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Bakir-Gungor B, Temiz M, Canakcimaksutoglu B, Yousef M. Prediction of colorectal cancer based on taxonomic levels of microorganisms and discovery of taxonomic biomarkers using the Grouping-Scoring-Modeling (G-S-M) approach. Comput Biol Med 2025; 187:109813. [PMID: 39929003 DOI: 10.1016/j.compbiomed.2025.109813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 01/09/2025] [Accepted: 02/05/2025] [Indexed: 02/12/2025]
Abstract
Colorectal cancer (CRC) is one of the most prevalent forms of cancer globally. The human gut microbiome plays an important role in the development of CRC and serves as a biomarker for early detection and treatment. This research effort focuses on the identification of potential taxonomic biomarkers of CRC using a grouping-based feature selection method. Additionally, this study investigates the effect of incorporating biological domain knowledge into the feature selection process while identifying CRC-associated microorganisms. Conventional feature selection techniques often fail to leverage existing biological knowledge during metagenomic data analysis. To address this gap, we propose taxonomy-based Grouping Scoring Modeling (G-S-M) method that integrates biological domain knowledge into feature grouping and selection. In this study, using metagenomic data related to CRC, classification is performed at three taxonomic levels (genus, family and order). The MetaPhlAn tool is employed to determine the relative abundance values of species in each sample. Comparative performance analyses involve six feature selection methods and four classification algorithms. When experimented on two CRC associated metagenomics datasets, the highest performance metric, yielding an AUC of 0.90, is observed at the genus taxonomic level. At this level, 7 out of top 10 groups (Parvimonas, Peptostreptococcus, Fusobacterium, Gemella, Streptococcus, Porphyromonas and Solobacterium) were commonly identified for both datasets. Moreover, the identified microorganisms at genus, family, and order levels are thoroughly discussed via refering to CRC-related metagenomic literature. This study not only contributes to our understanding of CRC development, but also highlights the applicability of taxonomy-based G-S-M method in tackling various diseases.
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Affiliation(s)
- Burcu Bakir-Gungor
- Department of Computer Engineering, Faculty of Engineering, Abdullah Gul University, Kayseri, 38080, Turkey
| | - Mustafa Temiz
- Department of Electrical and Computer Engineering, Faculty of Engineering, Abdullah Gul University, Kayseri, 38080, Turkey.
| | - Beyza Canakcimaksutoglu
- Department of Bioengineering, Faculty of Life and Natural Science, Abdullah Gul University, Kayseri, 38080, Turkey
| | - Malik Yousef
- Department of Information Systems, Zefat Academic College, Zefat, 13206, Israel; Galilee Digital Health Research Center (GDH), Zefat Academic College, Israel
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Deng D, Zhao L, Song H, Wang H, Cao H, Cui H, Zhou Y, Cui R. Microbiome analysis of gut microbiota in patients with colorectal polyps and healthy individuals. Sci Rep 2025; 15:7126. [PMID: 40021742 PMCID: PMC11871317 DOI: 10.1038/s41598-025-91626-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/21/2025] [Indexed: 03/03/2025] Open
Abstract
Colorectal polyps serve as the primary precursors for colorectal cancer. A close relationship has been observed between colorectal polyps and gut microbiota. However, the composition and role of the microbiome associated with tubular adenoma are not well understood. In this study, we prospectively evaluated alterations in gut microbiota among patients with colorectal polyps. A total of 60 subjects were enrolled in this study, including 30 patients with colorectal polyps (CP group) and 30 healthy controls (control group). The 16S rRNA sequencing was employed to characterize the gut microbiome in fecal samples. The results revealed that the beta diversity of the gut microbiota in the CP group significantly differs from that of the control group (p = 0.001). At the phylum level, the relative abundance of Bacteroides, Fusobacteria, and Proteobacteria was higher in the CP group compared to the control group (p < 0.05), whereas the relative abundance of Actinobacteria was higher in the control group in comparison to the CP group (p < 0.05). At the genus level, the abundance of Bacteroides increased in the CP group (p < 0.05), while Bifidobacterium declined in the CP group (p < 0.05). At the species level, the abundance of Clostridium perfringens, unidentified_Bacteroides, unidentified_Dorea, Escherichia coli, Clostridium ramosum, and Ruminococcus gnavus was higher (p < 0.05), whereas the abundance of Bifidobacterium adolescentis, unclassified_Bifidobacterium, Bifidobacterium longum, Faecalibacterium prausnitzii, and unidentified_Bifidobacterium is lower in CP group compared to the control group (p < 0.05). There was a structural imbalance in the composition of intestinal colonization flora for CP patients, characterized by a decrease in beneficial bacteria and an increase in harmful bacteria. Escherichia, Shigella, and Bacteroides may serve as promising biomarkers for early detection of colorectal polyps.
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Affiliation(s)
- Dayi Deng
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China
| | - Lin Zhao
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China
| | - Hui Song
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China
| | - Houming Wang
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China
| | - Hengjie Cao
- Department of Surgery, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Huimin Cui
- Department of Surgery, Jinan Licheng District Hospital of Chinese Medicine, Jinan, 250000, China
| | - Yong Zhou
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China.
| | - Rong Cui
- Department of Surgery, Jiading Hospital of Traditional Chinese Medicine, 222 Bole Road, Jiading District, Shanghai, 201800, China.
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Sameni F, Elkhichi PA, Dadashi A, Sadeghi M, Goudarzi M, Eshkalak MP, Dadashi M. Global prevalence of Fusobacterium nucleatum and Bacteroides fragilis in patients with colorectal cancer: an overview of case reports/case series and meta-analysis of prevalence studies. BMC Gastroenterol 2025; 25:71. [PMID: 39930345 PMCID: PMC11808969 DOI: 10.1186/s12876-025-03664-x] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/31/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second deadliest carcinoma across the globe and has been known as a multi-factor induced-disease. Emerging research have demonstrated that bacterial colonization may contribute to the initiation and promotion of the CRC. The presence of Fusobacterium nucleatum (F. nucleatum) and Bacteroides fragilis (B. fragilis) in the gut is associated with the development of CRC. In this study, the prevalence of F. nucleatum and B. fragilis among CRC patients has been assessed worldwide through a systematic review and meta-analysis. METHODS The extensive search was performed using "Fusobacterium nucleatum", "Bacteroides fragilis", "Colorectal cancer" and all relevant keywords. Then, a systematic paper screening was done following a comprehensive search in Embase, Web of Science, and PubMed databases while the time range was limited between the years 2000 and 2024. Afterwards, statistical analysis was performed utilizing the comprehensive meta-analysis (CMA) software (version 2.0, Biostat, USA). RESULTS According to the meta-analysis of prevalence studies, the prevalence of F. nucleatum among 19 countries and B. fragilis among 10 countries were indicated to be 38.9% (95% CI 33.7-44.3%) and 42.5% (95% CI 34.4-51.1%), respectively, among the CRC patients. It was then revealed that Asia had the highest prevalence of F. nucleatum while most of the B. fragilis isolates in CRC cases were reported in European countries. Moreover, the data suggested that the most common comorbidity observed among the CRC cases was diabetes. CONCLUSION Our results emphasized the high prevalence of F. nucleatum and B. fragilis in CRC patients. Based on this meta-analysis review, regulating the gut microbiota in CRC patients seemed to be a promising approach to improving the efficacy of CRC therapy.
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Affiliation(s)
- Fatemeh Sameni
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- Molecular Microbiology Research Center, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Parisa Abedi Elkhichi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Dadashi
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - Mohammad Sadeghi
- EA7375-EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers,, Paris East Créteil University (UPEC), Créteil, 94010, France
| | - Mehdi Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Masoud Dadashi
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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Feizi H, Kafil HS, Plotnikov A, Kataev V, Balkin A, Filonchikova E, Rezaee MA, Ghotaslou R, Sadrkabir M, Kadkhoda H, Kamounah FS, Nikitin S. Polyp and tumor microenvironment reprogramming in colorectal cancer: insights from mucosal bacteriome and metabolite crosstalk. Ann Clin Microbiol Antimicrob 2025; 24:9. [PMID: 39881353 PMCID: PMC11780822 DOI: 10.1186/s12941-025-00777-9] [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: 12/07/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Highly frequent colorectal cancer (CRC) is predicted to have 3.2 million novel cases by 2040. Tumor microenvironment (TME) bacteriome and metabolites are proposed to be involved in CRC development. In this regard, we aimed to investigate the bacteriome and metabolites of healthy, adenomatous polyp, and CRC tissues. METHODS Sixty samples including healthy (H), adenomatous polyps (AP), adenomatous polyps-adjacent (APA), cancer tumor (CT), and cancer tumor-adjacent (CA) tissues were collected and analyzed by 16 S rRNA sequencing and 1H NMR spectroscopy. RESULTS Our results revealed that the bacteriome and metabolites of the H, AP, and CT groups were significantly different. We observed that the Lachnospiraceae family depleted concomitant with acetoacetate and beta-hydroxybutyric acid (BHB) accumulations in the AP tissues. In addition, some bacterial species including Gemella morbillorum, and Morganella morganii were enriched in the AP compared to the H group. Furthermore, fumarate was accumulated concomitant to Aeromonas enteropelogenes, Aeromonas veronii, and Fusobacterium nucleatum subsp. animalis increased abundance in the CT compared to the H group. CONCLUSION These results proposed that beneficial bacteria including the Lachnospiraceae family depletion cross-talk with acetoacetate and BHB accumulations followed by an increased abundance of driver bacteria including G. morbillorum, and M. morganii may reprogram polyp microenvironment leading to tumor initiation. Consequently, passenger bacteria accumulation like A. enteropelogenes, A.veronii, and F. nucleatum subsp. animalis cross-talking fumarate in the TME may aggravate cancer development. So, knowledge of TME bacteriome and metabolites might help in cancer prevention, early diagnosis, and a good prognosis.
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Affiliation(s)
- Hadi Feizi
- Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Microbiology, Aalinasab Hospital, Social Security Organization, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Andrey Plotnikov
- Institute for Cellular and Intracellular Symbiosis of the Ural Branch of the Russian Academy of Sciences, Orenburg, Russia
| | - Vladimir Kataev
- Institute for Cellular and Intracellular Symbiosis of the Ural Branch of the Russian Academy of Sciences, Orenburg, Russia
| | - Alexander Balkin
- Institute for Cellular and Intracellular Symbiosis of the Ural Branch of the Russian Academy of Sciences, Orenburg, Russia
| | - Ekaterina Filonchikova
- Institute for Cellular and Intracellular Symbiosis of the Ural Branch of the Russian Academy of Sciences, Orenburg, Russia
| | - Mohammad Ahangarzadeh Rezaee
- Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Ghotaslou
- Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadrkabir
- Department of Internal Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Hiva Kadkhoda
- Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Mahabad Faculty of Medical Sciences, , Urmia University of Medical Sciences, Urmia, Iran
| | - Fadhil S Kamounah
- Department of Chemistry, University of Copenhagen, Copenhagen, Denmark
| | - Sergei Nikitin
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
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Lam HYP, Lai MJ, Wang PC, Wu WJ, Chen LK, Fan HW, Tseng CC, Peng SY, Chang KC. A Novel Bacteriophage with the Potential to Inhibit Fusobacterium nucleatum-Induced Proliferation of Colorectal Cancer Cells. Antibiotics (Basel) 2025; 14:45. [PMID: 39858331 PMCID: PMC11760851 DOI: 10.3390/antibiotics14010045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/26/2024] [Accepted: 01/01/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Increasing evidence shows that Fusobacterium nucleatum (F. nucleatum) largely affects colorectal cancer (CRC) growth and progression; therefore, the inhibition of intratumoral F. nucleatum may be one realistic approach to combat CRC. Although antibiotics are helpful in eliminating bacteria, the major problem remains the rise of potential antibiotic-resistant strains and antibiotic-associated adverse effects. Currently, bacteriophage therapy has gained interest because of its high selectivity to bacterial hosts and may become a realistic approach in treating bacteria-associated cancers. METHODS In this study, a new F. nucleatum bacteriophage, ØTCUFN3, was isolated and its biological characteristics were identified. In vitro and in vivo studies were performed to investigate the effect of ØTCUFN3 in combating F. nucleatum-induced CRC growth. RESULTS By applying ØTCUFN3 to F. nucleatum-induced CRC cell lines, p53+/+, and p53-/- isogenic HCT116 cells, our results revealed an inhibition of CRC proliferation and the expression of epithelial-to-mesenchymal transition (EMT) markers. ØTCUFN3 injection also reduced the growth of F. nucleatum-induced mouse xenografts. CONCLUSIONS Our results demonstrated the use of F. nucleatum bacteriophage against CRC, laying the foundation for the future usage of bacteriophage in cancer treatment.
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Affiliation(s)
- Ho Yin Pekkle Lam
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan;
- Institute of Medical Science, College of Medicine, Tzu Chi University, Hualien 970374, Taiwan;
| | - Meng-Jiun Lai
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970374, Taiwan; (M.-J.L.); (P.-C.W.); (W.-J.W.)
| | - Pin-Chun Wang
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970374, Taiwan; (M.-J.L.); (P.-C.W.); (W.-J.W.)
| | - Wen-Jui Wu
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970374, Taiwan; (M.-J.L.); (P.-C.W.); (W.-J.W.)
| | - Li-Kuang Chen
- Institute of Medical Science, College of Medicine, Tzu Chi University, Hualien 970374, Taiwan;
- Branch of Clinical Pathology, Department of Laboratory Medicine, Buddhist Tzu Chi General Hospital, Hualien 970473, Taiwan
| | - Hsiang-Wei Fan
- Master Program in Biomedical Science, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan;
| | - Chun-Chieh Tseng
- Department and Graduate Institute of Public Health, Tzu Chi University, Hualien 970374, Taiwan;
| | - Shih-Yi Peng
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan;
| | - Kai-Chih Chang
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970374, Taiwan; (M.-J.L.); (P.-C.W.); (W.-J.W.)
- Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan
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Hong BY, Chhaya A, Robles A, Cervantes J, Tiwari S. The role of Fusobacterium nucleatum in the pathogenesis of colon cancer. J Investig Med 2024; 72:819-827. [PMID: 39175147 DOI: 10.1177/10815589241277829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Previously, many studies have reported changes in the gut microbiota of patients with colorectal cancer (CRC). While CRC is a well-described disease, the relationship between its development and features of the intestinal microbiome is still being understood. Evidence linking Fusobacterium nucleatum enrichment in colorectal tumor tissue has prompted the elucidation of various molecular mechanisms and tumor-promoting attributes. In this review we highlight various aspects of our understanding of the relationship between the development of CRC and the alteration of intestinal microbiome, focusing specifically on the role of F. nucleatum. As the amount of F. nucleatum DNA in CRC tissue is associated with shorter survival, it may potentially serve as a prognostic biomarker, and most importantly may open the door for a role in CRC treatment.
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Affiliation(s)
- Bo-Young Hong
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Ajay Chhaya
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA
| | - Alejandro Robles
- Department of Internal Medicine, Division of Gastroenterology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Jorge Cervantes
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Sangeeta Tiwari
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA
- Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA
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Datorre JG, Dos Reis MB, de Carvalho AC, Porto J, Rodrigues GH, Lima AB, Reis MT, Hirai W, Hashimoto CL, Guimarães DP, Reis RM. Enhancing Colorectal Cancer Screening with Droplet Digital PCR Analysis of Fusobacterium nucleatum in Fecal Immunochemical Test Samples. Cancer Prev Res (Phila) 2024; 17:471-479. [PMID: 38953141 DOI: 10.1158/1940-6207.capr-23-0331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 01/18/2024] [Accepted: 06/28/2024] [Indexed: 07/03/2024]
Abstract
Fecal immunochemical test (FIT) followed by colonoscopy in positive cases is commonly used for population-based colorectal cancer screening. However, specificity of FIT for colorectal cancer is not ideal and has poor performance for advanced adenoma detection. Fecal Fusobacterium nucleatum (Fn) detection has been proposed as a potential noninvasive biomarker for colorectal cancer and advanced adenoma detection. We aimed to evaluate the diagnostic performance of Fn detection using droplet digital PCR (ddPCR) in FIT samples from individuals enrolled in a colorectal cancer screening program with colorectal adenoma or cancer. We evaluated Fn presence in DNA isolated from FIT leftover material of 300 participants in a colorectal cancer screening program using ddPCR. The Fn DNA amount was classified as Fn-low/negative and Fn-high, and the association with patients' clinicopathological features and accuracy measurements was calculated. Fn-high levels were more prevalent in FIT-positive (47.2%, n = 34 of 72) than FIT-negative samples (28.9%, n = 66 of 228; P < 0.04). Among FIT-positive samples, high Fn levels were significantly more frequent in patients with cancer (CA, n = 8) when compared to normal (NT, n = 16; P = 0.02), non-advanced adenomas (NAA, n = 36; P = 0.01), and advanced adenomas (AA, n = 12; P = 0.01). Performance analysis of Fn in FIT-positive samples for colorectal cancer detection yielded an AUC of 0.8203 [confidence interval (CI), 0.6464-0.9942], with high sensitivity (100%) and specificity of 50%. Concluding, we showed the feasibility of detecting Fn in FIT leftovers using the ultrasensitive ddPCR technique. Furthermore, we highlighted the potential use of Fn levels in fecal samples to ameliorate colorectal cancer detection. Prevention Relevance: Fusobacterium nucleatum detection by droplet digital PCR could prioritize the selection of fecal immunochemical test-positive individuals who might benefit the most from the colonoscopy procedure.
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Affiliation(s)
- José G Datorre
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
| | - Mariana B Dos Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
| | - Ana C de Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
| | - Jun Porto
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
| | | | - Adhara B Lima
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
| | - Monise T Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
- Department of Pathology, Barretos Cancer Hospital, São Paulo, Brazil
| | - Welinton Hirai
- Department of Statistics and Epidemiology, Barretos Cancer Hospital, São Paulo, Brazil
| | | | - Denise P Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
- Department of Prevention, Barretos Cancer Hospital, São Paulo, Brazil
| | - Rui M Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal
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Petkevicius V, Lehr K, Kupcinskas J, Link A. Fusobacterium nucleatum: Unraveling its potential role in gastric carcinogenesis. World J Gastroenterol 2024; 30:3972-3984. [PMID: 39351058 PMCID: PMC11438658 DOI: 10.3748/wjg.v30.i35.3972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/09/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024] Open
Abstract
Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation, such as periodontitis and gingivitis. In the last 10 years, F. nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression, metastasis and poor disease outcome. While the role of F. nucleatum in colon carcinogenesis has been intensively studied, its role in gastric carcinogenesis is still poorly understood. Although Helicobacter pylori infection has historically been recognized as the strongest risk factor for the development of gastric cancer (GC), with recent advances in DNA sequencing technology, other members of the gastric microbial community, and F. nucleatum in particular, have received increasing attention. In this review, we summarize the existing knowledge on the involvement of F. nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F. nucleatum in GC.
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Affiliation(s)
- Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Konrad Lehr
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg 39120, Germany
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg 39120, Germany
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Intarajak T, Udomchaiprasertkul W, Khoiri AN, Sutheeworapong S, Kusonmano K, Kittichotirat W, Thammarongtham C, Cheevadhanarak S. Distinct gut microbiomes in Thai patients with colorectal polyps. World J Gastroenterol 2024; 30:3336-3355. [PMID: 39086748 PMCID: PMC11287419 DOI: 10.3748/wjg.v30.i27.3336] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/30/2024] [Accepted: 05/31/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Colorectal polyps that develop via the conventional adenoma-carcinoma sequence [e.g., tubular adenoma (TA)] often progress to malignancy and are closely associated with changes in the composition of the gut microbiome. There is limited research concerning the microbial functions and gut microbiomes associated with colorectal polyps that arise through the serrated polyp pathway, such as hyperplastic polyps (HP). Exploration of microbiome alterations associated with HP and TA would improve the understanding of mechanisms by which specific microbes and their metabolic pathways contribute to colorectal carcinogenesis. AIM To investigate gut microbiome signatures, microbial associations, and microbial functions in HP and TA patients. METHODS Full-length 16S rRNA sequencing was used to characterize the gut microbiome in stool samples from control participants without polyps [control group (CT), n = 40], patients with HP (n = 52), and patients with TA (n = 60). Significant differences in gut microbiome composition and functional mechanisms were identified between the CT group and patients with HP or TA. Analytical techniques in this study included differential abundance analysis, co-occurrence network analysis, and differential pathway analysis. RESULTS Colorectal cancer (CRC)-associated bacteria, including Streptococcus gallolyticus (S. gallolyticus), Bacteroides fragilis, and Clostridium symbiosum, were identified as characteristic microbial species in TA patients. Mediterraneibacter gnavus, associated with dysbiosis and gastrointestinal diseases, was significantly differentially abundant in the HP and TA groups. Functional pathway analysis revealed that HP patients exhibited enrichment in the sulfur oxidation pathway exclusively, whereas TA patients showed dominance in pathways related to secondary metabolite biosynthesis (e.g., mevalonate); S. gallolyticus was a major contributor. Co-occurrence network and dynamic network analyses revealed co-occurrence of dysbiosis-associated bacteria in HP patients, whereas TA patients exhibited co-occurrence of CRC-associated bacteria. Furthermore, the co-occurrence of SCFA-producing bacteria was lower in TA patients than HP patients. CONCLUSION This study revealed distinct gut microbiome signatures associated with pathways of colorectal polyp development, providing insights concerning the roles of microbial species, functional pathways, and microbial interactions in colorectal carcinogenesis.
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Affiliation(s)
- Thoranin Intarajak
- Bioinformatics Unit, Chulabhorn Royal Academy, Lak Si 10210, Bangkok, Thailand
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | | | - Ahmad Nuruddin Khoiri
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | - Sawannee Sutheeworapong
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | - Kanthida Kusonmano
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | - Weerayuth Kittichotirat
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | - Chinae Thammarongtham
- National Center for Genetic Engineering and Biotechnology, King Mongkut's University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
| | - Supapon Cheevadhanarak
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
- School of Bioresources and Technology, King Mongkut’s University of Technology Thonburi, Bank Khun Thian 10150, Bangkok, Thailand
- Fungal Biotechnology Unit, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bang Khun Thian 10150, Bangkok, Thailand
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10
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Acharya S, Hegde U, Acharya AB, Nitin P. Dysbiosis linking periodontal disease and oral squamous cell carcinoma-A brief narrative review. Heliyon 2024; 10:e32259. [PMID: 38947439 PMCID: PMC11214465 DOI: 10.1016/j.heliyon.2024.e32259] [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] [Received: 01/03/2024] [Revised: 05/12/2024] [Accepted: 05/30/2024] [Indexed: 07/02/2024] Open
Abstract
An association between periodontal disease and oral squamous cell carcinoma (OSCC) has been recognized. However, there is no causal relationship between the two. The polymicrobial etiology of periodontal disease is confirmed, and so are the proven etiological factors for OSCC. Inflammation lies at the core of periodontal pathogenesis induced by the putative microbes. OSCC has inflammatory overtures in its pathobiology. Bacterial species involved in periodontal disease have been extensively documented and validated. The microbial profile in OSCC has been explored with no specific conclusions. The scientific reasoning to link a common microbial signature that connects periodontal disease to OSCC has led to many studies but has not provided conclusive evidence. Therefore, it would be beneficial to know the status of any plausible microbiota having a similarity in periodontal disease and OSCC. This brief review attempted to clarify the existence of a dysbiotic "fingerprint" that may link these two diseases. The review examined the literature with a focused objective of identifying periodontal microbial profiles in OSCC that could provide insights into pathogen commonality. The review concluded that there is great diversity in microbial association, but important bacterial species that correlate with periodontal disease and OSCC are forthcoming.
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Affiliation(s)
- Swetha Acharya
- Department of Oral Pathology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570004, Karnataka, India
| | - Usha Hegde
- Department of Oral Pathology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570004, Karnataka, India
| | - Anirudh B. Acharya
- Department of Preventive and Restorative Dentistry, College of Dental Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Priyanka Nitin
- Department of Oral Pathology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570004, Karnataka, India
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11
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Órdenes P, Carril Pardo C, Elizondo-Vega R, Oyarce K. Current Research on Molecular Biomarkers for Colorectal Cancer in Stool Samples. BIOLOGY 2023; 13:15. [PMID: 38248446 PMCID: PMC10813333 DOI: 10.3390/biology13010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/08/2023] [Accepted: 12/10/2023] [Indexed: 01/23/2024]
Abstract
Colorectal cancer (CRC) is one of the most diagnosed cancers worldwide, with a high incidence and mortality rate when diagnosed late. Currently, the methods used in healthcare to diagnose CRC are the fecal occult blood test, flexible sigmoidoscopy, and colonoscopy. However, the lack of sensitivity and specificity and low population adherence are driving the need to implement other technologies that can identify biomarkers that not only help with early CRC detection but allow for the selection of more personalized treatment options. In this regard, the implementation of omics technologies, which can screen large pools of biological molecules, coupled with molecular validation, stands out as a promising tool for the discovery of new biomarkers from biopsied tissues or body fluids. This review delves into the current state of the art in the identification of novel CRC biomarkers that can distinguish cancerous tissue, specifically from fecal samples, as this could be the least invasive approach.
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Affiliation(s)
- Patricio Órdenes
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
| | - Claudio Carril Pardo
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
| | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4070386, Chile;
| | - Karina Oyarce
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
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12
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Elahi Z, Shariati A, Bostanghadiri N, Dadgar-Zankbar L, Razavi S, Norzaee S, Vazirbani Arasi S, Darban-Sarokhalil D. Association of Lactobacillus, Firmicutes, Bifidobacterium, Clostridium, and Enterococcus with colorectal cancer in Iranian patients. Heliyon 2023; 9:e22602. [PMID: 38089982 PMCID: PMC10711133 DOI: 10.1016/j.heliyon.2023.e22602] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/08/2023] [Accepted: 11/15/2023] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the primary causes of cancer-associated deaths worldwide, and growing evidence shows that alteration in the gut microbiota may be a contributing factor to the development and progression of the disease. This study investigates the correlation between CRC and specific intestinal microbiota abundance, including Firmicutes, Lactobacillus, Enterococcus, Clostridium, and Bifidobacterium. MATERIAL AND METHODS In this study, 100 CRC samples and adjacent normal tissues were obtained from Iranian patients. Afterward, we assessed the abundance of the mentioned bacteria in matched tumor and normal tissue samples from 100 CRC patients, by TaqMan quantitative real-time polymerase chain reaction (qPCR). RESULTS Most of the patients (55 %) had grade II cancer (moderately differentiated), followed by grade III (poorly Differentiated) in 19 %, and the distribution of the tumor location was 65 % in the colon and 35 % in the rectum. Our research showed a substantial difference in the relative abundance of specific bacteria in tumors and healthy tissues. To this end, four genera of bacteria, including Bifidobacterium, Lactobacillus, Clostridium, and Firmicutes, exhibited statistically significant reductions in tumor tissues compared to adjacent normal tissue (p < 0.05). Conversely, Enterococcus demonstrated a statistically significant increase in tumor tissue samples (p < 0.05). Noteworthy, statistical analysis revealed a significant relationship between Enterococcus and prior cancer (p < 0.05). CONCLUSIONS These findings provide significant insight into the complex association between the gut microbiota and CRC and may pave the way for future research on novel screening methods, preventive measures, and therapeutic strategies targeting the gut microbiota in CRC patients.
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Affiliation(s)
- Zahra Elahi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Aref Shariati
- Student Research Committee, Khomein University of Medical Sciences, Khomein, Iran
- Molecular and Medicine Research Centre, Khomein University of Medical Sciences, Khomein, Iran
| | - Narjess Bostanghadiri
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Leila Dadgar-Zankbar
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Razavi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Norzaee
- Research Center for Environmental Health Technology, Iran University of Medical Sciences, Tehran, Iran
- Department of Environmental Health Engineering, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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13
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Ou S, Chen H, Wang H, Ye J, Liu H, Tao Y, Ran S, Mu X, Liu F, Zhu S, Luo K, Guan Z, Jin Y, Huang R, Song Y, Liu SL. Fusobacterium nucleatum upregulates MMP7 to promote metastasis-related characteristics of colorectal cancer cell via activating MAPK(JNK)-AP1 axis. J Transl Med 2023; 21:704. [PMID: 37814323 PMCID: PMC10561506 DOI: 10.1186/s12967-023-04527-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 09/15/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated. METHODS Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking. RESULTS F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC. CONCLUSIONS Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.
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Affiliation(s)
- Suwen Ou
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Haipeng Chen
- Department of Colorectal Surgery, National Clinical Research Center of Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hufei Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Jinhua Ye
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Huidi Liu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University-University of Calgary, Harbin Medical University, Harbin, 150081, China
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Songlin Ran
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Xiaoqin Mu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University-University of Calgary, Harbin Medical University, Harbin, 150081, China
| | - Fangzhou Liu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Shuang Zhu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315020, China
| | - Zilong Guan
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Yinghu Jin
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
| | - Yanni Song
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Shu-Lin Liu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University-University of Calgary, Harbin Medical University, Harbin, 150081, China.
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, T2N 4N1, Canada.
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Vázquez-Cuesta S, Lozano García N, Fernández AI, Olmedo M, Kestler M, Alcalá L, Marín M, Bermejo J, Díaz FFA, Muñoz P, Bouza E, Reigadas E. Microbiome profile and calprotectin levels as markers of risk of recurrent Clostridioides difficile infection. Front Cell Infect Microbiol 2023; 13:1237500. [PMID: 37780848 PMCID: PMC10534046 DOI: 10.3389/fcimb.2023.1237500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/23/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction Clostridioides difficile infection (CDI) is the main cause of nosocomial diarrhoea in developed countries. Recurrent CDI (R-CDI), which affects 20%-30% of patients and significantly increases hospital stay and associated costs, is a key challenge. The main objective of this study was to explore the role of the microbiome and calprotectin levels as predictive biomarkers of R-CDI. Methods We prospectively (2019-2021) included patients with a primary episode of CDI. Clinical data and faecal samples were collected. The microbiome was analysed by sequencing the hypervariable V4 region of the 16S rRNA gene on an Illumina Miseq platform. Results We enrolled 200 patients with primary CDI, of whom 54 developed R-CDI and 146 did not. We analysed 200 primary samples and found that Fusobacterium increased in abundance, while Collinsella, Senegalimassilia, Prevotella and Ruminococcus decreased in patients with recurrent versus non-recurrent disease. Elevated calprotectin levels correlated significantly with R-CDI (p=0.01). We built a risk index for R-CDI, including as prognostic factors age, sex, immunosuppression, toxin B amplification cycle, creatinine levels and faecal calprotectin levels (overall accuracy of 79%). Discussion Calprotectin levels and abundance of microbial genera such as Fusobacterium and Prevotella in primary episodes could be useful as early markers of R-CDI. We propose a readily available model for prediction of R-CDI that can be applied at the initial CDI episode. The use of this tool could help to better tailor treatments according to the risk of R-CDI.
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Affiliation(s)
- Silvia Vázquez-Cuesta
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Biochemistry and Molecular Biology Department, Faculty of Biology, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Nuria Lozano García
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Ana I. Fernández
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - María Olmedo
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Martha Kestler
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Luis Alcalá
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Mercedes Marín
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Javier Bermejo
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Francisco Fernández-Avilés Díaz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Patricia Muñoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
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15
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Garcia‐Serrano A, Mukhedkar D, Hultin E, Rudsander U, Wettergren Y, Ure AE, Dillner J, Arroyo‐Mühr LS. Assessment of bacterial and viral gut communities in healthy and tumoral colorectal tissue using RNA and DNA deep sequencing. Cancer Med 2023; 12:19291-19300. [PMID: 37641475 PMCID: PMC10557870 DOI: 10.1002/cam4.6483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is known to present a distinct microbiome profile compared to healthy mucosa. Non-targeted deep-sequencing strategies enable nowadays full microbiome characterization up to species level. AIM We aimed to analyze both bacterial and viral communities in CRC using these strategies. MATERIALS & METHODS We analyzed bacterial and viral communities using both DNA and RNA deep-sequencing (Novaseq) in colorectal tissue specimens from 10 CRC patients and 10 matched control patients. Following taxonomy classification using Kraken 2, different metrics for alpha and beta diversities as well as relative and differential abundance were calculated to compare tumoral and healthy samples. RESULTS No viral differences were identified between tissue types, but bacterial species Polynucleobacter necessarius had a highly increased presence for DNA in tumors (p = 0.001). RNA analyses showed that bacterial species Arabia massiliensis had a highly decreased transcription in tumors (p = 0.002) while Fusobacterium nucleatum transcription was highly increased in tumors (p = 0.002). DISCUSSION Sequencing of both DNA and RNA enables a wider perspective of micriobiome profiles. Lack of RNA transcription (Polynucleobacter necessarius) casts doubt on possible role of a microorganism in CRC. The association of F. nucleatum mainly with transcription, may provide further insights on its role in CRC. CONCLUSION Joint assessment of the metagenome (DNA) and the metatranscriptome (RNA) at the species level provided a huge coverage for both bacteria and virus and identifies differential specific bacterial species as tumor associated.
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Affiliation(s)
- Ainhoa Garcia‐Serrano
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
| | - Dhananjay Mukhedkar
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
- Hopsworks ABStockholmSweden
| | - Emilie Hultin
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
| | - Ulla Rudsander
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
| | - Yvonne Wettergren
- Department of SurgerySahlgrenska University Hospital, Sahlgrenska Academy at University of GothenburgGothenburgSweden
| | - Agustín Enrique Ure
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
| | - Joakim Dillner
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
- Center for Cervical Cancer EliminationForskningsgatan F56 Karolinska University Hospital HuddingeStockholmSweden
| | - Laila Sara Arroyo‐Mühr
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
- Center for Cervical Cancer EliminationForskningsgatan F56 Karolinska University Hospital HuddingeStockholmSweden
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Robinson AV, Allen-Vercoe E. Strain specificity in fusobacterial co-aggregation with colorectal cancer-relevant species. Anaerobe 2023; 82:102758. [PMID: 37423597 DOI: 10.1016/j.anaerobe.2023.102758] [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: 03/27/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/11/2023]
Abstract
OBJECTIVES The purpose of the present study was to characterize co-aggregation interactions between isolates of Fusobacterium nucleatum subsp. animalis and other colorectal cancer (CRC)-relevant species. METHODS Co-aggregation interactions were assessed by comparing optical density values following 2-h stationary strain co-incubations to strain optical density values when incubated alone. Co-aggregation was characterized between strains from a previously isolated, CRC biopsy-derived community and F. nucleatum subsp. animalis, a species linked to CRC and known to be highly aggregative. Interactions were also investigated between the fusobacterial isolates and strains sourced from alternate human gastrointestinal samples whose closest species match aligned with species in the CRC biopsy-derived community. RESULTS Co-aggregation interactions were observed to be strain-specific, varying between both F. nucleatum subsp. animalis strains and different strains of the same co-aggregation partner species. F. nucleatum subsp. animalis strains were observed to co-aggregate strongly with several taxa linked to CRC: Campylobacter concisus, Gemella spp., Hungatella hathewayi, and Parvimonas micra. CONCLUSIONS Co-aggregation interactions suggest the ability to encourage the formation of biofilms, and colonic biofilms, in turn, have been linked to promotion and/or progression of CRC. Co-aggregation between F. nucleatum subsp. animalis and CRC-linked species such as C. concisus, Gemella spp., H. hathewayi, and P. micra may contribute to both biofilm formation along CRC lesions and to disease progression.
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Affiliation(s)
- Avery V Robinson
- University of Guelph, 50 Stone Rd E, Guelph, ON, N1G 2W1, Canada.
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17
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Genua F, Butt J, Waterboer T, Hughes DJ. Association of Antibody Responses to Fusobacterium nucleatum and Streptococcus gallolyticus Proteins with Colorectal Adenoma and Colorectal Cancer. Dig Dis Sci 2023:10.1007/s10620-023-08001-4. [PMID: 37338617 PMCID: PMC10352388 DOI: 10.1007/s10620-023-08001-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/02/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND Streptococcus gallolyticus subspecies gallolyticus (SGG) and Fusobacterium (F.) nucleatum have been implicated in colorectal carcinogenesis. Here, the association of immune responses to bacterial exposure with advancing stages of colorectal neoplasia was assessed by multiplex serology. METHODS Immunoglobulin (Ig) A and G antibody responses to eleven proteins each of F. nucleatum and SGG were measured in plasma of controls (n = 100) and patients with colorectal cancer (CRC, n = 25), advanced adenoma (n = 82), or small polyps (n = 85). Multivariable logistic regression was used to evaluate the association of bacterial sero-positivity with colorectal neoplasia. In a cohort subset with matched data (n = 45), F. nucleatum sero-positivity was correlated with bacterial abundance in both neoplastic and matched normal tissue. RESULTS IgG sero-positivity to Fn1426 of F. nucleatum was associated with an increased CRC risk (OR = 4.84; 95% CI 1.46-16.0), while IgA sero-positivity to any SGG protein or specifically Gallo0272 and Gallo1675 alone was associated with increased advanced adenoma occurrence (OR = 2.02, 95% CI 1.10-3.71; OR = 2.67, 95% CI 1.10-6.46; and OR = 6.17, 95% CI 1.61-23.5, respectively). Only F. nucleatum abundance in the normal mucosa positively correlated with the IgA response to the Fn1426 antigen (Correlation coefficient (r) = 0.38, p < 0.01). CONCLUSION Antibody responses to SGG and F. nucleatum were associated with occurrence of colorectal adenomas and CRC, respectively. Further studies are needed to clarify the role these microbes or the immune response to their antigens may have in colorectal carcinogenesis stages.
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Affiliation(s)
- Flavia Genua
- Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, D04 V1W8, Ireland
| | - Julia Butt
- Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120, Heidelberg, Germany
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120, Heidelberg, Germany
| | - David J Hughes
- Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, D04 V1W8, Ireland.
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Characterization of the Gut Microbiota in Urban Thai Individuals Reveals Enterotype-Specific Signature. Microorganisms 2023; 11:microorganisms11010136. [PMID: 36677429 PMCID: PMC9866083 DOI: 10.3390/microorganisms11010136] [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: 12/02/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Gut microbiota play vital roles in human health, utilizing indigestible nutrients, producing essential substances, regulating the immune system, and inhibiting pathogen growth. Gut microbial profiles are dependent on populations, geographical locations, and long-term dietary patterns resulting in individual uniqueness. Gut microbiota can be classified into enterotypes based on their patterns. Understanding gut enterotype enables us to interpret the capability in macronutrient digestion, essential substance production, and microbial co-occurrence. However, there is still no detailed characterization of gut microbiota enterotype in urban Thai people. In this study, we characterized the gut microbiota of urban Thai individuals by amplicon sequencing and classified their profiles into enterotypes, including Prevotella (EnP) and Bacteroides (EnB) enterotypes. Enterotypes were associated with lifestyle, dietary habits, bacterial diversity, differential taxa, and microbial pathways. Microbe-microbe interactions have been studied via co-occurrence networks. EnP had lower α-diversities than those in EnB. A correlation analysis revealed that the Prevotella genus, the predominant taxa of EnP, has a negative correlation with α-diversities. Microbial function enrichment analysis revealed that the biosynthesis pathways of B vitamins and fatty acids were significantly enriched in EnP and EnB, respectively. Interestingly, Ruminococcaceae, resistant starch degraders, were the hubs of both enterotypes, and strongly correlated with microbial diversity, suggesting that traditional Thai food, consisting of rice and vegetables, might be the important drivers contributing to the gut microbiota uniqueness in urban Thai individuals. Overall findings revealed the biological uniqueness of gut enterotype in urban Thai people, which will be advantageous for developing gut microbiome-based diagnostic tools.
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Ou S, Wang H, Tao Y, Luo K, Ye J, Ran S, Guan Z, Wang Y, Hu H, Huang R. Fusobacterium nucleatum and colorectal cancer: From phenomenon to mechanism. Front Cell Infect Microbiol 2022; 12:1020583. [PMID: 36523635 PMCID: PMC9745098 DOI: 10.3389/fcimb.2022.1020583] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/09/2022] [Indexed: 11/30/2022] Open
Abstract
Colorectal cancer(CRC) is the third most frequent malignant tumor. The gut microbiome acts as a vital component of CRC etiology. Fusobacterium nucleatum(Fn) is a key member of colorectal cancer-associated bacteria. But we lack a systematic and in-depth understanding on its role in CRC evolution. In this article, We reviewed the abundance changes and distribution of Fn in CRC occurrence and development, potential effect of Fn in the initiation of CRC, the source of intratumoral Fn and the cause of its tropism to CRC. In addition, We described the mechanism by which Fn promotes the malignant biological behavior of CRC, affects CRC response to therapy, and shapes the tumor immune microenvironment in great detail. Based on the relationship between Fn and CRC, we proposed strategies for CRC prevention and treatment, and discussed the feasibility and limitations of specific cases, to gain insights into further basic and clinical research in the future.
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Affiliation(s)
- Suwen Ou
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hufei Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China,Department of Gastrointestinal Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Jinhua Ye
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Songlin Ran
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zilong Guan
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China,Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yuliuming Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hanqing Hu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China,*Correspondence: Rui Huang,
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20
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Vega L, Bohórquez L, Ramírez JD, Muñoz M. Do we need to change our perspective about gut biomarkers? A public data mining approach to identify differentially abundant bacteria in intestinal inflammatory diseases. Front Cell Infect Microbiol 2022; 12:918237. [PMID: 36478676 PMCID: PMC9719923 DOI: 10.3389/fcimb.2022.918237] [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: 04/12/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction The gut microbiome is involved in multiple processes that influence host physiology, and therefore, disruptions in microbiome homeostasis have been linked to diseases or secondary infections. Given the importance of the microbiome and the communities of microorganisms that compose it (microbiota), the term biomarkers were coined, which are bacteria correlated with disease states, diets, and the lifestyle of the host. However, a large field in the study of intestinal biomarkers remains unexplored because the bacterial communities associated with a given disease state have not been exactly defined yet. Methods Here, we analyzed public data of studies focused on describing the intestinal microbiota of patients with some intestinal inflammatory diseases together with their respective controls. With these analyses, we aimed to identify differentially abundant bacteria between the subjects with the disease and their controls. Results We found that frequently reported bacteria such as Fusobacterium, Streptococcus, and Escherichia/Shigella were differentially abundant between the groups, with a higher abundance mostly in patients with the disease in contrast with their controls. On the other hand, we also identified potentially beneficial bacteria such as Faecalibacterium and Phascolarctobacterium, with a higher abundance in control patients. Discussion Our results of the differentially abundant bacteria contrast with what was already reported in previous studies on certain inflammatory diseases, but we highlight the importance of considering more comprehensive approaches to redefine or expand the definition of biomarkers. For instance, the intra-taxa diversity within a bacterial community must be considered, as well as environmental and genetic factors of the host, and even consider a functional validation of these biomarkers through in vivo and in vitro approaches. With the above, these key bacterial communities in the intestinal microbiota may have potential as next-generation probiotics or may be functional for the design of specific therapies in certain intestinal diseases.
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Affiliation(s)
- Laura Vega
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Laura Bohórquez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Juan David Ramírez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia,Molecular Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Marina Muñoz
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia,*Correspondence: Marina Muñoz,
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Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models. Proc Natl Acad Sci U S A 2022; 119:e2209589119. [PMID: 36197997 PMCID: PMC9573096 DOI: 10.1073/pnas.2209589119] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.
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22
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Brenner H, Li H, Hoffmeister M. Reply. Gastroenterology 2022; 163:783. [PMID: 35643174 DOI: 10.1053/j.gastro.2022.05.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Hengjing Li
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
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23
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Risely A, Schmid DW, Müller-Klein N, Wilhelm K, Clutton-Brock TH, Manser MB, Sommer S. Gut microbiota individuality is contingent on temporal scale and age in wild meerkats. Proc Biol Sci 2022; 289:20220609. [PMID: 35975437 PMCID: PMC9382201 DOI: 10.1098/rspb.2022.0609] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/01/2022] [Indexed: 12/14/2022] Open
Abstract
Inter-individual differences in gut microbiota composition are hypothesized to generate variation in host fitness-a premise for the evolution of host-gut microbe symbioses. However, recent evidence suggests that gut microbial communities are highly dynamic, challenging the notion that individuals harbour unique gut microbial phenotypes. Leveraging a long-term dataset of wild meerkats, we reconcile these concepts by demonstrating that the relative importance of identity for shaping gut microbiota phenotypes depends on the temporal scale. Across meerkat lifespan, year-to-year variation overshadowed the effects of identity and social group in predicting gut microbiota composition, with identity explaining on average less than 2% of variation. However, identity was the strongest predictor of microbial phenotypes over short sampling intervals (less than two months), predicting on average 20% of variation. The effect of identity was also dependent on meerkat age, with the gut microbiota becoming more individualized and stable as meerkats aged. Nevertheless, while the predictive power of identity was negligible after two months, gut microbiota composition remained weakly individualized compared to that of other meerkats for up to 1 year. These findings illuminate the degree to which individualized gut microbial signatures can be expected, with important implications for the time frames over which gut microbial phenotypes may mediate host physiology, behaviour and fitness in natural populations.
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Affiliation(s)
- Alice Risely
- Institute for Evolutionary Ecology and Conservation Genomics, Ulm University, Ulm, Germany
| | - Dominik W. Schmid
- Institute for Evolutionary Ecology and Conservation Genomics, Ulm University, Ulm, Germany
| | - Nadine Müller-Klein
- Institute for Evolutionary Ecology and Conservation Genomics, Ulm University, Ulm, Germany
| | - Kerstin Wilhelm
- Institute for Evolutionary Ecology and Conservation Genomics, Ulm University, Ulm, Germany
| | - Tim H. Clutton-Brock
- Large Animal Research Group, Department of Zoology, University of Cambridge, Cambridge, UK
- Mammal Research Institute, University of Pretoria, Pretoria, South Africa
- Kalahari Research Trust, Kuruman River Reserve, Northern Cape, South Africa
| | - Marta B. Manser
- Mammal Research Institute, University of Pretoria, Pretoria, South Africa
- Kalahari Research Trust, Kuruman River Reserve, Northern Cape, South Africa
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland
| | - Simone Sommer
- Institute for Evolutionary Ecology and Conservation Genomics, Ulm University, Ulm, Germany
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24
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Fusobacterium Nucleatum Is a Risk Factor for Metastatic Colorectal Cancer. Curr Med Sci 2022; 42:538-547. [DOI: 10.1007/s11596-022-2597-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 12/29/2021] [Indexed: 12/24/2022]
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25
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Yu L, Zhao G, Wang L, Zhou X, Sun J, Li X, Zhu Y, He Y, Kofonikolas K, Bogaert D, Dunlop M, Zhu Y, Theodoratou E, Li X. A systematic review of microbial markers for risk prediction of colorectal neoplasia. Br J Cancer 2022; 126:1318-1328. [PMID: 35292756 PMCID: PMC9042911 DOI: 10.1038/s41416-022-01740-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/23/2021] [Accepted: 02/03/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Substantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance. METHODS A comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed. RESULTS Forty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9-485 cases) and lack of independent external validation (76.7%). CONCLUSIONS This review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.
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Affiliation(s)
- Lili Yu
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gang Zhao
- Center for Disease Control and Prevention of Hangzhou, Hangzhou, China
| | - Lijuan Wang
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuan Zhou
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Sun
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinxuan Li
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingshuang Zhu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yazhou He
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, China
| | | | - Debby Bogaert
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Malcolm Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Yimin Zhu
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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26
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Villar-Ortega P, Expósito-Ruiz M, Gutiérrez-Soto M, Ruiz-Cabello Jiménez M, Navarro-Marí JM, Gutiérrez-Fernández J. The association between Fusobacterium nucleatum and cancer colorectal: A systematic review and meta-analysis. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2022; 40:224-234. [PMID: 35256335 DOI: 10.1016/j.eimce.2022.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The etiological factors of colorectal cancer (CRC) are not precisely known, although genetic and environmental factors have been implicated. A possible association with Fusobacterium nucleatum may provide opportunities for an early diagnosis. OBJECTIVE To review studies that address the association between F. nucleatum and CRC. METHODS The MEDLINE PubMed database was searched using the terms «colorectal cancer» and "Fusobacterium nucleatum", retrieving publications published up to January 1 2020. Stata software was used for a meta-analysis. RESULTS The systematic review included 57 articles. Meta-analysis results indicated a more frequent presence of F. nucleatum in CRC tumour tissue samples in comparison to control samples of healthy tissue, with an odds ratio of 4.558 (95% CI: 3.312-6.272), and in comparison, to control samples of colorectal adenomas, with an odds ratio of 3.244 (95 % CI: 2.359-4.462). CONCLUSION There is a more frequent resence of F. nucleatum in the CRC. However, further studies are needed to verify this relationship.
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Affiliation(s)
- Paola Villar-Ortega
- Departamento de Microbiología, Universidad de Granada-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain
| | - Manuela Expósito-Ruiz
- Departamento de Bioestadística de FIBAO, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain
| | | | - Miguel Ruiz-Cabello Jiménez
- UGC de Digestivo, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain
| | - José María Navarro-Marí
- Laboratorio de Microbiología, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain
| | - José Gutiérrez-Fernández
- Departamento de Microbiología, Universidad de Granada-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain; Laboratorio de Microbiología, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, Spain.
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Effects of Dietary Protein Level on the Microbial Composition and Metabolomic Profile in Postweaning Piglets. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3355687. [PMID: 35401925 PMCID: PMC8986435 DOI: 10.1155/2022/3355687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/26/2021] [Accepted: 03/12/2022] [Indexed: 01/10/2023]
Abstract
Since the human and porcine digestive systems have similar anatomical structures and physiological functions, pigs are a useful animal model for studying human digestive diseases. By investigating intestinal metabolites in piglets after weaning, this study attempted to identify the inherent connection between dietary protein levels and changes in the intestinal microbiota of piglets. Casein was employed as the only source of protein for the piglets in this study to avoid the influence of other protein sources. 14 weaning at 28-day-old piglets (6.9 ± 0.19 kg) formed into two dietary groups: 17% casein fed group (LP) and 30% casein fed group (HP). Piglets were allowed to free food and water during the 2-week experiment. Throughout the trial, the piglets' diarrhea index (1: no diarrhea and 3: watery diarrhea) and food intake were noted during the experiment. We discovered piglets fed a high-protein diet developed diarrhea throughout the duration of the research, whereas piglets fed a normal protein diet did not. In addition, the HP group had lower feed intake and body weight than the control group (P < 0.05). The HP diet influenced the content of short-chain and branched-chain fatty acids in the colon, including acetate and isovaleric acid. The ileal microbiota's 16S rRNA gene was sequenced, and it was discovered that the relative abundance of gastrointestinal bacteria differed between the HP and control groups. Dietary protein levels influenced bile acid biosynthesis, alpha-linolenic acid metabolism, phospholipid biosynthesis, arachidonic acid metabolism, fatty acid biosynthesis, retinol metabolism, arginine and proline metabolism, pyrimidine metabolism, tryptophan metabolism, and glycine and serine metabolism, according to gas chromatography-mass spectrometry analysis. Furthermore, a correlation analysis of the pooled information revealed a possible link between intestinal metabolites and specific bacteria species. These findings demonstrate that weaned piglets' microbiota composition and metabolites are modified by a high-protein diet and thus inducing severe postweaning diarrhea and inhibiting growth performance. However, the potential molecular mechanism of this regulation in the growth of piglets remains unclear.
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28
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Berbert L, Santos A, Magro D, Guadagnini D, Assalin H, Lourenço L, Martinez C, Saad M, Coy C. Metagenomics analysis reveals universal signatures of the intestinal microbiota in colorectal cancer, regardless of regional differences. Braz J Med Biol Res 2022; 55:e11832. [PMID: 35293551 PMCID: PMC8922548 DOI: 10.1590/1414-431x2022e11832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Affiliation(s)
- L. Berbert
- Universidade Estadual de Campinas, Brasil
| | - A. Santos
- Universidade Estadual de Campinas, Brasil
| | - D.O. Magro
- Universidade Estadual de Campinas, Brasil
| | | | | | | | | | | | - C.S.R. Coy
- Universidade Estadual de Campinas, Brasil
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Ahmad Kendong SM, Raja Ali RA, Nawawi KNM, Ahmad HF, Mokhtar NM. Gut Dysbiosis and Intestinal Barrier Dysfunction: Potential Explanation for Early-Onset Colorectal Cancer. Front Cell Infect Microbiol 2021; 11:744606. [PMID: 34966694 PMCID: PMC8710575 DOI: 10.3389/fcimb.2021.744606] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease that commonly affects individuals aged more than 50 years old globally. Regular colorectal screening, which is recommended for individuals aged 50 and above, has decreased the number of cancer death toll over the years. However, CRC incidence has increased among younger population (below 50 years old). Environmental factors, such as smoking, dietary factor, urbanization, sedentary lifestyle, and obesity, may contribute to the rising trend of early-onset colorectal cancer (EOCRC) because of the lack of genetic susceptibility. Research has focused on the role of gut microbiota and its interaction with epithelial barrier genes in sporadic CRC. Population with increased consumption of grain and vegetables showed high abundance of Prevotella, which reduces the risk of CRC. Microbes, such as Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli deteriorate in the intestinal barrier, which leads to the infiltration of inflammatory mediators and chemokines. Gut dysbiosis may also occur following inflammation as clearly observed in animal model. Both gut dysbiosis pre- or post-inflammatory process may cause major alteration in the morphology and functional properties of the gut tissue and explain the pathological outcome of EOCRC. The precise mechanism of disease progression from an early stage until cancer establishment is not fully understood. We hypothesized that gut dysbiosis, which may be influenced by environmental factors, may induce changes in the genome, metabolome, and immunome that could destruct the intestinal barrier function. Also, the possible underlying inflammation may give impact microbial community leading to disruption of physical and functional role of intestinal barrier. This review explains the potential role of the interaction among host factors, gut microenvironment, and gut microbiota, which may provide an answer to EOCRC.
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Affiliation(s)
- Siti Maryam Ahmad Kendong
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Sarawak, Malaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Khairul Najmi Muhammad Nawawi
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Hajar Fauzan Ahmad
- Department of Industrial Biotechnology, Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Gambang, Malaysia.,Center for Research in Advanced Tropical Bioscience, Universiti Malaysia Pahang, Gambang, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Evaluation of Changes to the Oral Microbiome Based on 16S rRNA Sequencing among Children Treated for Cancer. Cancers (Basel) 2021; 14:cancers14010007. [PMID: 35008173 PMCID: PMC8750156 DOI: 10.3390/cancers14010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Childhood cancer survivors suffer from many oral complications during and after primary therapy. Our study focuses on changes in the oral microbiome of cancer survivors. Using 16S rRNA sequencing, we observed global and distinct changes in oral microbiome associated with a patient’s age and therapy duration, but not antibiotic therapy or cancer type. Observed changes in the oral microbiome could differentiate patients at higher risk of long-term oral complications. Abstract A child’s mouth is the gateway to many species of bacteria. Changes in the oral microbiome may affect the health of the entire body. The aim of the study was to evaluate the changes in the oral microbiome of childhood cancer survivors. Saliva samples before and after anti-cancer treatment were collected from 20 patients aged 6–18 years, diagnosed de novo with cancer in 2018–2019 (7 girls and 13 boys, 7.5–19 years old at the second time point). Bacterial DNA was extracted, and the microbial community profiles were assessed by 16S rRNA sequencing. The relative abundances of Cellulosilyticum and Tannerella genera were found to significantly change throughout therapy (p = 0.043 and p = 0.036, respectively). However, no differences in the alpha-diversity were observed (p = 0.817). The unsupervised classification revealed two clusters of patients: the first with significant changes in Campylobacter and Fusobacterium abundance, and the other with change in Neisseria. These two groups of patients differed in median age (10.25 vs. 16.16 years; p = 0.004) and the length of anti-cancer therapy (19 vs. 4 months; p = 0.003), but not cancer type or antibiotic treatment.
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A prospective interventional trial on the effect of periodontal treatment on Fusobacterium nucleatum abundance in patients with colorectal tumours. Sci Rep 2021; 11:23719. [PMID: 34887459 PMCID: PMC8660914 DOI: 10.1038/s41598-021-03083-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/26/2021] [Indexed: 12/09/2022] Open
Abstract
Fusobacterium nucleatum is associated with the progression of colorectal cancer. Thus, the possibility of preventing colorectal cancer or its progression by targeting F. nucleatum has been explored. As F. nucleatum is associated with periodontitis, we analysed whether treating periodontitis could influence F. nucleatum abundance in the colon. Patients with colorectal tumours who underwent colonoscopy were recruited. Patients diagnosed with periodontitis by a dentist were treated for approximately 3 months. Endoscopic resection of colorectal tumours was performed after periodontitis treatment, and resected tumours were pathologically classified as high-(HGD) or low-grade dysplasia (LGD). Saliva and stool samples were collected before and after the treatment. Of the 58 patients with colorectal tumours, 31 were included in the study, 16 showed improvement in periodontitis, and 11 showed no improvement. Stool F. nucleatum levels before treatment were significantly lower in the LGD group than in the HGD group. A significant decrease in faecal F. nucleatum levels was observed in patients who underwent successful treatment but not in those whose treatment failed. Salivary F. nucleatum levels were not altered in patients despite periodontal treatment. Thus, successful periodontitis treatment reduces stool F. nucleatum levels and may aid research on periodontitis and suppression of colorectal cancer development.
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32
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Duijster JW, Franz E, Neefjes J, Mughini-Gras L. Bacterial and Parasitic Pathogens as Risk Factors for Cancers in the Gastrointestinal Tract: A Review of Current Epidemiological Knowledge. Front Microbiol 2021; 12:790256. [PMID: 34956157 PMCID: PMC8692736 DOI: 10.3389/fmicb.2021.790256] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
The oncogenic potential of viral infections is well established and documented for many years already. However, the contribution of (commensal) bacteria and parasites to the development and progression of cancers has only recently gained momentum, resulting in a rapid growth of publications on the topic. Indeed, various bacteria and parasites have been suggested to play a role in the development of gastrointestinal cancer in particular. Therefore, an overview of the current epidemiological knowledge on the association between infections with bacteria and parasites and cancers of the gastrointestinal tract is needed. In this review, we summarized the methodological characteristics and main results of epidemiological studies investigating the association of 10 different bacteria (Bacteroides fragilis, Campylobacter spp., Clostridium spp., Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Porphyromonas gingivalis, non-typhoidal Salmonella, Salmonella Typhi, and Streptococcus spp.) and three parasites (Cryptosporidium spp., Schistosoma spp., and Strongyloides stercoralis) with gastrointestinal cancer. While the large body of studies based on microbiome sequencing provides valuable insights into the relative abundance of different bacterial taxa in cancer patients as compared to individuals with pre-malignant conditions or healthy controls, more research is needed to fulfill Koch's postulates, possibly making use of follow-up data, to assess the complex role of bacterial and parasitic infections in cancer epidemiology. Studies incorporating follow-up time between detection of the bacterium or parasite and cancer diagnosis remain valuable as these allow for estimation of cause-effect relationships.
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Affiliation(s)
- Janneke W. Duijster
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Eelco Franz
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Jacques Neefjes
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Lapo Mughini-Gras
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
- Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
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McIlvanna E, Linden GJ, Craig SG, Lundy FT, James JA. Fusobacterium nucleatum and oral cancer: a critical review. BMC Cancer 2021; 21:1212. [PMID: 34774023 PMCID: PMC8590362 DOI: 10.1186/s12885-021-08903-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023] Open
Abstract
There is a growing level of interest in the potential role inflammation has on the initiation and progression of malignancy. Notable examples include Helicobacter pylori-mediated inflammation in gastric cancer and more recently Fusobacterium nucleatum-mediated inflammation in colorectal cancer. Fusobacterium nucleatum is a Gram-negative anaerobic bacterium that was first isolated from the oral cavity and identified as a periodontal pathogen. Biofilms on oral squamous cell carcinomas are enriched with anaerobic periodontal pathogens, including F. nucleatum, which has prompted hypotheses that this bacterium could contribute to oral cancer development. Recent studies have demonstrated that F. nucleatum can promote cancer by several mechanisms; activation of cell proliferation, promotion of cellular invasion, induction of chronic inflammation and immune evasion. This review provides an update on the association between F. nucleatum and oral carcinogenesis, and provides insights into the possible mechanisms underlying it.
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Affiliation(s)
- Emily McIlvanna
- Patrick G Johnson Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Gerard J Linden
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Stephanie G Craig
- Patrick G Johnson Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, UK.,Precision Medicine Centre of Excellence, Health Sciences Building, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Fionnuala T Lundy
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK.
| | - Jacqueline A James
- Patrick G Johnson Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, UK. .,Precision Medicine Centre of Excellence, Health Sciences Building, Queen's University Belfast, Belfast, Northern Ireland, UK. .,Northern Ireland Biobank, Health Sciences Building, Queen's University Belfast, Belfast, Northern Ireland, UK.
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34
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Despins CA, Brown SD, Robinson AV, Mungall AJ, Allen-Vercoe E, Holt RA. Modulation of the Host Cell Transcriptome and Epigenome by Fusobacterium nucleatum. mBio 2021; 12:e0206221. [PMID: 34700376 PMCID: PMC8546542 DOI: 10.1128/mbio.02062-21] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/16/2021] [Indexed: 02/03/2023] Open
Abstract
Fusobacterium nucleatum is a ubiquitous opportunistic pathogen with an emerging role as an oncomicrobe in colorectal cancer and other cancer settings. F. nucleatum can adhere to and invade host cells in a manner that varies across F. nucleatum strains and host cell phenotypes. Here, we performed pairwise cocultures between three F. nucleatum strains and two immortalized primary host cell types (human colonic epithelial [HCE] cells and human carotid artery endothelial [HCAE] cells) followed by transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate transcriptional and epigenetic host cell responses. We observed that F. nucleatum-induced host cell transcriptional modulation involves strong upregulation of genes related to immune migration and inflammatory processes, such as TNF, CXCL8, CXCL1, and CCL20. Furthermore, we identified genes strongly upregulated in a cell line-specific manner. In HCE cells, overexpressed genes included UBD and DUOX2/DUOXA2, associated with p53 degradation-mediated proliferation and intestinal reactive oxygen species (ROS) production, respectively. In HCAE cells, overexpressed genes included EFNA1 and LIF, two genes commonly upregulated in colorectal cancer and associated with poor patient outcomes, and PTGS2 (COX2), a gene associated with the protective effect of aspirin in the colorectal cancer setting. Interestingly, we also observed downregulation of numerous histone modification genes upon F. nucleatum exposure. We used the ChIP-seq data to annotate chromatin states genome wide and found significant chromatin remodeling following F. nucleatum exposure in HCAE cells, with increased frequencies of active enhancer and low-signal/quiescent states. Thus, our results highlight increased inflammation and chemokine gene expression as conserved host cell responses to F. nucleatum exposure and extensive host cell epigenomic changes specific to host cell type. IMPORTANCE Fusobacterium nucleatum is a bacterium normally found in the healthy oral cavity but also has an emerging role in colorectal cancer and other cancer settings. The host-microbe interactions of F. nucleatum and its involvement in tumor initiation, progression, and treatment resistance are not fully understood. We explored host cell changes that occur in response to F. nucleatum. We identified key genes differentially expressed in response to various conditions of F. nucleatum exposure and determined that the conserved host cell response to F. nucleatum was dominated by increased inflammation and chemokine gene expression. Additionally, we found extensive host cell epigenomic changes as a novel aspect of host modulation associated with F. nucleatum exposure. These results extend our understanding of F. nucleatum as an emerging pathogen and highlight the importance of considering strain heterogeneity and host cell phenotypic variation when exploring pathogenic mechanisms of F. nucleatum.
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Affiliation(s)
- Cody A. Despins
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Scott D. Brown
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada
| | - Avery V. Robinson
- Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
| | - Andrew J. Mungall
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada
| | - Emma Allen-Vercoe
- Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
| | - Robert A. Holt
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
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Appunni S, Rubens M, Ramamoorthy V, Tonse R, Saxena A, McGranaghan P, Kaiser A, Kotecha R. Emerging Evidence on the Effects of Dietary Factors on the Gut Microbiome in Colorectal Cancer. Front Nutr 2021; 8:718389. [PMID: 34708063 PMCID: PMC8542705 DOI: 10.3389/fnut.2021.718389] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Dietary factors have important role in modulating the gut microbiome, which in-turn regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome are decisive factors in colorectal cancer (CRC) tumorigenesis. Altered gut microbiome is associated with impaired immune response, and the release of carcinogenic or genotoxic substances which are the major microbiome-induced mechanisms implicated in CRC pathogenesis. Diets low in dietary fibers and phytomolecules as well as high in red meat are important dietary changes which predispose to CRC. Dietary fibers which reach the colon in an undigested form are further metabolized by the gut microbiome into enterocyte friendly metabolites such as short chain fatty acid (SCFA) which provide anti-inflammatory and anti-proliferative effects. Healthy microbiome supported by dietary fibers and phytomolecules could decrease cell proliferation by regulating the epigenetic events which activate proto-oncogenes and oncogenic pathways. Emerging evidence show that predominance of microbes such as Fusobacterium nucleatum can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. Synbiotics can protect the intestinal mucosa by improving immune response and decreasing the production of toxic metabolites, oxidative stress and cell proliferation. In this narrative review, we aim to update the emerging evidence on how diet could modulate the gut microbial composition and revive colonic epithelium. This review highlights the importance of healthy plant-based diet and related supplements in CRC prevention by improving the gut microbiome.
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Affiliation(s)
- Sandeep Appunni
- Government Medical College, Kozhikode, India
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Muni Rubens
- Office of Clinical Research, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | | | - Raees Tonse
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | - Anshul Saxena
- Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
| | - Peter McGranaghan
- Office of Clinical Research, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | - Adeel Kaiser
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
| | - Rupesh Kotecha
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
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Wang S, Liu Y, Li J, Zhao L, Yan W, Lin B, Guo X, Wei Y. Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality. Front Cell Dev Biol 2021; 9:710165. [PMID: 34490259 PMCID: PMC8417943 DOI: 10.3389/fcell.2021.710165] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a common cancer worldwide with complex etiology. Fusobacterium nucleatum (F. nucleatum), an oral symbiotic bacterium, has been linked with CRC in the past decade. A series of gut microbiota studies show that CRC patients carry a high abundance of F. nucleatum in the tumor tissue and fecal, and etiological studies have clarified the role of F. nucleatum as a pro-carcinogenic bacterium in various stages of CRC. In this review, we summarize the biological characteristics of F. nucleatum and the epidemiological associations between F. nucleatum and CRC, and then highlight the mechanisms by which F. nucleatum participates in CRC progression, metastasis, and chemoresistance by affecting cancer cells or regulating the tumor microenvironment (TME). We also discuss the research gap in this field and give our perspective for future studies. These findings will pave the way for manipulating gut F. nucleatum to deal with CRC in the future.
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Affiliation(s)
- Shuang Wang
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Liu
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Li
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lei Zhao
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Yan
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baiqiang Lin
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao Guo
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunwei Wei
- Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Zhao J, Ning X, Liu B, Dong R, Bai M, Sun S. Specific alterations in gut microbiota in patients with chronic kidney disease: an updated systematic review. Ren Fail 2021; 43:102-112. [PMID: 33406960 PMCID: PMC7808321 DOI: 10.1080/0886022x.2020.1864404] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Emerging evidence demonstrates that gut dysbiosis is implicated in the pathogenesis of chronic kidney disease (CKD) with underlying mechanisms involving mucosal and/or systematic immunity or metabolic disorders. However, the profile of gut microbiota in patients with CKD has not been completely explored. METHODS Databases from their date of inception to 31 March 2020 were systematically searched for case-control or cross-sectional studies comparing the gut microbial profiles in adult patients with CKD or end-stage renal disease (ESRD) with those in healthy controls. Quantitative analysis of alterations in gut microbial profiles was conducted. RESULTS Twenty-five studies with a total of 1436 CKD patients and 918 healthy controls were included. The present study supports the increased abundance of, phylum Proteobacteria and Fusobacteria, genus Escherichia_Shigella, Desulfovibrio, and Streptococcus, while lower abundance of genus Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae_UCG-001, and Prevotella_9 in patients with CKD; and increased abundance of phylum Proteobacteria, and genus Streptococcus and Fusobacterium, while lower abundance of Prevotella, Coprococcus, Megamonas, and Faecalibacterium in patients with ESRD. Moreover, higher concentrations of trimethylamine-N-oxide and p-cresyl sulfate and lower concentrations of short-chain fatty acids were observed. Gut permeability in patients with CKD was not determined due to the heterogeneity of selected parameters. CONCLUSIONS Specific alterations of gut microbial parameters in patients with CKD were identified. However, a full picture of the gut microbiota could not be drawn from the data due to the differences in methodology, and qualitative and incomplete reporting of different studies.
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Affiliation(s)
- Jin Zhao
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xiaoxuan Ning
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Baojian Liu
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ruijuan Dong
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ming Bai
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
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Ponath F, Tawk C, Zhu Y, Barquist L, Faber F, Vogel J. RNA landscape of the emerging cancer-associated microbe Fusobacterium nucleatum. Nat Microbiol 2021; 6:1007-1020. [PMID: 34239075 DOI: 10.1038/s41564-021-00927-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/24/2021] [Indexed: 12/14/2022]
Abstract
Fusobacterium nucleatum, long known as a constituent of the oral microflora, has recently garnered renewed attention for its association with several different human cancers. The growing interest in this emerging cancer-associated bacterium contrasts with a paucity of knowledge about its basic gene expression features and physiological responses. As fusobacteria lack all established small RNA-associated proteins, post-transcriptional networks in these bacteria are also unknown. In the present study, using differential RNA-sequencing, we generate high-resolution global RNA maps for five clinically relevant fusobacterial strains-F. nucleatum subspecies nucleatum, animalis, polymorphum and vincentii, as well as F. periodonticum-for early, mid-exponential growth and early stationary phase. These data are made available in an online browser, and we use these to uncover fundamental aspects of fusobacterial gene expression architecture and a suite of non-coding RNAs. Developing a vector for functional analysis of fusobacterial genes, we discover a conserved fusobacterial oxygen-induced small RNA, FoxI, which serves as a post-transcriptional repressor of the major outer membrane porin FomA. Our findings provide a crucial step towards delineating the regulatory networks enabling F. nucleatum adaptation to different environments, which may elucidate how these bacteria colonize different compartments of the human body.
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Affiliation(s)
- Falk Ponath
- Helmholtz Institute for RNA-based Infection Research, Helmholtz Centre for Infection Research, Würzburg, Germany
| | - Caroline Tawk
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Yan Zhu
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Lars Barquist
- Helmholtz Institute for RNA-based Infection Research, Helmholtz Centre for Infection Research, Würzburg, Germany.,Faculty of Medicine, University of Würzburg, Würzburg, Germany
| | - Franziska Faber
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Jörg Vogel
- Helmholtz Institute for RNA-based Infection Research, Helmholtz Centre for Infection Research, Würzburg, Germany. .,Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany. .,Faculty of Medicine, University of Würzburg, Würzburg, Germany.
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Yamamoto S, Kinugasa H, Hirai M, Terasawa H, Yasutomi E, Oka S, Ohmori M, Yamasaki Y, Inokuchi T, Harada K, Hiraoka S, Nouso K, Tanaka T, Teraishi F, Fujiwara T, Okada H. Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer. J Gastroenterol Hepatol 2021; 36:1869-1876. [PMID: 33242360 DOI: 10.1111/jgh.15361] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/24/2020] [Accepted: 11/20/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIM Fusobacterium nucleatum (Fn) is involved in colorectal cancer (CRC) growth and is a biomarker for patient prognosis and management. However, the ecology of Fn in CRC and the distribution of intratumoral Fn are unknown. METHODS We evaluated Fn and the status of KRAS and BRAF in 200 colorectal neoplasms (118 adenomas and 82 cancers) and 149 matched adjacent normal mucosas. The differentiation status between "surface" and "deep" areas of cancer tissue and matched normal mucosa were analyzed in 46 surgical samples; the Ki-67 index was also evaluated in these samples. RESULTS Fusobacterium nucleatum presence in the tumor increased according to pathological stage (5.9% [adenoma] to 81.8% [stage III/IV]), while Fn presence in normal mucosa also increased (7.6% [adenoma] to 40.9% [stage III/IV]). The detection rates of Fn on the tumor surface and in deep areas were 45.7% and 32.6%, while that of normal mucosa were 26.1% and 23.9%, respectively. Stage III/IV tumors showed high Fn surface area expression (66.7%). Fn intratumoral heterogeneity (34.8%) was higher than that of KRAS (4.3%; P < 0.001) and BRAF (2.2%; P < 0.001). The Ki-67 index in Fn-positive cases was higher than that in negative cases (93.9% vs 89.0%; P = 0.01). CONCLUSIONS Fusobacterium nucleatum was strongly present in CRC superficial areas at stage III/IV. The presence of Fn in the deep areas of adjacent normal mucosa also increased. The intratumoral heterogeneity of Fn is important in the use of Fn as a biomarker, as Fn is associated with CRC proliferative capacity.
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Affiliation(s)
- Shumpei Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hideaki Kinugasa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Mami Hirai
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Terasawa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Eriko Yasutomi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Shohei Oka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Masayasu Ohmori
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yasushi Yamasaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Keita Harada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Fuminori Teraishi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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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: 2] [Impact Index Per Article: 0.5] [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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41
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Shariati A, Razavi S, Ghaznavi-Rad E, Jahanbin B, Akbari A, Norzaee S, Darban-Sarokhalil D. Association between colorectal cancer and Fusobacterium nucleatum and Bacteroides fragilis bacteria in Iranian patients: a preliminary study. Infect Agent Cancer 2021; 16:41. [PMID: 34108031 PMCID: PMC8191199 DOI: 10.1186/s13027-021-00381-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/31/2021] [Indexed: 12/02/2022] Open
Abstract
Background and aim Recent studies have proposed that commensal bacteria might be involved in the development and progression of gastrointestinal disorders such as colorectal cancer (CRC). Therefore, in this study, the relative abundance of Fusobacterium nucleatum, Bacteroides fragilis, Streptococcus bovis/gallolyticus, and Enteropathogenic Escherichia coli (EPEC) in CRC tissues, and their association with clinicopathologic characteristics of CRC was investigated in Iranian patients. Moreover, the role of these bacteria in the CRC-associated mutations including PIK3CA, KRAS, and BRAF was studied. Method To these ends, the noted bacteria were quantified in paired tumors and normal tissue specimens of 30 CRC patients, by TaqMan quantitative Real-Time Polymerase Chain Reaction (qPCR). Next, possible correlations between clinicopathologic factors and mutations in PIK3CA, KRAS, and BRAF genes were analyzed. Results In studied samples, B. fragilis was the most abundant bacteria that was detected in 66 and 60% of paired tumor and normal samples, respectively. Furthermore, 15% of the B. fragilis-positive patients were infected with Enterotoxigenic B. fragilis (ETBF) in both adenocarcinoma and matched adjacent normal samples. F. nucleatum was also identified in 23% of tumors and 13% of adjacent normal tissue samples. Moreover, the relative abundance of these bacteria determined by 2-ΔCT was significantly higher in CRC samples than in adjacent normal mucosa (p < 0.05). On the other hand, our findings indicated that S. gallolyticus and EPEC, compared to adjacent normal mucosa, were not prevalent in CRC tissues. Finally, our results revealed a correlation between F. nucleatum-positive patients and the KRAS mutation (p = 0.02), while analyses did not show any association between bacteria and mutation in PIK3CA and BRAF genes. Conclusion The present study is the first report on the analysis of different bacteria in CRC tissue samples of Iranian patients. Our findings revealed that F. nucleatum and B. fragilis might be linked to CRC. However, any link between gut microbiome dysbiosis and CRC remains unknown.
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Affiliation(s)
- Aref Shariati
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Razavi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Microbial Biotechnology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ehsanollah Ghaznavi-Rad
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran
| | - Behnaz Jahanbin
- Department of Pathology, Cancer Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Science, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Norzaee
- Research Center for Environmental Health Technology, Iran University of Medical Sciences, Tehran, Iran
| | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Microbial Biotechnology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Young C, Wood HM, Fuentes Balaguer A, Bottomley D, Gallop N, Wilkinson L, Benton SC, Brealey M, John C, Burtonwood C, Thompson KN, Yan Y, Barrett JH, Morris EJA, Huttenhower C, Quirke P. Microbiome Analysis of More Than 2,000 NHS Bowel Cancer Screening Programme Samples Shows the Potential to Improve Screening Accuracy. Clin Cancer Res 2021; 27:2246-2254. [PMID: 33658300 PMCID: PMC7610626 DOI: 10.1158/1078-0432.ccr-20-3807] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/05/2020] [Accepted: 02/12/2021] [Indexed: 02/03/2023]
Abstract
PURPOSE There is potential for fecal microbiome profiling to improve colorectal cancer screening. This has been demonstrated by research studies, but it has not been quantified at scale using samples collected and processed routinely by a national screening program. EXPERIMENTAL DESIGN Between 2016 and 2019, the largest of the NHS Bowel Cancer Screening Programme hubs prospectively collected processed guaiac fecal occult blood test (gFOBT) samples with subsequent colonoscopy outcomes: blood-negative [n = 491 (22%)]; colorectal cancer [n = 430 (19%)]; adenoma [n = 665 (30%)]; colonoscopy-normal [n = 300 (13%)]; nonneoplastic [n = 366 (16%)]. Samples were transported and stored at room temperature. DNA underwent 16S rRNA gene V4 amplicon sequencing. Taxonomic profiling was performed to provide features for classification via random forests (RF). RESULTS Samples provided 16S amplicon-based microbial profiles, which confirmed previously described colorectal cancer-microbiome associations. Microbiome-based RF models showed potential as a first-tier screen, distinguishing colorectal cancer or neoplasm (colorectal cancer or adenoma) from blood-negative with AUC 0.86 (0.82-0.89) and AUC 0.78 (0.74-0.82), respectively. Microbiome-based models also showed potential as a second-tier screen, distinguishing from among gFOBT blood-positive samples, colorectal cancer or neoplasm from colonoscopy-normal with AUC 0.79 (0.74-0.83) and AUC 0.73 (0.68-0.77), respectively. Models remained robust when restricted to 15 taxa, and performed similarly during external validation with metagenomic datasets. CONCLUSIONS Microbiome features can be assessed using gFOBT samples collected and processed routinely by a national colorectal cancer screening program to improve accuracy as a first- or second-tier screen. The models required as few as 15 taxa, raising the potential of an inexpensive qPCR test. This could reduce the number of colonoscopies in countries that use fecal occult blood test screening.
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Affiliation(s)
- Caroline Young
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom.
| | - Henry M Wood
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Alba Fuentes Balaguer
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Daniel Bottomley
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Niall Gallop
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Lyndsay Wilkinson
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Sally C Benton
- NHS Bowel Cancer Screening Programme - Southern Hub, Surrey Research Park, Guildford, United Kingdom
| | - Martin Brealey
- NHS Bowel Cancer Screening Programme - Southern Hub, Surrey Research Park, Guildford, United Kingdom
| | - Cerin John
- NHS Bowel Cancer Screening Programme - Southern Hub, Surrey Research Park, Guildford, United Kingdom
| | - Carole Burtonwood
- NHS Bowel Cancer Screening Programme - Southern Hub, Surrey Research Park, Guildford, United Kingdom
| | - Kelsey N Thompson
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Yan Yan
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Jennifer H Barrett
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Eva J A Morris
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
- Big Data Institute, Nuffield Department of Population Health, Old Road Campus, University of Oxford, Oxford, United Kingdom
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Philip Quirke
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's University Hospital, University of Leeds, Leeds, United Kingdom
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Ferrari A, Neefs I, Hoeck S, Peeters M, Van Hal G. Towards Novel Non-Invasive Colorectal Cancer Screening Methods: A Comprehensive Review. Cancers (Basel) 2021; 13:1820. [PMID: 33920293 PMCID: PMC8070308 DOI: 10.3390/cancers13081820] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Since the 70s, many countries have adopted different CRC screening programs, which has resulted in a decrease in mortality. However, current screening test options still present downsides. The commercialized stool-based tests present high false-positive rates and low sensitivity, which negatively affects the detection of early stage carcinogenesis. The gold standard colonoscopy has low uptake due to its invasiveness and the perception of discomfort and embarrassment that the procedure may bring. In this review, we collected and described the latest data about alternative CRC screening techniques that can overcome these disadvantages. Web of Science and PubMed were employed as search engines for studies reporting on CRC screening tests and future perspectives. The searches generated 555 articles, of which 93 titles were selected. Finally, a total of 50 studies, describing 14 different CRC alternative tests, were included. Among the investigated techniques, the main feature that could have an impact on CRC screening perception and uptake was the ease of sample collection. Urine, exhaled breath, and blood-based tests promise to achieve good diagnostic performance (sensitivity of 63-100%, 90-95%, and 47-97%, respectively) while minimizing stress and discomfort for the patient.
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Affiliation(s)
- Allegra Ferrari
- Social Epidemiology and Health Policy, University of Antwerp, 2610 Antwerpen, Belgium; (S.H.); (G.V.H.)
| | - Isabelle Neefs
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, 2610 Antwerpen, Belgium; (I.N.); (M.P.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2610 Antwerpen, Belgium
| | - Sarah Hoeck
- Social Epidemiology and Health Policy, University of Antwerp, 2610 Antwerpen, Belgium; (S.H.); (G.V.H.)
- Center for Cancer Detection, 8000 Bruges, Belgium
| | - Marc Peeters
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, 2610 Antwerpen, Belgium; (I.N.); (M.P.)
- Department of Oncology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Guido Van Hal
- Social Epidemiology and Health Policy, University of Antwerp, 2610 Antwerpen, Belgium; (S.H.); (G.V.H.)
- Center for Cancer Detection, 8000 Bruges, Belgium
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The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review. Cancer Cell Int 2021; 21:194. [PMID: 33823861 PMCID: PMC8025348 DOI: 10.1186/s12935-021-01886-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer globally and the fourth attributable cause of mortality and morbidity due to cancer. An emerging factor contributing to CRC is the gut microbiota and the cellular changes associated with it. Further insights on this may help in the prevention, diagnosis and new therapeutic approaches to colorectal cancer. In most cases of CRC, genetic factors appear to contribute less to its aetiology than environmental and epigenetic factors; therefore, it may be important to investigate these environmental factors, their effects, and the mechanisms that may contribute to this cancer. The gut microbiota has recently been highlighted as a potential risk factor that may affect the structural components of the tumor microenvironment, as well as free radical and enzymatic metabolites directly, or indirectly. Many studies have reported changes in the gut microbiota of patients with colorectal cancer. What is controversial is whether the cancer is the cause or consequence of the change in the microbiota. There is strong evidence supporting both possibilities. The presence of Fusobacterium nucleatum in human colorectal specimens has been demonstrated by RNA-sequencing. F. nucleatum has been shown to express high levels of virulence factors such as FadA, Fap2 and MORN2 proteins. Our review of the published data suggest that F. nucleatum may be a prognostic biomarker of CRC risk, and hence raises the potential of antibiotic treatment of F. nucleatum for the prevention of CRC.
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45
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Profile of gut flora in hypertensive patients with insufficient sleep duration. J Hum Hypertens 2021; 36:390-404. [PMID: 33785906 DOI: 10.1038/s41371-021-00529-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/24/2021] [Accepted: 03/11/2021] [Indexed: 12/30/2022]
Abstract
Recently, the contribution of both insufficient sleep duration and gut microbiome dysbiosis to hypertension (HTN) have been revealed, yet the profile of gut flora in hypertensive patients with insufficient sleep duration remains unknown. To examine this condition, the specific shifts in the fecal microbiome of 53 participants with or without HTN were investigated. The patients were divided into those who slept short (≤6 h) or optimal (6-9 h) duration per day. Comprehensive metagenomic sequencing analysis of fecal specimens was performed in healthy controls with sufficient sleep (s-CTR, n = 10), healthy controls with insufficient sleep (ins-CTR, n = 6), hypertensive patients with sufficient sleep (s-HTN, n = 25), and HTNs complicated by short sleep duration (ins-HTN, n = 12). We found that the α-diversity and β-diversity were quite similar between s-HTN and ins-HTN. Similarities were also observed in the enterotype distribution between s-HTN and ins-HTN subjects. In addition, the enrichment of gut bacteria was evident, such as Fusobacterium mortiferum and Roseburia inulinivorans in ins-HTN subjects. Several functional modules that were distinct between s-HTN and ins-HTN subjects were identified, which were unique to hypertensive patients with insufficient sleep duration. Overall, the data demonstrated that the gut microbial features were largely maintained in hypertensive participants with insufficient sleep duration.
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46
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Zhang Q, Zou R, Guo M, Duan M, Li Q, Zheng H. Comparison of gut microbiota between adults with autism spectrum disorder and obese adults. PeerJ 2021; 9:e10946. [PMID: 33717692 PMCID: PMC7931713 DOI: 10.7717/peerj.10946] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 01/25/2021] [Indexed: 02/02/2023] Open
Abstract
Background Autism spectrum disorder (ASD) and obesity are serious global public health problems. Studies have shown that ASD children are at a higher risk of obesity than the general population. To investigate the gut microbe characteristics of adults ASD and obese adults, we compared the gut microbiota of adults with ASD to obese adults. Methods The fecal samples were collected from 21 adult patients with ASD and 21 obese adults, and V3–V4 regions of 16S rRNA genes were sequenced by high-throughput DNA sequencing. The gut microbiota of adults with ASD and obese adults was compared. Results We observed the proportion of Firmicutes/Bacteroidetes in ASD was significantly increased, with families Lachnospiraceae and Ruminococcaceae significantly enriched in adult ASD. Eighteen genera, including Lachnospiracea incertae sedis, Ruminococcus, Blautia, and Holdemanella were significantly increased in adult ASD, whereas Megamonas and Fusobacterium were significantly increased in obesity. At the species level, we found six species enriched in ASD and three species enriched in obesity, including Phascolarctobacterium succinatuten producing propionate. Dialister succinatiphilus may be as a biomarker for predicting obesity, as well as Prevotella copri may be a common-owned pathogens of ASD and obesity. Conclusions Some conflicting results have been reported in microbiota studies of ASD, which may be related to age and obesity. Thus, the body mass index should be evaluated before analyzing the gut microbiota of patients with ASD, as obesity is prevalent in these individuals and gut microbiota is severally affected by obesity.
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Affiliation(s)
- Qiang Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Rong Zou
- NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Min Guo
- NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Mengmeng Duan
- NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Quan Li
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Huajun Zheng
- NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
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Pilla R, Suchodolski JS. The Gut Microbiome of Dogs and Cats, and the Influence of Diet. Vet Clin North Am Small Anim Pract 2021; 51:605-621. [PMID: 33653538 DOI: 10.1016/j.cvsm.2021.01.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The gut microbiome is a functional organ, and responds metabolically to the nutrient composition within the diet. Fiber, starch, and protein content have strong effects on the microbiome composition, and changes in these nutrient profiles can induce rapid shifts. Due to functional redundancy of bacteria within microbial communities, important metabolites for health can be produced by different bacteria. Microbiome alterations associated with disease are of greater magnitude than those seen in healthy dogs on different diets. Dietary changes, addition of prebiotics, and probiotics, can be beneficial to improve microbial diversity and to normalize metabolite production in diseased dogs.
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Affiliation(s)
- Rachel Pilla
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, Texas A&M College of Veterinary Medicine & Biomedical Sciences, 4474 TAMU, College Station, TX 77843-4474, USA.
| | - Jan S Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, Texas A&M College of Veterinary Medicine & Biomedical Sciences, 4474 TAMU, College Station, TX 77843-4474, USA
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Villar-Ortega P, Expósito-Ruiz M, Gutiérrez-Soto M, Ruiz-Cabello Jiménez M, Navarro-Marí JM, Gutiérrez-Fernández J. The association between Fusobacterium nucleatum and cancer colorectal: a systematic review and meta-analysis. Enferm Infecc Microbiol Clin 2021; 40:S0213-005X(21)00026-4. [PMID: 33632539 DOI: 10.1016/j.eimc.2021.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The etiological factors of colorectal cancer (CRC) are not precisely known, although genetic and environmental factors have been implicated. A possible association with Fusobacterium nucleatum may provide opportunities for an early diagnosis. OBJECTIVE To review studies that address the association between F. nucleatum and CRC. METHODS The MEDLINE PubMed database was searched using the terms «colorectal cancer» and «Fusobacterium nucleatum», retrieving publications published up to January 1 2020. Stata software was used for a meta-analysis. RESULTS The systematic review included 57 articles. Meta-analysis results indicated a more frequent presence of F. nucleatum in CRC tumor tissue samples in comparison to control samples of healthy tissue, with an odds ratio of 4.558 (95% CI: 3.312-6.272), and in comparison, to control samples of colorectal adenomas, with an odds ratio of 3.244 (95% CI: 2.359-4.462). CONCLUSION There is a more frequent presence of F. nucleatum in the CRC. However, further studies are needed to verify this relationship.
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Affiliation(s)
- Paola Villar-Ortega
- Departamento de Microbiología, Universidad de Granada-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España
| | - Manuela Expósito-Ruiz
- Departamento de Bioestadística de FIBAO. Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España
| | | | - Miguel Ruiz-Cabello Jiménez
- UGC de Digestivo, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España
| | - José María Navarro-Marí
- Laboratorio de Microbiología, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España
| | - José Gutiérrez-Fernández
- Departamento de Microbiología, Universidad de Granada-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España; Laboratorio de Microbiología, Hospital Universitario Virgen de las Nieves-Instituto de Investigación BioSanitaria-ibs-Granada, Granada, España.
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Oliva M, Mulet-Margalef N, Ochoa-De-Olza M, Napoli S, Mas J, Laquente B, Alemany L, Duell EJ, Nuciforo P, Moreno V. Tumor-Associated Microbiome: Where Do We Stand? Int J Mol Sci 2021; 22:1446. [PMID: 33535583 PMCID: PMC7867144 DOI: 10.3390/ijms22031446] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022] Open
Abstract
The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome-microbe communities located either in the tumor or within its body compartment-seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.
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Affiliation(s)
- Marc Oliva
- Medical Oncology Department, Catalan Institute of Oncology L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (N.M.-M.); (B.L.)
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
| | - Nuria Mulet-Margalef
- Medical Oncology Department, Catalan Institute of Oncology L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (N.M.-M.); (B.L.)
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
| | - Maria Ochoa-De-Olza
- Service of Immuno-Oncology, Department of Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland;
- Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland
| | - Stefania Napoli
- Molecular Oncology Group, Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (S.N.); (P.N.)
| | - Joan Mas
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, 08908 Catalonia, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain;
| | - Berta Laquente
- Medical Oncology Department, Catalan Institute of Oncology L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (N.M.-M.); (B.L.)
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
| | - Laia Alemany
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain;
- Cancer Epidemiology Research Program, Catalan Institute of Oncology, L’Hospitalet de Llobregat, 08908 Catalonia, Spain
- EPIBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain
| | - Eric J. Duell
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, 08908 Catalonia, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain;
| | - Paolo Nuciforo
- Molecular Oncology Group, Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (S.N.); (P.N.)
| | - Victor Moreno
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Catalonia, Spain; (J.M.); (E.J.D.); (V.M.)
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, 08908 Catalonia, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain;
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Wang Y, Wan X, Wu X, Zhang C, Liu J, Hou S. Eubacterium rectale contributes to colorectal cancer initiation via promoting colitis. Gut Pathog 2021; 13:2. [PMID: 33436075 PMCID: PMC7805161 DOI: 10.1186/s13099-020-00396-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease caused by microbial dysbiosis is an important factor contributing to colorectal cancer (CRC) initiation. The 'driver-passenger' model in human gut microbial dysbiosis suggests that 'driver' bacteria may colonize with low relative abundance on tumor site but persistently induce chronic change in normal intestinal epithelium and initiate CRC. They are gradually replaced by 'passenger' bacteria later on, due to their low adaptability to the on-tumor site niche. RESULTS To reveal site-specific bacterial taxon markers in CRC patients, we analyzed the gut mucosal microbiome of 75 paired samples of on-tumor and tumor-adjacent sites, 75 off-tumor sites, and 26 healthy controls. Linear discriminant analysis of relative abundance profiles revealed unique bacterial taxon distribution correlated with specific tumor sites, with Eubacterium having the distribution characteristic of potential driver bacteria. We further show that Eubacterium rectale endotoxin activates the transcription factor NF-κΒ, which regulates multiple aspects of innate and adaptive immune responses in normal colon epithelial cells. Unlike the 'passenger' bacterium Fusobacterium nucleatum, E. rectale promotes dextran sodium sulfate-induced colitis in Balb/c mice. CONCLUSIONS Our findings reveal that E. rectale functions as a 'driver' bacterium and contributes to cancer initiation via promoting inflammation.
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Affiliation(s)
- Yijia Wang
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Nankai University, No. 190 Jieyuan Rd., Hongqiao district, Tianjin, 300121, China
| | - Xuehua Wan
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, 300071, China
| | - Xiaojing Wu
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Nankai University, No. 190 Jieyuan Rd., Hongqiao district, Tianjin, 300121, China
| | - Chunze Zhang
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Nankai University, No. 190 Jieyuan Rd., Hongqiao district, Tianjin, 300121, China
| | - Jun Liu
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Nankai University, No. 190 Jieyuan Rd., Hongqiao district, Tianjin, 300121, China.
| | - Shaobin Hou
- Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii At Manoa, 2538 McCarthy Mall, Snyder Hall, Honolulu, HI, 96822, USA.
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