering the surgical risk of upper gastrointestinal cancer among those with liver cirrhosis, a radical gastrectomy with D1 or D2 lymph node dissection can be undertaken in Child class A patients. D1 lymph node dissection can be performed in Child class B patients. Endoscopic submucosal dissection for gastric cancer or esophageal cancer can be undertaken safely in selected cirrhotic patients. In Child class C patients, a radical gastrectomy is potentially fatal. Pancreatic radical surgery should be avoided in those with liver cirrhosis with Child class B or a MELD score over 15. The current review focuses on the recent reports on some factors in liver cirrhosis that contribute to the development of upper gastrointestinal cancer. Quitting alcohol drinking and tobacco use is important. How to decrease the risk of the development of gastrointestinal cancer in those with liver cirrhosis remains a challenging problem.
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25
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Anipindi M, Bitetto D. Diagnostic and Therapeutic Uses of the Microbiome in the Field of Oncology. Cureus 2022; 14:e24890. [PMID: 35698690 PMCID: PMC9184241 DOI: 10.7759/cureus.24890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer is a leading cause of death worldwide and it can affect almost every part of the human body. Effective screening and early diagnosis of cancers is extremely difficult due to the multifactorial etiology of the disease and delayed presentation of the patients. The available treatments are usually not specific to the affected organ system, leading to intolerable systemic side effects and early withdrawal from therapies. In vivo and in vitro studies have revealed an association of specific microbiome signatures with individual cancers. The cancer-related human microbiome has also been shown to affect the response of tissues to chemotherapy, immunotherapy, and radiation. This is an excellent opportunity for us to design specific screening markers using the microbiome to prevent cancers and diagnose them early. We can also develop precise treatments that can target cancer-affected specific organ systems and probably use a lesser dose of chemotherapy or radiation for the same effect. This prevents adverse effects and early cessation of treatments. However, we need further studies to exactly clarify and characterize these associations. In this review article, we focus on the association of the microbiome with individual cancers and highlight its future role in cancer screenings, diagnosis, prognosis, and treatments.
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Affiliation(s)
- Manasa Anipindi
- Internal Medicine, Einstein Medical Center Philadelphia, East Norriton, USA
| | - Daniel Bitetto
- Internal Medicine, Einstein Medical Center Philadelphia, East Norriton, USA
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26
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Dan W, Peng L, Yan B, Li Z, Pan F. Human Microbiota in Esophageal Adenocarcinoma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Implications. Front Microbiol 2022; 12:791274. [PMID: 35126331 PMCID: PMC8815000 DOI: 10.3389/fmicb.2021.791274] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/23/2021] [Indexed: 11/29/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) is one of the main subtypes of esophageal cancer. The incidence rate of EAC increased progressively while the 5-year relative survival rates were poor in the past two decades. The mechanism of EAC has been studied extensively in relation to genetic factors, but less so with respect to human microbiota. Currently, researches about the relationship between EAC and the human microbiota is a newly emerging field of study. Herein, we present the current state of knowledge linking human microbiota to esophageal adenocarcinoma and its precursor lesion—gastroesophageal reflux disease and Barrett’s esophagus. There are specific human bacterial alternations in the process of esophageal carcinogenesis. And bacterial dysbiosis plays an important role in the process of esophageal carcinogenesis via inflammation, microbial metabolism and genotoxicity. Based on the human microbiota alternation in the EAC cascade, it provides potential microbiome-based clinical application. This review is focused on novel targets in prevention, diagnosis, prognosis, and therapy for esophageal adenocarcinoma.
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Affiliation(s)
- Wanyue Dan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Nankai University, Tianjin, China
| | - Lihua Peng
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bin Yan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhengpeng Li
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Fei Pan,
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27
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Mahapatra S, Mohanty S, Mishra R, Prasad P. An overview of cancer and the human microbiome. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 191:83-139. [DOI: 10.1016/bs.pmbts.2022.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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28
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Ishaq HM, Mohammad IS, Sher Muhammad K, Li H, Abbas RZ, Din Sindhu ZU, Ullah S, Fan Y, Sadiq A, Raza MA, Hussain R, Arshad HM, Khan I, Waqas MU, Ul-Rahman A, Yasin R, Rehman A, Akhtar RW, Xu J. Gut microbial dysbiosis and its association with esophageal cancer. J Appl Biomed 2021; 19:1-13. [PMID: 34907711 DOI: 10.32725/jab.2021.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 01/22/2021] [Indexed: 12/15/2022] Open
Abstract
Due to its aggressive nature and low survival rate, esophageal cancer is one of the deadliest cancer. While the intestinal microbiome significantly influences human health and disease. This research aimed to investigate and characterize the relative abundance of intestinal bacterial composition in esophageal cancer patients. The fecal samples were collected from esophageal cancer patients (n = 15) and healthy volunteers (n = 10). The PCR-DGGE was carried out by focusing on the V3 region of the 16S rRNA gene, and qPCR was performed for Bacteroides vulgatus, Escherichia coli, Bifidobacterium, Clostridium leptum and Lactobacillus. High-throughput sequencing of the 16S rRNA gene targeting the V3+V4 region was performed on 20 randomly selected samples. PCR-DGGE and High-throughput diversity results showed a significant alteration of gut bacterial composition between the experimental and control groups, which indicates the gut microbial dysbiosis in esophageal cancer patients. At the phylum level, there was significant enrichment of Bacteroidetes, while a non-significant decrease of Firmicutes in the experimental group. At family statistics, a significantly higher level of Bacteroidaceae and Enterobacteriaceae, while a significantly lower abundance of Prevotellaceae and Veillonellaceae were observed. There was a significantly high prevalence of genera Bacteroides, Escherichia-Shigella, while a significantly lower abundance of Prevotella_9 and Dialister in the experimental group as compared to the control group. Furthermore, the species analysis also showed significantly raised level of Bacteroides vulgatus and Escherichia coli in the experimental group. These findings revealed a significant gut microbial dysbiosis in esophageal cancer patients. So, the current study can be used for the understanding of esophageal cancer treatment, disease pathway, mechanism, and probiotic development.
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Affiliation(s)
- Hafiz Muhammad Ishaq
- University of Veterinary and Animal Sciences, Department of Clinical Sciences, Section of Epidemiology and public Health, Lahore Sub-campus Jhang, Pakistan.,Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Imran Shair Mohammad
- Sun Yat-sen University, University Town, School of Pharmaceutical Sciences, Guangzhou 510006, China
| | - Kiran Sher Muhammad
- University of Agriculture, Department of Zoology Wild-life and Fisheries, Faisalabad, Pakistan
| | - Huan Li
- Xi'an Mental Health Centre, Xi'an, China
| | - Rao Zahid Abbas
- University of Agriculture Faisalabad-38040, Department of Parasitology, Faisalabad, Pakistan
| | - Zia Ud Din Sindhu
- University of Agriculture Faisalabad-38040, Department of Parasitology, Faisalabad, Pakistan
| | - Shakir Ullah
- University of Veterinary and Animal Sciences, Department of Clinical Sciences, Section of Epidemiology and public Health, Lahore Sub-campus Jhang, Pakistan
| | - Yang Fan
- Xinxiang Medical University, School of Basic Medical Science, Department of Microbiology, Xinxiang, China
| | - Abbas Sadiq
- Faculty of Veterinary and Animal Sciences Lahore, Department of Pathology, Lahore, Pakistan
| | - Muhammad Asif Raza
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Riaz Hussain
- Islamia University of Bahawalpur-63100, Faculty of Veterinary and Animal Sciences, Department of Pathology, Bahawalpur, Pakistan
| | | | | | - Muhammad Umair Waqas
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Aziz Ul-Rahman
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Riffat Yasin
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Atif Rehman
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Rana Waseem Akhtar
- Muhammad Nawaz Shareef University of Agriculture Multan, Department of Veterinary and Animal Sciences, Multan, Pakistan
| | - Jiru Xu
- University of Veterinary and Animal Sciences, Department of Clinical Sciences, Section of Epidemiology and public Health, Lahore Sub-campus Jhang, Pakistan
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29
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Huang X, Li M, Hou S, Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021; 59:101. [PMID: 34738624 PMCID: PMC8577795 DOI: 10.3892/ijo.2021.5281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
A large body of evidence has revealed that the microbiome serves a role in all aspects of cancer, particularly cancer treatment. To date, studies investigating the relationship between the microbiome and systemic therapy for pancreatic ductal adenocarcinoma (PDAC) are lacking. PDAC is a high‑mortality malignancy (5‑year survival rate; <9% for all stages). Systemic therapy is one of the most important treatment choices for all patients; however, resistance or toxicity can affect its efficacy. Studies have supported the hypothesis that the microbiome is closely associated with the response to systemic therapy in PDAC, including the induction of drug resistance, or toxicity and therapy‑related changes in microbiota composition. The present review comprehensively summarized the role of the microbiome in systemic therapy for PDAC and the associated molecular mechanisms in an attempt to provide a novel direction for the improvement of treatment response and proposed potential directions for in‑depth research.
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Affiliation(s)
| | | | - Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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30
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Amatya SB, Salmi S, Kainulainen V, Karihtala P, Reunanen J. Bacterial Extracellular Vesicles in Gastrointestinal Tract Cancer: An Unexplored Territory. Cancers (Basel) 2021; 13:5450. [PMID: 34771614 PMCID: PMC8582403 DOI: 10.3390/cancers13215450] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022] Open
Abstract
Bacterial extracellular vesicles are membrane-enclosed, lipid bi-layer nanostructures that carry different classes of biomolecules, such as nucleic acids, lipids, proteins, and diverse types of small molecular metabolites, as their cargo. Almost all of the bacteria in the gut secrete extracellular vesicles to assist them in competition, survival, material exchange, host immune modulation, infection, and invasion. The role of gut microbiota in the development, progression, and pathogenesis of gastrointestinal tract (GIT) cancer has been well documented. However, the possible involvement of bacterial extracellular vesicles (bEVs) in GIT cancer pathophysiology has not been given due attention. Studies have illustrated the ability of bEVs to cross physiological barriers, selectively accumulate near tumor cells, and possibly alter the tumor microenvironment (TME). A systematic search of original published works related to bacterial extracellular vesicles on gastrointestinal cancer was performed for this review. The current systemic review outlines the possible impact of gut microbiota derived bEVs in GIT cancer in light of present-day understanding. The necessity of using advanced sequencing technologies, such as genetic, proteomic, and metabolomic investigation methodologies, to facilitate an understanding of the interrelationship between cancer-associated bacterial vesicles and gastrointestinal cancer is also emphasized. We further discuss the clinical and pharmaceutical potential of bEVs, along with future efforts needed to understand the mechanism of interaction of bEVs in GIT cancer pathogenesis.
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Affiliation(s)
- Sajeen Bahadur Amatya
- Biocenter Oulu & Cancer and Translational Medicine Research Unit, University of Oulu, 90014 Oulu, Finland; (S.B.A.); (S.S.)
| | - Sonja Salmi
- Biocenter Oulu & Cancer and Translational Medicine Research Unit, University of Oulu, 90014 Oulu, Finland; (S.B.A.); (S.S.)
| | - Veera Kainulainen
- Human Microbiome Research Program Unit, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland;
| | - Peeter Karihtala
- Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, 00290 Helsinki, Finland;
| | - Justus Reunanen
- Biocenter Oulu & Cancer and Translational Medicine Research Unit, University of Oulu, 90014 Oulu, Finland; (S.B.A.); (S.S.)
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31
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Flashner S, Yan KS, Nakagawa H. 3D Organoids: An Untapped Platform for Studying Host-Microbiome Interactions in Esophageal Cancers. Microorganisms 2021; 9:2182. [PMID: 34835308 PMCID: PMC8622040 DOI: 10.3390/microorganisms9112182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/15/2021] [Accepted: 10/17/2021] [Indexed: 12/12/2022] Open
Abstract
The microbiome is an emerging key co-factor in the development of esophageal cancer, the sixth leading cause of cancer death worldwide. However, there is a paucity of data delineating how the microbiome contributes to the pathobiology of the two histological subtypes of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma. This critical knowledge gap is partially due to inadequate modeling of host-microbiome interactions in the etiology of esophageal cancers. Recent advances have enabled progress in this field. Three dimensional (3D) organoids faithfully recapitulate the structure and function of the normal, preneoplastic, and neoplastic epithelia of the esophagus ex vivo and serve as a platform translatable for applications in precision medicine. Elsewhere in the gastrointestinal (GI) tract, the co-culture of 3D organoids with the bacterial microbiome has fostered insight into the pathogenic role of the microbiome in other GI cancers. Herein, we will summarize our current understanding of the relationship between the microbiome and esophageal cancer, discuss 3D organoid models of esophageal homeostasis, review analogous models of host-microbiome interactions in other GI cancers, and advocate for the application of these models to esophageal cancers. Together, we present a promising, novel approach with the potential to ameliorate the burden of esophageal cancer-related morbidity and mortality via improved prevention and therapeutic interventions.
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Affiliation(s)
- Samuel Flashner
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.F.); (K.S.Y.)
| | - Kelley S. Yan
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.F.); (K.S.Y.)
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Hiroshi Nakagawa
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.F.); (K.S.Y.)
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
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32
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Youssef M, Ahmed HY, Zongo A, Korin A, Zhan F, Hady E, Umair M, Shahid Riaz Rajoka M, Xiong Y, Li B. Probiotic Supplements: Their Strategies in the Therapeutic and Prophylactic of Human Life-Threatening Diseases. Int J Mol Sci 2021; 22:11290. [PMID: 34681948 PMCID: PMC8537706 DOI: 10.3390/ijms222011290] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/10/2021] [Accepted: 10/13/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic diseases and viral infections have threatened human life over the ages and constitute the main reason for increasing death globally. The rising burden of these diseases extends to negatively affecting the economy and trading globally, as well as daily life, which requires inexpensive, novel, and safe therapeutics. Therefore, scientists have paid close attention to probiotics as safe remedies to combat these morbidities owing to their health benefits and biotherapeutic effects. Probiotics have been broadly adopted as functional foods, nutraceuticals, and food supplements to improve human health and prevent some morbidity. Intriguingly, recent research indicates that probiotics are a promising solution for treating and prophylactic against certain dangerous diseases. Probiotics could also be associated with their essential role in animating the immune system to fight COVID-19 infection. This comprehensive review concentrates on the newest literature on probiotics and their metabolism in treating life-threatening diseases, including immune disorders, pathogens, inflammatory and allergic diseases, cancer, cardiovascular disease, gastrointestinal dysfunctions, and COVID-19 infection. The recent information in this report will particularly furnish a platform for emerging novel probiotics-based therapeutics as cheap and safe, encouraging researchers and stakeholders to develop innovative treatments based on probiotics to prevent and treat chronic and viral diseases.
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Affiliation(s)
- Mahmoud Youssef
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
- Food Science and Technology Department, Faculty of Agriculture, Al-Azhar University, Cairo 11651, Egypt
| | - Hanaa Y. Ahmed
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo 11787, Egypt;
| | - Abel Zongo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
- Biological Sciences, Food and Nutrition Research Center, Department of Biochemistry and Microbiology, University Joseph Ki-Zerbo, Ouagadougou 03 BP 7021, Burkina Faso
| | - Ali Korin
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
- Food Science and Technology Department, Faculty of Agriculture, Al-Azhar University, Cairo 11651, Egypt
| | - Fuchao Zhan
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
| | - Essam Hady
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
- Food Science and Technology Department, Faculty of Agriculture, Al-Azhar University, Cairo 11651, Egypt
| | - Muhammad Umair
- Department of Food Science and Engineering, College of Chemistry and Engineering, Shenzhen University, Shenzhen 518060, China; (M.U.); (M.S.R.R.)
| | - Muhammad Shahid Riaz Rajoka
- Department of Food Science and Engineering, College of Chemistry and Engineering, Shenzhen University, Shenzhen 518060, China; (M.U.); (M.S.R.R.)
| | - Yongai Xiong
- Department of Pharmaceutics, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Bin Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (M.Y.); (A.Z.); (A.K.); (F.Z.); (E.H.)
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Jaworska K, Koper M, Ufnal M. Gut microbiota and renin-angiotensin system: a complex interplay at local and systemic levels. Am J Physiol Gastrointest Liver Physiol 2021; 321:G355-G366. [PMID: 34405730 PMCID: PMC8486428 DOI: 10.1152/ajpgi.00099.2021] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders.
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Affiliation(s)
- Kinga Jaworska
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Koper
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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Smet A, Kupcinskas J, Link A, Hold GL, Bornschein J. The Role of Microbiota in Gastrointestinal Cancer and Cancer Treatment: Chance or Curse? Cell Mol Gastroenterol Hepatol 2021; 13:857-874. [PMID: 34506954 PMCID: PMC8803618 DOI: 10.1016/j.jcmgh.2021.08.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 08/18/2021] [Accepted: 08/18/2021] [Indexed: 02/08/2023]
Abstract
The gastrointestinal (GI) tract is home to a complex and dynamic community of microorganisms, comprising bacteria, archaea, viruses, yeast, and fungi. It is widely accepted that human health is shaped by these microbes and their collective microbial genome. This so-called second genome plays an important role in normal functioning of the host, contributing to processes involved in metabolism and immune modulation. Furthermore, the gut microbiota also is capable of generating energy and nutrients (eg, short-chain fatty acids and vitamins) that are otherwise inaccessible to the host and are essential for mucosal barrier homeostasis. In recent years, numerous studies have pointed toward microbial dysbiosis as a key driver in many GI conditions, including cancers. However, comprehensive mechanistic insights on how collectively gut microbes influence carcinogenesis remain limited. In addition to their role in carcinogenesis, the gut microbiota now has been shown to play a key role in influencing clinical outcomes to cancer immunotherapy, making them valuable targets in the treatment of cancer. It also is becoming apparent that, besides the gut microbiota's impact on therapeutic outcomes, cancer treatment may in turn influence GI microbiota composition. This review provides a comprehensive overview of microbial dysbiosis in GI cancers, specifically esophageal, gastric, and colorectal cancers, potential mechanisms of microbiota in carcinogenesis, and their implications in diagnostics and cancer treatment.
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Affiliation(s)
- Annemieke Smet
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences; Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Juozas Kupcinskas
- Institute for Digestive Research, Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Georgina L Hold
- Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia
| | - Jan Bornschein
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
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Zhang Z, Curran G, Altinok Dindar D, Wu Y, Wu H, Sharpton T, Zhao L, Lieberman D, Otaki F. Insights Into the Oral Microbiome and Barrett's Esophagus Early Detection: A Narrative Review. Clin Transl Gastroenterol 2021; 12:e00390. [PMID: 34446641 PMCID: PMC8397287 DOI: 10.14309/ctg.0000000000000390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/09/2021] [Indexed: 11/29/2022] Open
Abstract
Barrett's esophagus (BE) prevalence has increased steadily over the past several decades and continues to be the only known precursor of esophageal adenocarcinoma. The exact cause of BE is still unknown. Most evidence has linked BE to gastroesophageal reflux disease, which injures squamous esophageal mucosa and can result in the development of columnar epithelium with intestinal metaplasia. However, this relationship is inconsistent-not all patients with severe gastroesophageal reflux disease develop BE. There is increasing evidence that the host microbiome spanning the oral and esophageal environments differs in patients with and without BE. Several studies have documented the oral and esophageal microbiome's composition for BE with inconsistent findings. The scarcity and inconsistency of the literature and the dynamic phenomena of microbiota all warrant further studies to validate the findings and dissect the effects of oral microbiota, which are considered a viable proxy to represent esophageal microbiota by many researchers. This review aims to summarize the variability of the oral and esophageal microbiome in BE by using the example of Streptococcus to discuss the limitations of the current studies and suggest future directions. Further characterization of the sensitivity and specificity of the oral microbiome as a potential risk prediction or prevention marker of BE is critical, which will help develop noninvasive early detection methods for BE, esophageal adenocarcinoma, and other esophageal diseases.
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Affiliation(s)
- Zhenzhen Zhang
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Grace Curran
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Duygu Altinok Dindar
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Ying Wu
- Department of Integrative Biomedical and Diagnostic Sciences, School of Dentistry, Oregon Health & Science University, Portland, Oregon, USA
| | - Hui Wu
- Department of Integrative Biomedical and Diagnostic Sciences, School of Dentistry, Oregon Health & Science University, Portland, Oregon, USA
| | - Thomas Sharpton
- Department of Microbiology, Oregon State University, Corvallis, Oregon, USA
- Department of Statistics, Oregon State University, Corvallis, Oregon, USA
| | - Lianmei Zhao
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China;
| | - David Lieberman
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Oregon Health Sciences University, Portland, Oregon, USA
| | - Fouad Otaki
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Oregon Health Sciences University, Portland, Oregon, USA
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Grover K, Gregory S, Gibbs JF, Emenaker NJ. A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach. J Gastrointest Oncol 2021; 12:S290-S300. [PMID: 34422393 DOI: 10.21037/jgo-2019-gi-07] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 06/10/2020] [Indexed: 12/27/2022] Open
Abstract
The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.
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Affiliation(s)
- Karan Grover
- Department of Surgery, Rutgers Biomedical Health Sciences-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Stephanie Gregory
- Department of Surgery, Rutgers Biomedical Health Sciences-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - John F Gibbs
- Department of Surgery, Hackensack Meridian Health School of Medicine at Seton Hall University, Nutley, NJ, USA
| | - Nancy J Emenaker
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
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Yu ZK, Xie RL, You R, Liu YP, Chen XY, Chen MY, Huang PY. The role of the bacterial microbiome in the treatment of cancer. BMC Cancer 2021; 21:934. [PMID: 34412621 PMCID: PMC8375149 DOI: 10.1186/s12885-021-08664-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 08/04/2021] [Indexed: 02/07/2023] Open
Abstract
The human microbiome is defined as the microorganisms that reside in or on the human body, such as bacteria, viruses, fungi, and protozoa, and their genomes. The human microbiome participates in the modulation of human metabolism by influencing several intricate pathways. The association between specific bacteria or viruses and the efficacy of cancer treatments and the occurrence of treatment-related toxicity in cancer patients has been reported. However, the understanding of the interaction between the host microbiome and the cancer treatment response is limited, and the microbiome potentially plays a greater role in the treatment of cancer than reported to date. Here, we provide a thorough review of the potential role of the gut and locally resident bacterial microbiota in modulating responses to different cancer therapeutics to demonstrate the association between the gut or locally resident bacterial microbiota and cancer therapy. Probable mechanisms, such as metabolism, the immune response and the translocation of microbiome constituents, are discussed to promote future research into the association between the microbiome and other types of cancer. We conclude that the interaction between the host immune system and the microbiome may be the basis of the role of the microbiome in cancer therapies. Future research on the association between host immunity and the microbiome may improve the efficacy of several cancer treatments and provide insights into the cause of treatment-related side effects.
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Affiliation(s)
- Zi-Kun Yu
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
| | - Rui-Ling Xie
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
| | - Rui You
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
| | - You-Ping Liu
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
| | - Xu-Yin Chen
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
| | - Ming-Yuan Chen
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. .,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China.
| | - Pei-Yu Huang
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. .,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China.
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Ma T, Ru J, Xue J, Schulz S, Mirzaei MK, Janssen KP, Quante M, Deng L. Differences in Gut Virome Related to Barrett Esophagus and Esophageal Adenocarcinoma. Microorganisms 2021; 9:microorganisms9081701. [PMID: 34442780 PMCID: PMC8401523 DOI: 10.3390/microorganisms9081701] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/01/2021] [Accepted: 08/06/2021] [Indexed: 12/22/2022] Open
Abstract
The relationship between viruses (dominated by bacteriophages or phages) and lower gastrointestinal (GI) tract diseases has been investigated, whereas the relationship between gut bacteriophages and upper GI tract diseases, such as esophageal diseases, which mainly include Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC), remains poorly described. This study aimed to reveal the gut bacteriophage community and their behavior in the progression of esophageal diseases. In total, we analyzed the gut phage community of sixteen samples from patients with esophageal diseases (six BE patients and four EAC patients) as well as six healthy controls. Differences were found in the community composition of abundant and rare bacteriophages among three groups. In addition, the auxiliary metabolic genes (AMGs) related to bacterial exotoxin and virulence factors such as lipopolysaccharides (LPS) biosynthesis proteins were found to be more abundant in the genome of rare phages from BE and EAC samples compared to the controls. These results suggest that the community composition of gut phages and functional traits encoded by them were different in two stages of esophageal diseases. However, the findings from this study need to be validated with larger sample sizes in the future.
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Affiliation(s)
- Tianli Ma
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Jinlong Ru
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Jinling Xue
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Sarah Schulz
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Mohammadali Khan Mirzaei
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Klaus-Peter Janssen
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany;
| | - Michael Quante
- II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany
- Innere Medizin II, Universitätsklinik Freiburg, Universität Freiburg, 79106 Freiburg, Germany
- Correspondence: (M.Q.); (L.D.)
| | - Li Deng
- Helmholtz Centre Munich—German Research Center for Environmental Health, Institute of Virology, 85764 Neuherberg, Germany; (T.M.); (J.R.); (J.X.); (S.S.); (M.K.M.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
- Correspondence: (M.Q.); (L.D.)
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Suraya R, Nagano T, Kobayashi K, Nishimura Y. Microbiome as a Target for Cancer Therapy. Integr Cancer Ther 2021; 19:1534735420920721. [PMID: 32564632 PMCID: PMC7307392 DOI: 10.1177/1534735420920721] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Recently, the microbiome has been gaining traction as a major player regulating
various functions that correlate with many pathological conditions, including
cancer. The central gut microbiota population has the capability to regulate
normal inflammatory, immune, and metabolic functions, and disturbance in the
balance of the normal microbiota population can subsequently induce pathological
responses that closely relate with the mechanistic development and progression
of cancer in various forms and sites. As a disease with major socioeconomic
burden partly due to its current therapeutic options, modulating the imbalanced
gut microbiota represents a novel option not only as an adjuvant therapy to
relieve cancer treatment–related symptoms but also to influence cancer
progression itself. In this review, we will discuss how the microbiome,
specifically the gut microbiota, could affect cancer pathogenesis and what the
effect of gut microbiota–targeting treatment options have on the many aspects of
cancer pathologies based on the knowledge of recent years.
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Affiliation(s)
- Ratoe Suraya
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kazuyuki Kobayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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40
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The Role of Microbiota in the Pathogenesis of Esophageal Adenocarcinoma. BIOLOGY 2021; 10:biology10080697. [PMID: 34439930 PMCID: PMC8389269 DOI: 10.3390/biology10080697] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/05/2021] [Accepted: 07/12/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary Esophageal adenocarcinoma has a poor 5-year survival rate and is among the highest mortality cancers. Changes in the esophageal microbiome have been associated with cancer pathogenesis; however, the molecular mechanism remains obscure. This review article critically analyzes the molecular mechanisms through which microbiota may mediate the development and progression of esophageal adenocarcinoma and its precursors-gastroesophageal reflux disease and Barrett’s esophagus. It summarizes changes in esophageal microbiome composition in normal and pathologic states and subsequently discusses the role of altered microbiota in disease progression. The potential role of esophageal microbiota in protecting against the development of esophageal adenocarcinoma is also discussed. By doing so, this article highlights specific directions for future research developing microbiome-mediated therapeutics for esophageal adenocarcinoma. Abstract Esophageal adenocarcinoma (EAC) is associated with poor overall five-year survival. The incidence of esophageal cancer is on the rise, especially in Western societies, and the pathophysiologic mechanisms by which EAC develops are of extreme interest. Several studies have proposed that the esophageal microbiome may play an important role in the pathophysiology of EAC, as well as its precursors—gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE). Gastrointestinal microbiomes altered by inflammatory states have been shown to mediate tumorigenesis directly and are now being considered as novel targets for both cancer treatment and prevention. Elucidating molecular mechanisms through which the esophageal microbiome potentiates the development of GERD, BE, and EAC will provide a foundation on which new therapeutic targets can be developed. This review summarizes current findings that elucidate the molecular mechanisms by which microbiota promote the pathogenesis of GERD, BE, and EAC, revealing potential directions for additional research on the microbiome-mediated pathophysiology of EAC.
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Mughal MJ, Kwok HF. Multidimensional role of bacteria in cancer: Mechanisms insight, diagnostic, preventive and therapeutic potential. Semin Cancer Biol 2021; 86:1026-1044. [PMID: 34119644 DOI: 10.1016/j.semcancer.2021.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/28/2021] [Accepted: 06/08/2021] [Indexed: 02/08/2023]
Abstract
The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.
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Affiliation(s)
- Muhammad Jameel Mughal
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau; MOE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau.
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Elagan SK, Almalki SJ, Alharthi MR, Mohamed MS, EL-Badawy MF. Role of Bacteria in the Incidence of Common GIT Cancers: The Dialectical Role of Integrated Bacterial DNA in Human Carcinogenesis. Infect Drug Resist 2021; 14:2003-2014. [PMID: 34103947 PMCID: PMC8179827 DOI: 10.2147/idr.s309051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the wide medical knowledge about the direct role of many viruses in the pathogenesis of certain cancers, there is still ambiguity and hazy vision about the direct role of bacteria in cancer incidence. Understanding the role of bacteria in carcinogenesis is no longer a scientific luxury, but it has become an urgent and extremely important necessity to realize the pathogenesis of cancer caused by oncogenic bacteria as an attempt to overcome the oncogenic mechanisms exhibited by these oncogenic bacteria. This review shed the light on the indirect role of the host's inflammatory and immunological responses in the pathogenesis of bacteria-induced cancer. Also, this review discussed the indirect role of the bacterial toxins and virulence factors in the induction of common gastrointestinal cancers, such as gallbladder cancer (GBC), colorectal cancer (CRC), and gastric cancer (GC). Finally, this review dealt with the debate about the possibility of bacterial DNA integration into the human genome and cancer incidence.
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Affiliation(s)
- Sayed K Elagan
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Saad J Almalki
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - M R Alharthi
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Mohamed S Mohamed
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Mohamed F EL-Badawy
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Sadat City, Sadat City, 32958, Egypt
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43
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D'Souza SM, Houston K, Keenan L, Yoo BS, Parekh PJ, Johnson DA. Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease: A paradigm shift from acid to bacteria? World J Gastroenterol 2021; 27:2054-2072. [PMID: 34025064 PMCID: PMC8117736 DOI: 10.3748/wjg.v27.i18.2054] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/06/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genomic sequencing, bioinformatics, and initial speciation (e.g., relative abundance) of the commensal microbiome have revolutionized the way we think about the "human" body in health and disease. The interactions between the gut bacteria and the immune system of the host play a key role in the pathogenesis of gastrointestinal diseases, including those impacting the esophagus. Although relatively stable, there are a number of factors that may disrupt the delicate balance between the luminal esophageal microbiome (EM) and the host. These changes are thought to be a product of age, diet, antibiotic and other medication use, oral hygiene, smoking, and/or expression of antibiotic products (bacteriocins) by other flora. These effects may lead to persistent dysbiosis which in turn increases the risk of local inflammation, systemic inflammation, and ultimately disease progression. Research has suggested that the etiology of gastroesophageal reflux disease-related esophagitis includes a cytokine-mediated inflammatory component and is, therefore, not merely the result of esophageal mucosal exposure to corrosives (i.e., acid). Emerging evidence also suggests that the EM plays a major role in the pathogenesis of disease by inciting an immunogenic response which ultimately propagates the inflammatory cascade. Here, we discuss the potential role for manipulating the EM as a therapeutic option for treating the root cause of various esophageal disease rather than just providing symptomatic relief (i.e., acid suppression).
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Affiliation(s)
- Steve M D'Souza
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Kevin Houston
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Lauren Keenan
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Byung Soo Yoo
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Parth J Parekh
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - David A Johnson
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
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Mennini M, Tambucci R, Riccardi C, Rea F, De Angelis P, Fiocchi A, Assa'ad A. Eosinophilic Esophagitis and Microbiota: State of the Art. Front Immunol 2021; 12:595762. [PMID: 33679739 PMCID: PMC7933523 DOI: 10.3389/fimmu.2021.595762] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic, food-triggered, immune-mediated disease of the oesophagus, clinically characterized by symptoms referred to oesophagal dysfunction, and histologically defined by an eosinophil productive inflammation of the oesophagal mucosa, among other cell types. The involvement of an adaptive Th2-type response to food antigens in EoE was known since 2000; several cytokines and chemokines promote food-specific responses, during which local production of IgE, but also IgG4 derived from plasma cells in lamina propria of oesophagal mucosa might play an important role. Evidence pointing towards a possible role for the innate immunity in EoE has arisen recently. Together, this evidence gives rise to a potential role that the innate immune system in general, and also the microbial pattern recognition receptors (PRRs) might play in EoE pathogenesis. Among PRRs, Toll-like receptors (TLRs) are type-I transmembrane receptors expressed both on epithelial and lamina propria cells with the capacity to distinguish between pathogen and commensal microbes. As TLRs in the different intestinal epithelia represent the primary mechanism of epithelial recognition of bacteria, this evidence underlines that oesophagal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease. The oesophagal mucosa hosts a resident microbiota, although in a smaller population as compared with other districts of the gastrointestinal tract. Few studies have focused on the composition of the microbiota of the normal oesophagus alone. Still, additional information has come from studies investigating the oesophagal microbiota in disease and including healthy patients as controls. Our review aims to describe all the evidence on the oesophagal and intestinal microbiota in patients with EoE to identify the specific features of dysbiosis in this condition.
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Affiliation(s)
- Maurizio Mennini
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Carla Riccardi
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Francesca Rea
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Paola De Angelis
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Alessandro Fiocchi
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Amal Assa'ad
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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Garajová I, Balsano R, Wang H, Leonardi F, Giovannetti E, Deng D, Peters GJ. The role of the microbiome in drug resistance in gastrointestinal cancers. Expert Rev Anticancer Ther 2021; 21:165-176. [PMID: 33115280 DOI: 10.1080/14737140.2021.1844007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023]
Abstract
Introduction: The microbiota is recognized for its impact on both human health and disease. The human microbiota is made up of trillions of cells, including bacteria, viruses, and fungi. The largest population of microbes reside in the gut, prompting research for better understanding of the impact of gastrointestinal microbiota in different diseases. Evidence from numerous studies has pointed out the role of commensal microbes as key determinants of cancer pathogenesis. Moreover, gut microbiota may play an important role in chemoresistance; consequently, this knowledge might be important for novel strategies to improve anticancer treatment efficacy.Areas covered: We describe the role of microbiota in different gastrointestinal cancer types (esophageal, gastric, colorectal, hepatocellular and pancreatic-biliary tract cancers). Moreover, we analyzed the impact of the microbiota on resistance to anticancer therapies, and, lastly, we focused on possibilities of microbiota modulation to enhance anticancer therapy efficacy.Expert opinion: Increasing evidence shows that gut microbiota might influence resistance to anticancer treatment, including conventional chemotherapy, immunotherapy, radiotherapy, and surgery. Therefore, a better knowledge of gut microbiota and its interactions with anticancer drugs will enable us to develop novel anticancer treatment strategies and subsequently improve the cancer patients' outcome.
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Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Heling Wang
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands
| | | | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienz, Pisa, Italy
| | - Dongmei Deng
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
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Liu D, Qian T, Sun S, Jiang JJ. Laryngopharyngeal Reflux and Inflammatory Responses in Mucosal Barrier Dysfunction of the Upper Aerodigestive Tract. J Inflamm Res 2021; 13:1291-1304. [PMID: 33447069 PMCID: PMC7801919 DOI: 10.2147/jir.s282809] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/16/2020] [Indexed: 12/29/2022] Open
Abstract
The upper aerodigestive tract (UAT) is the first line of defense against environmental stresses such as antigens, microbes, inhalants, foods, etc., and mucins, intracellular junctions, epithelial cells, and immune cells are the major constituents of this defensive mucosal barrier. Laryngopharyngeal reflux (LPR) is recognized as an independent risk factor for UAT mucosal disorders, and in this review, we describe the components and functions of the mucosal barrier and the results of LPR-induced mucosal inflammation in the UAT. We discuss the interactions between the refluxate and the mucosal components and the mechanisms through which these damaging events disrupt and alter the mucosal barriers. In addition, we discuss the dynamic alterations in the mucosal barrier that might be potential therapeutic targets for LPR-induced disorders.
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Affiliation(s)
- Danling Liu
- Otorhinolaryngology Department, ENT Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai 200032, People's Republic of China
| | - Tingting Qian
- Otorhinolaryngology Department, ENT Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai 200032, People's Republic of China
| | - Shan Sun
- Otorhinolaryngology Department, ENT Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai 200032, People's Republic of China
| | - Jack J Jiang
- Otorhinolaryngology Department, ENT Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai 200032, People's Republic of China.,Department of Surgery, Division of Otolaryngology Head and Neck Surgery, University of Wisconsin Medical School, Madison, WI 53792-7375, USA
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Liu F, Liu M, Liu Y, Guo C, Zhou Y, Li F, Xu R, Liu Z, Deng Q, Li X, Zhang C, Pan Y, Ning T, Dong X, Hu Z, Bao H, Cai H, Silva IDS, He Z, Ke Y. Oral microbiome and risk of malignant esophageal lesions in a high-risk area of China: A nested case-control study. Chin J Cancer Res 2020; 32:742-754. [PMID: 33446997 PMCID: PMC7797237 DOI: 10.21147/j.issn.1000-9604.2020.06.07] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Objective We aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk. Methods We conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls. DESeq analysis was performed to identify taxa of differential abundance. Differential oral species together with subject characteristics were evaluated for their potential in predicting SDA risk by constructing conditional logistic regression models. Results A total of 125 taxa including 37 named species showed significantly different abundance between SDA cases and controls (all P<0.05 & false discovery rate-adjusted Q<0.10). A multivariate logistic model including 11 SDA lesion-related species and family history of esophageal cancer provided an area under the receiver operating characteristic curve (AUC) of 0.89 (95% CI, 0.84−0.93). Cross-validation and sensitivity analysis, excluding cases diagnosed within 1 year of collection of the baseline specimen and their matched controls, or restriction to screen-endoscopic-detected or clinically diagnosed case-control triads, or using only bacterial data measured at the baseline, yielded AUCs>0.84. Conclusions The oral microbiome may play an etiological and predictive role in esophageal cancer, and it holds promise as a non-invasive early warning biomarker for risk stratification for esophageal cancer screening programs.
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Affiliation(s)
- Fangfang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Mengfei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ying Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chuanhai Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | | | - Fenglei Li
- Hua County People's Hospital, Anyang 456400, China
| | - Ruiping Xu
- Anyang Cancer Hospital, Anyang 455000, China
| | - Zhen Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Qiuju Deng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiang Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chaoting Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yaqi Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Tao Ning
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiao Dong
- Novogene Co., Ltd, Beijing 100080, China
| | - Zhe Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Huanyu Bao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Hong Cai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Isabel Dos Santos Silva
- Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK
| | - Zhonghu He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yang Ke
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Deng Y, Tang D, Hou P, Shen W, Li H, Wang T, Liu R. Dysbiosis of gut microbiota in patients with esophageal cancer. Microb Pathog 2020; 150:104709. [PMID: 33378710 DOI: 10.1016/j.micpath.2020.104709] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023]
Abstract
A number of studies have identified that gut microbiota influences the development of cancer. However, there is little known about gut microbiota and esophageal cancer (EC). The aim of this study was to investigate the gut microbiota profile associated with EC. In this study, 23 patients with EC and 23 sex- and age-matched healthy controls (NC) were recruited between July 2019 and August 2019 at Huai'an First People's Hospital (Huai'an, China) and the gut microbiota was analyzed by 16S rRNA gene sequencing of fresh stool samples. We found that the microbial richness of intestinal flora in patients with EC were higher than NC, whereas evenness did not change obviously. Principal coordinate analysis (PCoA) and Unweighted Pair Group Method with Arithmetic Mean (UPGMA) analysis both revealed that a distinct separation in bacterial community composition between the EC and NC. At the phylum level, the EC group showed significantly higher abundances of Firmicutes and Actinobacteria, but a lower Bacteroidetes than NC. At the genus level, a significantly increased abundance of Streptococcus, Bifidobacterium, Subdoligranulum, Blautia, Romboutsia, Collinsella, Paeniclostridium, Dorea, and Atopobium were observed in EC patients, while Lachnospira, Bacteroides, Agathobacter, Lachnoclostridium, Parabacteroides, Paraprevotella, Butyricicoccus, Tyzzerella, Fusicatenibacter, and Sutterella were reduced. Receiver operating characteristic (ROC) analysis revealed that Lachnospira, Bacteroides, Streptococcus, and Bifidobacterium both achieved a high accuracy in EC diagnosis (area under the curve was more than 0.85), and the Lachnospira was found to be the best classifier. This study firstly characterized the gut microbiota composition of EC patients and screened out the optimal potential microbiota biomarkers for EC diagnosis. It may provide a fundamental reference for further studies on the gut microbiome for the diagnosis and treatment of EC.
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Affiliation(s)
- YaLi Deng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - DeRong Tang
- Department of Thoracic Surgery, The Affiliated Huaian Peoples NO.1 Hospital of Nanjing Medical University, Huaian, 223001, China
| | - PanFei Hou
- Department of Clinical Laboratory, Lianshui County People's Hospital, Lianshui, 223400, China
| | - WeiTao Shen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - HuiLin Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Tian Wang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China.
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The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor-immune-microbiome interaction. Hum Genet 2020; 140:725-746. [PMID: 33180176 DOI: 10.1007/s00439-020-02235-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Metagenomic studies using next-generation sequencing technologies have revealed rich human intestinal microbiome, which likely influence host immunity and health conditions including cancer. Evidence indicates a biological link between altered microbiome and cancers in the digestive system. Escherichia coli and Bacteroides fragilis have been found to be enriched in colorectal mucosal tissues from patients with familial adenomatous polyposis that is caused by germline APC mutations. In addition, recent studies have found enrichment of certain oral bacteria, viruses, and fungi in tumor tissue and fecal specimens from patients with gastrointestinal cancer. An integrative approach is required to elucidate the role of microorganisms in the pathogenic process of gastrointestinal cancers, which develop through the accumulation of somatic genetic and epigenetic alterations in neoplastic cells, influenced by host genetic variations, immunity, microbiome, and environmental exposures. The transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to link germline genetics and environmental factors (including diet, lifestyle, and pharmacological factors) to pathologic phenotypes. The integration of microbiology into the MPE model (microbiology-MPE) can contribute to better understanding of the interactive role of environment, tumor cells, immune cells, and microbiome in various diseases. We review major clinical and experimental studies on the microbiome, and describe emerging evidence from the microbiology-MPE research in gastrointestinal cancers. Together with basic experimental research, this new research paradigm can help us to develop new prevention and treatment strategies for gastrointestinal cancers through targeting of the microbiome.
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Peter S, Pendergraft A, VanDerPol W, Wilcox CM, Kyanam Kabir Baig KR, Morrow C, Izard J, Mannon PJ. Mucosa-Associated Microbiota in Barrett's Esophagus, Dysplasia, and Esophageal Adenocarcinoma Differ Similarly Compared With Healthy Controls. Clin Transl Gastroenterol 2020; 11:e00199. [PMID: 32955191 PMCID: PMC7473866 DOI: 10.14309/ctg.0000000000000199] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 06/12/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Alterations in the composition of the human gut microbiome and its metabolites have been linked to gut epithelial neoplasia. We hypothesized that differences in mucosa-adherent Barrett's microbiota could link to risk factors, providing risk of progression to neoplasia. METHODS Paired biopsies from both diseased and nonaffected esophagus (as well as gastric cardia and gastric juice for comparison) from patients with intestinal metaplasia (n = 10), low grade dysplasia (n = 10), high grade dysplasia (n = 10), esophageal adenocarcinoma (n = 12), and controls (n = 10) were processed for mucosa-associated bacteria and analyzed by 16S ribosomal ribonucleic acid V4 gene DNA sequencing. Taxa composition was tested using a generalized linear model based on the negative binomial distribution and the log link functions of the R Bioconductor package edgeR. RESULTS The microbe composition of paired samples (disease vs nondisease) comparing normal esophagus with intestinal metaplasia, low grade dysplasia, high grade dysplasia, and adenocarcinoma showed significant decreases in the phylum Planctomycetes and the archaean phylum Crenarchaeota (P < 0.05, false discovery rate corrected) in diseased tissue compared with healthy controls and intrasample controls (gastric juice and unaffected mucosa). Genera Siphonobacter, Balneola, Nitrosopumilus, and Planctomyces were significantly decreased (P < 0.05, false discovery rate corrected), representing <10% of the entire genus community. These changes were unaffected by age, tobacco use, or sex for Crenarcha. DISCUSSSION There are similar significant changes in bacterial genera in Barrett's esophageal mucosa, dysplasia, and adenocarcinoma compared with controls and intrapatient unaffected esophagus. Further work will establish the biologic plausibility of these specific microbes' contributions to protection from or induction of esophageal epithelial dysplasia.
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Affiliation(s)
- Shajan Peter
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
| | | | - William VanDerPol
- Center for Clinical and Translational Science, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - C. Mel Wilcox
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
| | - Kondal R. Kyanam Kabir Baig
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
| | - Casey Morrow
- Department of Cell Developmental and Integrative Biology, UAB, Birmingham, Alabama, USA
| | - Jacques Izard
- Nebraska Food for Health Center, University of Nebraska, Lincoln, Nebraska, USA
| | - Peter J. Mannon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
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