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Hetta HF, Ahmed R, Ramadan YN, Fathy H, Khorshid M, Mabrouk MM, Hashem M. Gut virome: New key players in the pathogenesis of inflammatory bowel disease. World J Methodol 2025; 15:92592. [DOI: 10.5662/wjm.v15.i2.92592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/28/2024] [Accepted: 07/23/2024] [Indexed: 11/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory illness of the intestine. While the mechanism underlying the pathogenesis of IBD is not fully understood, it is believed that a complex combination of host immunological response, environmental exposure, particularly the gut microbiota, and genetic susceptibility represents the major determinants. The gut virome is a group of viruses found in great frequency in the gastrointestinal tract of humans. The gut virome varies greatly among individuals and is influenced by factors including lifestyle, diet, health and disease conditions, geography, and urbanization. The majority of research has focused on the significance of gut bacteria in the progression of IBD, although viral populations represent an important component of the microbiome. We conducted this review to highlight the viral communities in the gut and their expected roles in the etiopathogenesis of IBD regarding published research to date.
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Affiliation(s)
- Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
- Division of Microbiology, Immunology and Biotechnology, Faculty of pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Rehab Ahmed
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Yasmin N Ramadan
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Hayam Fathy
- Department of Internal Medicine, Division Hepatogastroenterology, Assiut University, Assiut 71515, Egypt
| | - Mohammed Khorshid
- Department of Clinical Research, Egyptian Developers of Gastroenterology and Endoscopy Foundation, Cairo 11936, Egypt
| | - Mohamed M Mabrouk
- Department of Internal Medicine, Faculty of Medicine. Tanta University, Tanta 31527, Egypt
| | - Mai Hashem
- Department of Tropical Medicine, Gastroenterology and Hepatology, Assiut University Hospital, Assiut 71515, Egypt
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Rybicka I, Kaźmierczak Z. The human phageome: niche-specific distribution of bacteriophages and their clinical implications. Appl Environ Microbiol 2025:e0178824. [PMID: 40237489 DOI: 10.1128/aem.01788-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025] Open
Abstract
Bacteriophages (phages) play a crucial role in shaping the composition and diversity of the human microbiome across various body niches. Recent advancements in high-throughput sequencing technologies have enabled comprehensive analysis of the human phageome in different body sites. This review comprehensively analyzes phage populations across major human body niches, examining their distribution and dynamics through recent metagenomic discoveries. We explore how phage-bacteria interactions within different body sites contribute to homeostasis and disease development. Emerging evidence demonstrates that phageome perturbations can serve as early indicators of various disorders, particularly in the gut microbiome. Understanding these complex microbial interactions offers promising opportunities for developing novel diagnostic markers and therapeutic approaches. However, the causal relationship between phages, bacteria, and disease development remains unclear. Further research is needed to elucidate the role of phages in human health and disease and to explore their potential as diagnostic or therapeutic tools. Understanding the intricate interactions between phages, bacteria, and the human host is crucial for unraveling the complexities of the human microbiome and its impact on health and disease.
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Affiliation(s)
- Izabela Rybicka
- Laboratory of Phage Molecular Biology, Hirszfeld Institute of Immunology and Experimental Therapy, Wrocław, Poland
| | - Zuzanna Kaźmierczak
- Laboratory of Phage Molecular Biology, Hirszfeld Institute of Immunology and Experimental Therapy, Wrocław, Poland
- Research and Development Center, Regional Specialist Hospital in Wrocław, Wrocław, Poland
- Faculty of Medicine, Department of Preclinical Sciences, Pharmacology and Medical Diagnostics, Wrocław University of Science and Technology, Wrocław, Poland
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Xiao Y, Yue X, Zhang X, Yang Y, Zhang Y, Sun L. The role of bacteriophage in inflammatory bowel disease and its therapeutic potential. Crit Rev Microbiol 2025:1-15. [PMID: 40219702 DOI: 10.1080/1040841x.2025.2492154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory disorders impacting the gastrointestinal (GI) tract. It represents a significant public health challenge due to its rising global incidence and substantial impact on patients' quality of life. Emerging research suggests a pivotal role of the human microbiome in IBD pathogenesis. Bacteriophages, integral components of the human microbiome, are indicated to influence the disease onset, progression, and therapeutic strategies. Here, we review the effect of bacteriophages on the pathogenesis of IBD and, more specifically, on the gut bacteria, the systemic immunity, and the susceptibility genes. Additionally, we explore the potential therapeutic use of the bacteriophages to modify gut microbiota and improve the health outcomes of IBD patients. This review highlights the potential of therapeutic bacteriophages in regulating gut microbiota and modulating the immune response to improve health outcomes in IBD patients. Future studies on personalized bacteriophage therapy and its integration into clinical practice could advance treatment strategies for IBD.
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Affiliation(s)
- Yuyang Xiao
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xinyu Yue
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xupeng Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Yifei Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Yibo Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Lang Sun
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
- Department of Microbiology, Xiangya School of the Basic Medical Science, Central South University, Changsha, Hunan Province, China
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Wu Y, Cheng R, Lin H, Li L, Jia Y, Philips A, Zuo T, Zhang H. Gut virome and its implications in the pathogenesis and therapeutics of inflammatory bowel disease. BMC Med 2025; 23:183. [PMID: 40140901 PMCID: PMC11948845 DOI: 10.1186/s12916-025-04016-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Inflammatory bowel disease (IBD) refers to chronic, recurrent inflammatory intestinal disorders, primarily including Crohn's disease (CD) and Ulcerative colitis (UC). Numerous studies have elucidated the importance of the gut microbiome in IBD. Recently, numerous studies have focused on the gut virome, an intriguing and enigmatic aspect of the gut microbiome. Alterations in the composition of phages, eukaryotic viruses, and human endogenous retroviruses that occur in IBD suggest potential involvement of the gut virome in IBD. Nevertheless, the mechanisms by which it maintains intestinal homeostasis and interacts with diseases are only beginning to be understood. Here, we thoroughly reviewed the composition of the gut virome in both healthy individuals and IBD patients, emphasizing the key viruses implicated in the onset and progression of IBD. Furthermore, the complex connections between the gut virome and the intestinal barrier, immunity, and gut microbiome were dissected to advance the interpretation of IBD pathogenesis. The updated discussion of the evidence regarding the gut virome will advance our knowledge in gut virome and chronic gastrointestinal diseases. Targeting the gut virome is a promising avenue for IBD treatment in future.
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Affiliation(s)
- Yushan Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yongbin Jia
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Anna Philips
- Laboratory of Bioinformatics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Tao Zuo
- Key Laboratory of Human Microbiome and Chronic Diseases, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
- Guangdong Institute of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Centre, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China.
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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Beauchemin ET, Hunter C, Maurice CF. Dextran sodium sulfate-induced colitis alters the proportion and composition of replicating gut bacteria. mSphere 2025; 10:e0082524. [PMID: 39723822 PMCID: PMC11774032 DOI: 10.1128/msphere.00825-24] [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: 10/08/2024] [Accepted: 11/15/2024] [Indexed: 12/28/2024] Open
Abstract
The bacteria living in the human gut are essential for host health. Though the composition and metabolism of these bacteria are well described in both healthy hosts and those with intestinal disease, less is known about the metabolic activity of the gut bacteria prior to, and during, disease development-especially regarding gut bacterial replication. Here, we use a recently developed single-cell technique alongside existing metagenomics-based tools to identify, track, and quantify replicating gut bacteria both ex vivo and in situ in the dextran sodium sulfate (DSS) mouse model of colitis. We show that the proportion of replicating gut bacteria decreases when mice have the highest levels of inflammation and returns to baseline levels as mice begin recovering. In addition, we report significant alterations in the composition of the replicating gut bacterial community ex vivo during colitis development. On the taxa level, we observe significant changes in the abundance of taxa such as the mucus-degrading Akkermansia and the poorly described Erysipelatoclostridium genus. We further demonstrate that many taxa exhibit variable replication rates in situ during colitis, including Akkermansia muciniphila. Lastly, we show that colitis development is positively correlated with increases in the presence and abundance of bacteria in situ which are predicted to be fast replicators. This could suggest that taxa with the potential to replicate quickly may have an advantage during intestinal inflammation. These data support the need for additional research using activity-based approaches to further characterize the gut bacterial response to intestinal inflammation and its consequences for both the host and the gut microbial community.IMPORTANCEIt is well known that the bacteria living inside the gut are important for human health. Indeed, the type of bacteria that are present and their metabolism are different in healthy people versus those with intestinal disease. However, less is known about how these gut bacteria are replicating, especially as someone begins to develop intestinal disease. This is particularly important as it is thought that metabolically active gut bacteria may be more relevant to health. Here, we begin to address this gap using several complementary approaches to characterize the replicating gut bacteria in a mouse model of intestinal inflammation. We reveal which gut bacteria are replicating, and how quickly, as mice develop and recover from inflammation. This work can serve as a model for future research to identify how actively growing gut bacteria may be impacting health, or why these particular bacteria tend to thrive during intestinal inflammation.
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Affiliation(s)
- Eve T. Beauchemin
- Department of Microbiology & Immunology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Claire Hunter
- Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom
| | - Corinne F. Maurice
- Department of Microbiology & Immunology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
- McGill Centre for Microbiome Research, Montreal, Quebec, Canada
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Ma B, Hu X, Ai X, Zhang Y. Research progress of ferroptosis and inflammatory bowel disease. Biometals 2024; 37:1039-1062. [PMID: 38713412 DOI: 10.1007/s10534-024-00604-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024]
Abstract
Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disorder of the gastrointestinal tract, imposing significant burdens on both society and individuals. As a new type of regulated cell death (RCD), ferroptosis is different from classic RCDs such as apoptosis and necrosis in cell morphology, biochemistry and genetics. The main molecular mechanisms of ferroptosis include dysregulation of iron metabolism, impaired antioxidant capacity, mitochondrial dysfunction, accumulation of lipid-associated super-oxides, and membrane disruption. In recent years, increasing evidence has shown that ferroptosis is involved in the pathophysiology of inflammatory bowel disease. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This article reviews the mechanism of ferroptosis in the occurrence and development of inflammatory bowel disease, in order to provide new ideas for the pathophysiological research of inflammatory bowel disease. Additionally, we discuss potential strategies for the prevention and treatment of inflammatory bowel disease by targeting ferroptosis.
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Affiliation(s)
- Baolian Ma
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Xiaoxue Hu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Xiaowen Ai
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Yonglan Zhang
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China.
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Tian X, Li S, Wang C, Zhang Y, Feng X, Yan Q, Guo R, Wu F, Wu C, Wang Y, Huo X, Ma X. Gut virome-wide association analysis identifies cross-population viral signatures for inflammatory bowel disease. MICROBIOME 2024; 12:130. [PMID: 39026313 PMCID: PMC11256409 DOI: 10.1186/s40168-024-01832-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/08/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking. RESULTS In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn's disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients. These characterized 139 differentially abundant viral signatures, including elevated phages predicted to infect Escherichia, Klebsiella, Enterococcus_B, Streptococcus, and Veillonella species, as well as IBD-depleted phages targeting Prevotella, Ruminococcus_E, Bifidobacterium, and Blautia species. Remarkably, these viral signatures demonstrated high consistency across diverse populations such as those in Europe and the USA, emphasizing their significance and broad relevance in the disease context. Furthermore, fecal virome transplantation experiments verified that the colonization of these IBD-characterized viruses can modulate experimental colitis in mouse models. CONCLUSIONS Building upon these insights into the IBD gut virome, we identified potential biomarkers for prognosis and therapy in IBD patients, laying the foundation for further exploration of viromes in related conditions. Video Abstract.
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Affiliation(s)
- Xiangge Tian
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Shenghui Li
- Puensum Genetech Institute, Wuhan, 430076, China
| | - Chao Wang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yanyan Zhang
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Xiaoying Feng
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
| | - Qiulong Yan
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China.
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
| | - Ruochun Guo
- Puensum Genetech Institute, Wuhan, 430076, China
| | - Fan Wu
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
| | - Chunxue Wu
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
| | - Yan Wang
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China
| | - Xiaokui Huo
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China.
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
| | - Xiaochi Ma
- Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China.
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol 2024; 15:1386607. [PMID: 38887284 PMCID: PMC11180809 DOI: 10.3389/fimmu.2024.1386607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 04/11/2024] [Indexed: 06/20/2024] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease's multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS's pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease's complexity and the multifaceted approach required for its study and management.
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Affiliation(s)
- Hayley E. Arron
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
| | - Benjamin D. Marsh
- MRCPCH Consultant Paediatric Neurodisability, Exeter, Devon, United Kingdom
| | - Douglas B. Kell
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - M. Asad Khan
- Directorate of Respiratory Medicine, Manchester University Hospitals, Wythenshawe Hospital, Manchester, United Kingdom
| | - Beate R. Jaeger
- Long COVID department, Clinic St Georg, Bad Aibling, Germany
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
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Vestergaard MV, Allin KH, Eriksen C, Zakerska-Banaszak O, Arasaradnam RP, Alam MT, Kristiansen K, Brix S, Jess T. Gut microbiota signatures in inflammatory bowel disease. United European Gastroenterol J 2024; 12:22-33. [PMID: 38041519 PMCID: PMC10859715 DOI: 10.1002/ueg2.12485] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/10/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), affect millions of people worldwide with increasing incidence. OBJECTIVES Several studies have shown a link between gut microbiota composition and IBD, but results are often limited by small sample sizes. We aimed to re-analyze publicly available fecal microbiota data from IBD patients. METHODS We extracted original fecal 16S rRNA amplicon sequencing data from 45 cohorts of IBD patients and healthy individuals using the BioProject database at the National Center for Biotechnology Information. Unlike previous meta-analyses, we merged all study cohorts into a single dataset, including sex, age, geography, and disease information, based on which microbiota signatures were analyzed, while accounting for varying technical platforms. RESULTS Among 2518 individuals in the combined dataset, we discovered a hitherto unseen number of genera associated with IBD. A total of 77 genera associated with CD, of which 38 were novel associations, and a total of 64 genera associated with UC, of which 28 represented novel associations. Signatures were robust across different technical platforms and geographic locations. Reduced alpha diversity in IBD compared to healthy individuals, in CD compared to UC, and altered microbiota composition (beta diversity) in UC and especially in CD as compared to healthy individuals were found. CONCLUSIONS Combining original microbiota data from 45 cohorts, we identified a hitherto unseen large number of genera associated with IBD. Identification of microbiota features robustly associated with CD and UC may pave the way for the identification of new treatment targets.
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Affiliation(s)
- Marie Vibeke Vestergaard
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Kristine H Allin
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Carsten Eriksen
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | | | - Ramesh P Arasaradnam
- Warwick Medical School & Cancer Research Centre, University of Leicester, Leicester, UK
| | - Mohammad T Alam
- Warwick Medical School & Cancer Research Centre, University of Leicester, Leicester, UK
- Department of Biology, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Karsten Kristiansen
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Laboratory of Genomics and Molecular Medicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Susanne Brix
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
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10
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Ramos-Barbero MD, Gómez-Gómez C, Vique G, Sala-Comorera L, Rodríguez-Rubio L, Muniesa M. Recruitment of complete crAss-like phage genomes reveals their presence in chicken viromes, few human-specific phages, and lack of universal detection. THE ISME JOURNAL 2024; 18:wrae192. [PMID: 39361891 PMCID: PMC11475920 DOI: 10.1093/ismejo/wrae192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/25/2024] [Accepted: 10/01/2024] [Indexed: 10/05/2024]
Abstract
The order Crassvirales, which includes the prototypical crAssphage (p-crAssphage), is predominantly associated with humans, rendering it the most abundant and widely distributed group of DNA phages in the human gut. The reported human specificity and wide global distribution of p-crAssphage makes it a promising human fecal marker. However, the specificity for the human gut as well as the geographical distribution around the globe of other members of the order Crassvirales remains unknown. To determine this, a recruitment analysis using 91 complete, non-redundant genomes of crAss-like phages in human and animal viromes revealed that only 13 crAss-like phages among the 91 phages analyzed were highly specific to humans, and p-crAssphage was not in this group. Investigations to elucidate whether any characteristic of the phages was responsible for their prevalence in humans showed that the 13 human crAss-like phages do not share a core genome. Phylogenomic analysis placed them in three independent families, indicating that within the Crassvirales group, human specificity is likely not a feature of a common ancestor but rather was introduced on separate/independent occasions in their evolutionary history. The 13 human crAss-like phages showed variable geographical distribution across human metagenomes worldwide, with some being more prevalent in certain countries than in others, but none being universally identified. The varied geographical distribution and the absence of a phylogenetic relationship among the human crAss-like phages are attributed to the emergence and dissemination of their bacterial host, the symbiotic human strains of Bacteroides, across various human populations occupying diverse ecological niches worldwide.
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Affiliation(s)
- María Dolores Ramos-Barbero
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
| | - Clara Gómez-Gómez
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
| | - Gloria Vique
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
| | - Laura Sala-Comorera
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
| | - Lorena Rodríguez-Rubio
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
| | - Maite Muniesa
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 643, Prevosti Building, Floor 0. Barcelona E-08028, Spain
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Pandey H, Jain D, Tang DWT, Wong SH, Lal D. Gut microbiota in pathophysiology, diagnosis, and therapeutics of inflammatory bowel disease. Intest Res 2024; 22:15-43. [PMID: 37935653 PMCID: PMC10850697 DOI: 10.5217/ir.2023.00080] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/23/2023] [Accepted: 08/27/2023] [Indexed: 11/09/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial disease, which is thought to be an interplay between genetic, environment, microbiota, and immune-mediated factors. Dysbiosis in the gut microbial composition, caused by antibiotics and diet, is closely related to the initiation and progression of IBD. Differences in gut microbiota composition between IBD patients and healthy individuals have been found, with reduced biodiversity of commensal microbes and colonization of opportunistic microbes in IBD patients. Gut microbiota can, therefore, potentially be used for diagnosing and prognosticating IBD, and predicting its treatment response. Currently, there are no curative therapies for IBD. Microbiota-based interventions, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been recognized as promising therapeutic strategies. Clinical studies and studies done in animal models have provided sufficient evidence that microbiota-based interventions may improve inflammation, the remission rate, and microscopic aspects of IBD. Further studies are required to better understand the mechanisms of action of such interventions. This will help in enhancing their effectiveness and developing personalized therapies. The present review summarizes the relationship between gut microbiota and IBD immunopathogenesis. It also discusses the use of gut microbiota as a noninvasive biomarker and potential therapeutic option.
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Affiliation(s)
| | | | - Daryl W. T. Tang
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Sunny H. Wong
- Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Devi Lal
- Department of Zoology, Ramjas College, University of Delhi, Delhi, India
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12
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Jansen D, Falony G, Vieira-Silva S, Simsek C, Marcelis T, Caenepeel C, Machiels K, Raes J, Vermeire S, Matthijnssens J. Community Types of the Human Gut Virome are Associated with Endoscopic Outcome in Ulcerative Colitis. J Crohns Colitis 2023; 17:1504-1513. [PMID: 37052201 PMCID: PMC10588789 DOI: 10.1093/ecco-jcc/jjad061] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Indexed: 04/14/2023]
Abstract
BACKGROUND Inflammatory bowel disease [IBD] is a major debilitating disease. Recently, the gut microbiota has gained attention as an important factor involved in the pathophysiology of IBD. As a complement to the established bacterial 'enterotypes' associated with IBD, we focused here on viruses. We investigated the intestinal virome of IBD patients undergoing biological therapy for the presence of virome configurations associated with IBD, and to uncover how those configurations are associated with therapeutic success. METHODS Viral-like particle enrichment followed by deep sequencing was performed on 432 faecal samples from 181 IBD patients starting biological therapy. Redundancy analysis and Dirichlet Multinomial Mixtures were applied to determine covariates of the virome composition and to condense the gut virota into 'viral community types', respectively. RESULTS Patients were stratified based on unsupervised clustering into two viral community types. Community type CA showed a low α-diversity and a high relative abundance of Caudoviricetes [non-CrAss] phages and was associated with the dysbiotic Bact2-enterotype. Community type CrM showed a high α-diversity and a high relative abundance of Crassvirales and Malgrandaviricetes phages. During post-interventional analysis, endoscopic outcome was associated with gut virome composition. Remitting UC patients had a high percentage of community type CrM, a high Shannon diversity and a low lysogenic potential. Pre-interventional analyses also identified five novel phages associated with treatment success. CONCLUSIONS This study proposed two gut virome configurations that may be involved in the pathophysiology of IBD. Interestingly, those viral configurations are further associated with therapeutic success, suggesting a potential clinical relevance.
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Affiliation(s)
- Daan Jansen
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Gwen Falony
- KU Leuven, Department of Microbiology Immunology and Transplantation, Rega Institute, Laboratory of Molecular Bacteriology, Leuven, Belgium
- Center for Microbiology, VIB, B-3000 Leuven, Belgium
| | - Sara Vieira-Silva
- KU Leuven, Department of Microbiology Immunology and Transplantation, Rega Institute, Laboratory of Molecular Bacteriology, Leuven, Belgium
- Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute of Molecular Biology (IMB), Mainz, Germany
| | - Ceren Simsek
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Tine Marcelis
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Clara Caenepeel
- KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium
| | - Kathleen Machiels
- KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium
| | - Jeroen Raes
- KU Leuven, Department of Microbiology Immunology and Transplantation, Rega Institute, Laboratory of Molecular Bacteriology, Leuven, Belgium
- Center for Microbiology, VIB, B-3000 Leuven, Belgium
| | - Séverine Vermeire
- KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium
| | - Jelle Matthijnssens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Viral Metagenomics, Leuven, Belgium
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13
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Abstract
The gut microbiome is a dense and metabolically active consortium of microorganisms and viruses located in the lower gastrointestinal tract of the human body. Bacteria and their viruses (phages) are the most abundant members of the gut microbiome. Investigating their biology and the interplay between the two is important if we are to understand their roles in human health and disease. In this review, we summarize recent advances in resolving the taxonomic structure and ecological functions of the complex community of phages in the human gut-the gut phageome. We discuss how age, diet, and geography can all have a significant impact on phageome composition. We note that alterations to the gut phageome have been observed in several diseases such as inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer, and we evaluate whether these phageome changes can directly or indirectly contribute to disease etiology and pathogenesis. We also highlight how lack of standardization in studying the gut phageome has contributed to variation in reported results.
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Affiliation(s)
- Ciara A Tobin
- APC Microbiome Ireland, Cork, Ireland; , ,
- School of Microbiology, University College Cork, Cork, Ireland
| | - Colin Hill
- APC Microbiome Ireland, Cork, Ireland; , ,
- School of Microbiology, University College Cork, Cork, Ireland
| | - Andrey N Shkoporov
- APC Microbiome Ireland, Cork, Ireland; , ,
- School of Microbiology, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
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14
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Weiner A, Turjeman S, Koren O. Gut microbes and host behavior: The forgotten members of the gut-microbiome. Neuropharmacology 2023; 227:109453. [PMID: 36738776 DOI: 10.1016/j.neuropharm.2023.109453] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/15/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023]
Abstract
The gut microbiota refers to an entire population of microorganisms that colonize the gut. This community includes viruses, prokaryotes (bacteria and archaea), and eukaryotes (fungi and parasites). Multiple studies in the last decades described the significant involvement of gut bacteria in gut-brain axis communication; however, the involvement of other members of the gut microbiota has been neglected. Recent studies found that these 'forgotten' members of the gut microbiota may also have a role in gut-brain communication, although it is still unclear whether they have a direct effect on the brain or if their effects are mediated by gut bacteria. Here, we provide concrete suggestions for future research to tease out mechanisms of the microbiota-gut-brain axis. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".
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Affiliation(s)
- Ariel Weiner
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Sondra Turjeman
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
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15
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Jansen D, Matthijnssens J. The Emerging Role of the Gut Virome in Health and Inflammatory Bowel Disease: Challenges, Covariates and a Viral Imbalance. Viruses 2023; 15:173. [PMID: 36680214 PMCID: PMC9861652 DOI: 10.3390/v15010173] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/03/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Virome research is a rapidly growing area in the microbiome field that is increasingly associated with human diseases, such as inflammatory bowel disease (IBD). Although substantial progress has been made, major methodological challenges limit our understanding of the virota. In this review, we describe challenges that must be considered to accurately report the virome composition and the current knowledge on the virome in health and IBD. First, the description of the virome shows strong methodological biases related to wetlab (e.g., VLP enrichment) and bioinformatics approaches (viral identification and classification). Second, IBD patients show consistent viral imbalances characterized by a high relative abundance of phages belonging to the Caudovirales and a low relative abundance of phages belonging to the Microviridae. Simultaneously, a sporadic contraction of CrAss-like phages and a potential expansion of the lysogenic potential of the intestinal virome are observed. Finally, despite numerous studies that have conducted diversity analysis, it is difficult to draw firm conclusions due to methodological biases. Overall, we present the many methodological and environmental factors that influence the virome, its current consensus in health and IBD, and a contributing hypothesis called the "positive inflammatory feedback loop" that may play a role in the pathophysiology of IBD.
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Affiliation(s)
| | - Jelle Matthijnssens
- Laboratory of Viral Metagenomics, Rega Institute, Department of Microbiology, Immunology and Transplantation, University of Leuven, B-3000 Leuven, Belgium
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16
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Lau HCH, Yu J. Uncovering novel human gut virome using ultra-deep metagenomic sequencing. Chin Med J (Engl) 2022; 135:2395-2397. [PMID: 36583859 PMCID: PMC9945418 DOI: 10.1097/cm9.0000000000002382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Indexed: 12/31/2022] Open
Affiliation(s)
- Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong SAR, China
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17
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Boix-Amorós A, Monaco H, Sambataro E, Clemente JC. Novel technologies to characterize and engineer the microbiome in inflammatory bowel disease. Gut Microbes 2022; 14:2107866. [PMID: 36104776 PMCID: PMC9481095 DOI: 10.1080/19490976.2022.2107866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
We present an overview of recent experimental and computational advances in technology used to characterize the microbiome, with a focus on how these developments improve our understanding of inflammatory bowel disease (IBD). Specifically, we present studies that make use of flow cytometry and metabolomics assays to provide a functional characterization of microbial communities. We also describe computational methods for strain-level resolution, temporal series, mycobiome and virome data, co-occurrence networks, and compositional data analysis. In addition, we review novel techniques to therapeutically manipulate the microbiome in IBD. We discuss the benefits and drawbacks of these technologies to increase awareness of specific biases, and to facilitate a more rigorous interpretation of results and their potential clinical application. Finally, we present future lines of research to better characterize the relation between microbial communities and IBD pathogenesis and progression.
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Affiliation(s)
- Alba Boix-Amorós
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA
| | - Hilary Monaco
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA
| | - Elisa Sambataro
- Department of Biological Sciences, CUNY Hunter College, New York, NY, USA
| | - Jose C. Clemente
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA,CONTACT Jose C. Clemente Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY10029USA
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18
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Zhao L, Shi Y, Lau HCH, Liu W, Luo G, Wang G, Liu C, Pan Y, Zhou Q, Ding Y, Sung JJY, Yu J. Uncovering 1058 Novel Human Enteric DNA Viruses Through Deep Long-Read Third-Generation Sequencing and Their Clinical Impact. Gastroenterology 2022; 163:699-711. [PMID: 35679948 DOI: 10.1053/j.gastro.2022.05.048] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 05/17/2022] [Accepted: 05/31/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND & AIMS Lack of viral reference genomes poses a challenge to virome study. We investigated human gut virome and its clinical implication by ultra-deep metagenomic sequencing. METHODS We extracted sufficient viral DNA from human feces for ultra-deep PacBio sequencing (>10 μg) and Illumina sequencing (>1 μg). Upon de novo assembly and 6 stages of strict filtering, viral genomes were generated and validated in 3 cohorts of 2819 published fecal metagenomes. Diagnostic performance of assembled viruses for colorectal cancer were tested in a training cohort and 2 independent validation cohorts. Virus mapping ratio, evolutionary history, and virus status (lytic or temperate) were also examined. RESULTS The mean amount of extracted viral DNA increased by 14-fold compared with previous protocols. We obtained PacBio long reads and Illumina short reads with 290-fold higher depth than previous studies. We assembled and validated 1178 contigs as complete viral genomes, of which 1058 were newly identified. Thirteen viral genomes (398-839 kb) that are longer than the largest bacteriophage found in humans (393 kb) were discovered. Phylogenetic tree was constructed based on Hidden Markov Models alignment scores of 4 conserved viral proteins. Incorporating our assembled genomes into the National Center for Biotechnology Information database improved the mapping ratio of published metagenomes ≤18 times. Lytic viruses (75.9% ± 12.2% of total) were predominantly present in our sample. A biomarker panel of 14 novel viruses could discriminate patients with colorectal cancer from controls with an area under the receiver operating characteristics curve of 0.87 in the training cohort, which was validated with areas under the receiver operating characteristics curve of 0.85 and 0.73 in 2 independent cohorts. CONCLUSIONS We uncovered 1058 novel human gut viruses. These findings can contribute to clinical diagnosis, current viral reference genome, and future virome investigation.
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Affiliation(s)
- Liuyang Zhao
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Yu Shi
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Harry Cheuk-Hay Lau
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Weixin Liu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Guangwen Luo
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Guoping Wang
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Changan Liu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Yasi Pan
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Qiming Zhou
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Yanqiang Ding
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong
| | - Joseph Jao-Yiu Sung
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong.
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19
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Rashed R, Valcheva R, Dieleman LA. Manipulation of Gut Microbiota as a Key Target for Crohn's Disease. Front Med (Lausanne) 2022; 9:887044. [PMID: 35783604 PMCID: PMC9244564 DOI: 10.3389/fmed.2022.887044] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) sub-type characterized by transmural chronic inflammation of the gastrointestinal tract. Research indicates a complex CD etiology involving genetic predisposition and immune dysregulation in response to environmental triggers. The chronic mucosal inflammation has been associated with a dysregulated state, or dysbiosis, of the gut microbiome (bacteria), mycobiome (fungi), virome (bacteriophages and viruses), and archeaome (archaea) further affecting the interkingdom syntrophic relationships and host metabolism. Microbiota dysbiosis in CD is largely described by an increase in facultative anaerobic pathobionts at the expense of strict anaerobic Firmicutes, such as Faecalibacterium prausnitzii. In the mycobiome, reduced fungal diversity and fungal-bacteria interactions, along with a significantly increased abundance of Candida spp. and a decrease in Saccharomyces cerevisiae are well documented. Virome analysis also indicates a significant decrease in phage diversity, but an overall increase in phages infecting bacterial groups associated with intestinal inflammation. Finally, an increase in methanogenic archaea such as Methanosphaera stadtmanae exhibits high immunogenic potential and is associated with CD etiology. Common anti-inflammatory medications used in CD management (amino-salicylates, immunomodulators, and biologics) could also directly or indirectly affect the gut microbiome in CD. Other medications often used concomitantly in IBD, such as antibiotics, antidepressants, oral contraceptives, opioids, and proton pump inhibitors, have shown to alter the gut microbiota and account for increased susceptibility to disease onset or worsening of disease progression. In contrast, some environmental modifications through alternative therapies including fecal microbiota transplant (FMT), diet and dietary supplements with prebiotics, probiotics, and synbiotics have shown potential protective effects by reversing microbiota dysbiosis or by directly promoting beneficial microbes, together with minimal long-term adverse effects. In this review, we discuss the different approaches to modulating the global consortium of bacteria, fungi, viruses, and archaea in patients with CD through therapies that include antibiotics, probiotics, prebiotics, synbiotics, personalized diets, and FMT. We hope to provide evidence to encourage clinicians and researchers to incorporate these therapies into CD treatment options, along with making them aware of the limitations of these therapies, and indicate where more research is needed.
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20
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Li M, Wang C, Guo Q, Xu C, Xie Z, Tan J, Wu S, Wang P, Guo J, Fang Z, Zhu S, Duan L, Jiang X, Zhu H. More Positive or More Negative? Metagenomic Analysis Reveals Roles of Virome in Human Disease-Related Gut Microbiome. Front Cell Infect Microbiol 2022; 12:846063. [PMID: 35493727 PMCID: PMC9040671 DOI: 10.3389/fcimb.2022.846063] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/07/2022] [Indexed: 12/04/2022] Open
Abstract
Viruses are increasingly viewed as vital components of the human gut microbiota, while their roles in health and diseases remain incompletely understood. Here, we first sequenced and analyzed the 37 metagenomic and 18 host metabolomic samples related to irritable bowel syndrome (IBS) and found that some shifted viruses between IBS and controls covaried with shifted bacteria and metabolites. Especially, phages that infect beneficial lactic acid bacteria depleted in IBS covaried with their hosts. We also retrieved public whole-genome metagenomic datasets of another four diseases (type 2 diabetes, Crohn’s disease, colorectal cancer, and liver cirrhosis), totaling 438 samples including IBS, and performed uniform analysis of the gut viruses in diseases. By constructing disease-specific co-occurrence networks, we found viruses actively interacting with bacteria, negatively correlated with possible dysbiosis-related and inflammation-mediating bacteria, increasing the connectivity between bacteria modules, and contributing to the robustness of the networks. Functional enrichment analysis showed that phages interact with bacteria through predation or expressing genes involved in the transporter and secretion system, metabolic enzymes, etc. We further built a viral database to facilitate systematic functional classification and explored the functions of viral genes on interacting with bacteria. Our analyses provided a systematic view of the gut virome in the disease-related microbial community and suggested possible positive roles of viruses concerning gut health.
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Affiliation(s)
- Mo Li
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Ph.D. Program, School of Life Sciences, Peking University, Beijing, China
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Chunhui Wang
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Ph.D. Program, School of Life Sciences, Peking University, Beijing, China
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Qian Guo
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Congmin Xu
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Zhongjie Xie
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Jie Tan
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Shufang Wu
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Peihong Wang
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Jinyuan Guo
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
| | - Zhencheng Fang
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Shiwei Zhu
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Liping Duan
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiaoqing Jiang
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
- *Correspondence: Huaiqiu Zhu, ; Xiaoqing Jiang,
| | - Huaiqiu Zhu
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Ph.D. Program, School of Life Sciences, Peking University, Beijing, China
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
- Institute of Medical Technology, Peking University Health Science Center, Beijing, China
- *Correspondence: Huaiqiu Zhu, ; Xiaoqing Jiang,
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21
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Spencer L, Olawuni B, Singh P. Gut Virome: Role and Distribution in Health and Gastrointestinal Diseases. Front Cell Infect Microbiol 2022; 12:836706. [PMID: 35360104 PMCID: PMC8960297 DOI: 10.3389/fcimb.2022.836706] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/10/2022] [Indexed: 12/11/2022] Open
Abstract
The study of the intestinal microbiome is an evolving field of research that includes comprehensive analysis of the vast array of microbes – bacterial, archaeal, fungal, and viral. Various gastrointestinal (GI) diseases, such as Crohn’s disease and ulcerative colitis, have been associated with instability of the gut microbiota. Many studies have focused on importance of bacterial communities with relation to health and disease in humans. The role of viruses, specifically bacteriophages, have recently begin to emerge and have profound impact on the host. Here, we comprehensively review the importance of viruses in GI diseases and summarize their influence in the complex intestinal environment, including their biochemical and genetic activities. We also discuss the distribution of the gut virome as it relates with treatment and immunological advantages. In conclusion, we suggest the need for further studies on this critical component of the intestinal microbiome to decipher the role of the gut virome in human health and disease.
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22
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El Mouzan M, Assiri A, Al Sarkhy A, Alasmi M, Saeed A, Al-Hussaini A, AlSaleem B, Al Mofarreh M. Viral dysbiosis in children with new-onset celiac disease. PLoS One 2022; 17:e0262108. [PMID: 35030192 PMCID: PMC8759644 DOI: 10.1371/journal.pone.0262108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 12/16/2021] [Indexed: 01/01/2023] Open
Abstract
Viruses are common components of the intestinal microbiome, modulating host bacterial metabolism and interacting with the immune system, with a possible role in the pathogenesis of immune-mediated diseases such as celiac disease (CeD). The objective of this study was to characterize the virome profile in children with new-onset CeD. We used metagenomic analysis of viral DNA in mucosal and fecal samples from children with CeD and controls and performed sequencing using the Nextera XT library preparation kit. Abundance log2 fold changes were calculated using differential expression and linear discriminant effect size. Shannon alpha and Bray–Curtis beta diversity were determined. A total of 40 children with CeD and 39 controls were included. We found viral dysbiosis in both fecal and mucosal samples. Examples of significantly more abundant species in fecal samples of children with CeD included Human polyomavirus 2, Enterobacteria phage mEpX1, and Enterobacteria phage mEpX2; whereas less abundant species included Lactococcus phages ul36 and Streptococcus phage Abc2. In mucosal samples however, no species were significantly associated with CeD. Shannon alpha diversity was not significantly different between CeD and non-CeD groups and Bray–Curtis beta diversity showed no significant separation between CeD and non-CeD samples in either mucosal or stool samples, whereas separation was clear in all samples. We identified significant viral dysbiosis in children with CeD, suggesting a potential role in the pathogenesis of CeD indicating the need for further studies.
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Affiliation(s)
- Mohammad El Mouzan
- Department of Pediatrics (Gastroenterology), King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia
- * E-mail: ,
| | - Asaad Assiri
- Department of Pediatrics (Gastroenterology), King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, Prince Abdullah Bin Khalid Celiac Disease Research Chair, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Ahmed Al Sarkhy
- Department of Pediatrics (Gastroenterology), King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mona Alasmi
- Department of Pediatrics (Gastroenterology), King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Anjum Saeed
- Department of Pediatrics (Gastroenterology), King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdulrahman Al-Hussaini
- Division of Pediatric Gastroenterology, Children’s Specialist Hospital, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
- Faculty of Medicine, AlFaisal University, Riyadh, Kingdom of Saudi Arabia
| | - Badr AlSaleem
- Division of Gastroenterology, The Children Hospital, King Fahad Medical City, Pediatric Intestinal Failure and Parenteral Nutrition Program, Riyadh, Kingdom of Saudi Arabia
| | - Mohammad Al Mofarreh
- Department of Gastroenterology, Al Mofarreh PolyClinic, Riyadh, Kingdom of Saudi Arabia
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23
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Guzzo GL, Andrews JM, Weyrich LS. The Neglected Gut Microbiome: Fungi, Protozoa, and Bacteriophages in Inflammatory Bowel Disease. Inflamm Bowel Dis 2022; 28:1112-1122. [PMID: 35092426 PMCID: PMC9247841 DOI: 10.1093/ibd/izab343] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Indexed: 12/14/2022]
Abstract
The gut microbiome has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Studies suggest that the IBD gut microbiome is less diverse than that of the unaffected population, a phenomenon often referred to as dysbiosis. However, these studies have heavily focused on bacteria, while other intestinal microorganisms-fungi, protozoa, and bacteriophages-have been neglected. Of the nonbacterial microbes that have been studied in relation to IBD, most are thought to be pathogens, although there is evidence that some of these species may instead be harmless commensals. In this review, we discuss the nonbacterial gut microbiome of IBD, highlighting the current biases, limitations, and outstanding questions that can be addressed with high-throughput DNA sequencing methods. Further, we highlight the importance of studying nonbacterial microorganisms alongside bacteria for a comprehensive view of the whole IBD biome and to provide a more precise definition of dysbiosis in patients. With the rise in popularity of microbiome-altering therapies for the treatment of IBD, such as fecal microbiota transplantation, it is important that we address these knowledge gaps to ensure safe and effective treatment of patients.
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Affiliation(s)
- Gina L Guzzo
- Address correspondence to: Gina L. Guzzo, The University of Adelaide, Adelaide, South Australia, Australia ()
| | - Jane M Andrews
- Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital and School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Laura S Weyrich
- School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia,Department of Anthropology and Huck Institutes of the Life Sciences, Pennsylvania State University, State College, PA, USA
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24
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The Periodontopathic Pathogen, Porphyromonas gingivalis, Involves a Gut Inflammatory Response and Exacerbates Inflammatory Bowel Disease. Pathogens 2022; 11:pathogens11010084. [PMID: 35056032 PMCID: PMC8779656 DOI: 10.3390/pathogens11010084] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/07/2022] [Accepted: 01/08/2022] [Indexed: 12/13/2022] Open
Abstract
Periodontal disease (PD) is one of the most prevalent disorders globally and is strongly associated with many other diseases. Inflammatory bowel disease (IBD), an inflammatory condition of the colon and the small intestine, is reported to be associated with PD through undetermined mechanisms. We analyzed taxonomic assignment files from the Crohn’s Disease Viral and Microbial Metagenome Project (PRJEB3206). The abundance of Porphyromonadaceae in fecal samples was significantly different between patients with Crohn’s disease and control volunteers. Dextran sulfate sodium was used to induce colitis in mice to reveal the effect of this periodontopathic pathogen in vivo. After intrarectal implantation of Porphyromonas gingivalis (Pg)—the primary pathogen causing PD—the disease activity index score, colonic epithelial loss, and inflammatory cell infiltration were intensified. In addition, tumor necrosis factor-α and interleukin-6 showed the highest levels in Pg-infected colons. This revealed the importance of Pg in the exacerbation of IBD. Thus, simultaneous treatment of PD should be considered for people with IBD. Moreover, implantation of Pg in the rectum worsened the clinical symptoms of colitis in mice. Because Pg participates in the pathogenesis of IBD, reducing the chances of it entering the intestine might prevent the worsening of this disorder.
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25
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Marongiu L, Landry JJM, Rausch T, Abba ML, Delecluse S, Delecluse H, Allgayer H. Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors. Mol Oncol 2021; 15:3363-3384. [PMID: 34328665 PMCID: PMC8637581 DOI: 10.1002/1878-0261.13070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/09/2021] [Accepted: 07/29/2021] [Indexed: 12/18/2022] Open
Abstract
The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial cofactors of colorectal cancer (CRC) carcinogenesis or progression. We analysed whole-genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs. The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. 948. Enrichment of Escherichia coli strains IAI1, SE11, K-12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast-confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR-validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues, and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t-test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co)risk factors of CRC and extend putative suggestions on critical microbiome species in CRC metastasis.
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Affiliation(s)
- Luigi Marongiu
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
| | | | - Tobias Rausch
- Genomics Core FacilityEuropean Molecular Biology Laboratory (EMBL)HeidelbergGermany
| | - Mohammed L. Abba
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
| | | | | | - Heike Allgayer
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
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Liang G, Cobián-Güemes AG, Albenberg L, Bushman F. The gut virome in inflammatory bowel diseases. Curr Opin Virol 2021; 51:190-198. [PMID: 34763180 DOI: 10.1016/j.coviro.2021.10.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
Dysbiosis of the microbiome has been extensively studied in inflammatory bowel diseases (IBD). The roles of bacteria and fungi have been studied in detail, but viral communities, an important component of the microbiome, have been less thoroughly investigated. Metagenomics provided a way to fill this gap by using DNA sequencing to enumerate all viruses in a sample, termed the 'virome'. Such methods have now been employed in several studies to assess associations between viral communities and IBD, yielding several commonly seen properties, including an increase in tailed bacteriophage (Caudovirales) and a decrease in the spherical Microviridae. Numerous studies of single human viruses have been carried out, but no one virus has emerged as tightly associated, focusing attention on whole virome communities and further factors. This review provides an overview of research on the human virome in IBD, with emphasis on (1) dynamics of the gut virome, (2) candidate mechanisms of virome alterations with disease, (3) methods for studying the virome, and (4) potentially actionable implications of virome data.
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Affiliation(s)
- Guanxiang Liang
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6076, USA.
| | - Ana Georgina Cobián-Güemes
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6076, USA
| | - Lindsey Albenberg
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104-4399, USA
| | - Frederic Bushman
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6076, USA.
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27
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Van Espen L, Bak EG, Beller L, Close L, Deboutte W, Juel HB, Nielsen T, Sinar D, De Coninck L, Frithioff-Bøjsøe C, Fonvig CE, Jacobsen S, Kjærgaard M, Thiele M, Fullam A, Kuhn M, Holm JC, Bork P, Krag A, Hansen T, Arumugam M, Matthijnssens J. A Previously Undescribed Highly Prevalent Phage Identified in a Danish Enteric Virome Catalog. mSystems 2021; 6:e0038221. [PMID: 34665009 PMCID: PMC8525569 DOI: 10.1128/msystems.00382-21] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/02/2021] [Indexed: 01/06/2023] Open
Abstract
Gut viruses are important, yet often neglected, players in the complex human gut microbial ecosystem. Recently, the number of human gut virome studies has been increasing; however, we are still only scratching the surface of the immense viral diversity. In this study, 254 virus-enriched fecal metagenomes from 204 Danish subjects were used to generate the Danish Enteric Virome Catalog (DEVoC) containing 12,986 nonredundant viral scaffolds, of which the majority was previously undescribed, encoding 190,029 viral genes. The DEVoC was used to compare 91 healthy DEVoC gut viromes from children, adolescents, and adults that were used to create the DEVoC. Gut viromes of healthy Danish subjects were dominated by phages. While most phage genomes (PGs) only occurred in a single subject, indicating large virome individuality, 39 PGs were present in more than 10 healthy subjects. Among these 39 PGs, the prevalences of three PGs were associated with age. To further study the prevalence of these 39 prevalent PGs, 1,880 gut virome data sets of 27 studies from across the world were screened, revealing several age-, geography-, and disease-related prevalence patterns. Two PGs also showed a remarkably high prevalence worldwide-a crAss-like phage (20.6% prevalence), belonging to the tentative AlphacrAssvirinae subfamily, and a previously undescribed circular temperate phage infecting Bacteroides dorei (14.4% prevalence), called LoVEphage because it encodes lots of viral elements. Due to the LoVEphage's high prevalence and novelty, public data sets in which the LoVEphage was detected were de novo assembled, resulting in an additional 18 circular LoVEphage-like genomes (67.9 to 72.4 kb). IMPORTANCE Through generation of the DEVoC, we added numerous previously uncharacterized viral genomes and genes to the ever-increasing worldwide pool of human gut viromes. The DEVoC, the largest human gut virome catalog generated from consistently processed fecal samples, facilitated the analysis of the 91 healthy Danish gut viromes. Characterizing the biggest cohort of healthy gut viromes from children, adolescents, and adults to date confirmed the previously established high interindividual variation in human gut viromes and demonstrated that the effect of age on the gut virome composition was limited to the prevalence of specific phage (groups). The identification of a previously undescribed prevalent phage illustrates the usefulness of developing virome catalogs, and we foresee that the DEVoC will benefit future analysis of the roles of gut viruses in human health and disease.
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Affiliation(s)
- Lore Van Espen
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Emilie Glad Bak
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Leen Beller
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Lila Close
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Ward Deboutte
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Helene Bæk Juel
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Trine Nielsen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Deniz Sinar
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Lander De Coninck
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Christine Frithioff-Bøjsøe
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Children’s Obesity Clinic, accredited European Centre for Obesity Management, Department of Paediatrics, Copenhagen University Hospital Holbaek, Holbaek, Denmark
| | - Cilius Esmann Fonvig
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Children’s Obesity Clinic, accredited European Centre for Obesity Management, Department of Paediatrics, Copenhagen University Hospital Holbaek, Holbaek, Denmark
| | - Suganya Jacobsen
- Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Maria Kjærgaard
- Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Anthony Fullam
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Kuhn
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Jens-Christian Holm
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Children’s Obesity Clinic, accredited European Centre for Obesity Management, Department of Paediatrics, Copenhagen University Hospital Holbaek, Holbaek, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peer Bork
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- Max Delbrück Centre for Molecular Medicine, Berlin, Germany
- Yonsei Frontier Lab (YFL), Yonsei University, Seoul, South Korea
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Manimozhiyan Arumugam
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jelle Matthijnssens
- KU Leuven, Department of Microbiology, Immunology, & Transplantation, Rega Institute, Division of Clinical & Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
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28
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Abstract
Mediators of the initiation, development, and recurrence of periodontitis include the oral microbiome embedded in subgingival plaque and the host immune response to a dysbiosis within this dynamic and complex microbial community. Although mediators have been studied extensively, researchers in the field have been unable to fully ascribe certain clinical presentations of periodontitis to their nature. Emergence of high-throughput sequencing technologies has resulted in better characterization of the microbial oral dysbiosis that extends beyond the extensively studied putative bacterial periodontopathogens to a shift in the oral virome composition during disease conditions. Although the biological dark matter inserted by retroviruses was once believed to be nonfunctional, research has revealed that it encodes historical viral-eukaryotic interactions and influences host development. The objective of this review is to evaluate the proposed association of herpesviruses to the etiology and pathogenesis of periodontal disease and survey the highly abundant prokaryotic viruses to delineate their potential roles in biofilm dynamics, as well as their interactions with putative bacterial periodontopathogens and eukaryotic cells. The findings suggest that potential novel periodontal therapies targeting or utilizing the oral virome can alleviate certain clinical presentations of periodontitis. Perhaps it is time to embrace the viral dark matter within the periodontal environment to fully comprehend the pathogenesis and systemic implications of periodontitis.
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Affiliation(s)
- April Martínez
- Orofacial Sciences DepartmentSchool of DentistryUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Ryutaro Kuraji
- Orofacial Sciences DepartmentSchool of DentistryUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Department of Life Science DentistryThe Nippon Dental UniversityTokyoJapan
- Department of PeriodontologyThe Nippon Dental University School of Life Dentistry at TokyoTokyoJapan
| | - Yvonne L. Kapila
- Orofacial Sciences DepartmentSchool of DentistryUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
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29
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Aldars-García L, Chaparro M, Gisbert JP. Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms 2021; 9:microorganisms9050977. [PMID: 33946482 PMCID: PMC8147118 DOI: 10.3390/microorganisms9050977] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing-remitting systemic disease of the gastrointestinal tract. It is well established that the gut microbiome has a profound impact on IBD pathogenesis. Our aim was to systematically review the literature on the IBD gut microbiome and its usefulness to provide microbiome-based biomarkers. A systematic search of the online bibliographic database PubMed from inception to August 2020 with screening in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. One-hundred and forty-four papers were eligible for inclusion. There was a wide heterogeneity in microbiome analysis methods or experimental design. The IBD intestinal microbiome was generally characterized by reduced species richness and diversity, and lower temporal stability, while changes in the gut microbiome seemed to play a pivotal role in determining the onset of IBD. Multiple studies have identified certain microbial taxa that are enriched or depleted in IBD, including bacteria, fungi, viruses, and archaea. The two main features in this sense are the decrease in beneficial bacteria and the increase in pathogenic bacteria. Significant differences were also present between remission and relapse IBD status. Shifts in gut microbial community composition and abundance have proven to be valuable as diagnostic biomarkers. The gut microbiome plays a major role in IBD, yet studies need to go from casualty to causality. Longitudinal designs including newly diagnosed treatment-naïve patients are needed to provide insights into the role of microbes in the onset of intestinal inflammation. A better understanding of the human gut microbiome could provide innovative targets for diagnosis, prognosis, treatment and even cure of this relevant disease.
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Affiliation(s)
- Laila Aldars-García
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28006 Madrid, Spain; (L.A.-G.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - María Chaparro
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28006 Madrid, Spain; (L.A.-G.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - Javier P. Gisbert
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28006 Madrid, Spain; (L.A.-G.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
- Correspondence: ; Tel.: +34-913-093-911; Fax: +34-915-204-013
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30
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Fernández L, Duarte AC, Rodríguez A, García P. The relationship between the phageome and human health: are bacteriophages beneficial or harmful microbes? Benef Microbes 2021; 12:107-120. [PMID: 33789552 DOI: 10.3920/bm2020.0132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In the context of the global antibiotic resistance crisis, bacteriophages are increasingly becoming promising antimicrobial agents against multi-resistant bacteria. Indeed, a huge effort is being made to bring phage-derived products to the market, a process that will also require revising the current regulations in order to facilitate their approval. However, despite the evidence supporting the safety of phages for humans, the general public would still be reluctant to use 'viruses' for therapeutic purposes. In this scenario, we consider that it is important to discuss the role of these microorganisms in the equilibrium of the microbiota and how this relates to human health. To do that, this review starts by examining the role of phages as key players in bacterial communities (including those that naturally inhabit the human body), modulating the species composition and contributing to maintain a 'healthy' status quo. Additionally, in specific situations, e.g. an infectious disease, bacteriophages can be used as target-specific antimicrobials against pathogenic bacteria (phage therapy), while being harmless to the desirable microbiota. Apart from that, incipient research shows the potential application of these viruses to treat diseases caused by bacterial dysbiosis. This latter application would be comparable to the use of probiotics or prebiotics, since bacteriophages can indirectly improve the growth of beneficial bacteria in the gastrointestinal tract by removing undesirable competitors. On the other hand, possible adverse effects do not appear to be an impediment to promote phage therapy. Nonetheless, it is important to remember their potentially negative impact, mainly concerning their immunogenicity or their potential spread of virulence and antibiotic resistance genes, especially by temperate phages. Overall, we believe that phages should be largely considered beneficial microbes, although it is paramount not to overlook their potential risks.
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Affiliation(s)
- L Fernández
- Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.,DairySafe Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. del Hospital Universitario s/n, 33011 Oviedo, Spain
| | - A C Duarte
- Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.,DairySafe Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. del Hospital Universitario s/n, 33011 Oviedo, Spain
| | - A Rodríguez
- Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.,DairySafe Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. del Hospital Universitario s/n, 33011 Oviedo, Spain
| | - P García
- Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.,DairySafe Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. del Hospital Universitario s/n, 33011 Oviedo, Spain
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31
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The Role of Enterobacteriaceae in Gut Microbiota Dysbiosis in Inflammatory Bowel Diseases. Microorganisms 2021; 9:microorganisms9040697. [PMID: 33801755 PMCID: PMC8066304 DOI: 10.3390/microorganisms9040697] [Citation(s) in RCA: 162] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of chronic gastrointestinal inflammatory diseases with unknown etiology. There is a combination of well documented factors in their pathogenesis, including intestinal microbiota dysbiosis. The symbiotic microbiota plays important functions in the host, and the loss of beneficial microbes could favor the expansion of microbial pathobionts. In particular, the bloom of potentially harmful Proteobacteria, especially Enterobacteriaceae, has been described as enhancing the inflammatory response, as observed in IBDs. Herein, we seek to investigate the contribution of Enterobacteriaceae to IBD pathogenesis whilst considering the continuous expansion of the literature and data. Despite the mechanism of their expansion still remaining unclear, their expansion could be correlated with the increase in nitrate and oxygen levels in the inflamed gut and with the bile acid dysmetabolism described in IBD patients. Furthermore, in several Enterobacteriaceae studies conducted at a species level, it has been suggested that some adherent-invasive Escherichia coli (AIEC) play an important role in IBD pathogenesis. Overall, this review highlights the pivotal role played by Enterobacteriaceae in gut dysbiosis associated with IBD pathogenesis and progression.
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32
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Aldars-García L, Marin AC, Chaparro M, Gisbert JP. The Interplay between Immune System and Microbiota in Inflammatory Bowel Disease: A Narrative Review. Int J Mol Sci 2021; 22:ijms22063076. [PMID: 33802883 PMCID: PMC8002696 DOI: 10.3390/ijms22063076] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/14/2022] Open
Abstract
The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain–gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.
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Affiliation(s)
- Laila Aldars-García
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (A.C.M.); (M.C.); (J.P.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
- Correspondence:
| | - Alicia C. Marin
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (A.C.M.); (M.C.); (J.P.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (A.C.M.); (M.C.); (J.P.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - Javier P. Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (A.C.M.); (M.C.); (J.P.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
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Standard Bacteriophage Purification Procedures Cause Loss in Numbers and Activity. Viruses 2021; 13:v13020328. [PMID: 33672780 PMCID: PMC7924620 DOI: 10.3390/v13020328] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
For decades, bacteriophage purification has followed structured protocols focused on generating high concentrations of phage in manageable volumes. As research moves toward understanding complex phage populations, purification needs have shifted to maximize the amount of phage while maintaining diversity and activity. The effects of standard phage purification procedures such as polyethylene glycol (PEG) precipitation and cesium chloride (CsCl) density gradients on both diversity and activity of a phage population are not known. We have examined the effects of PEG precipitation and CsCl density gradients on a number of known phage (M13, T4, and ΦX 174) of varying structure and size, individually and as mixed sample. Measurement of phage numbers and activity throughout the purification process was performed. We demonstrate that these methods, used routinely to generate "pure" phage samples, are in fact detrimental to retention of phage number and activity; even more so in mixed phage samples. As such, minimal amounts of processing are recommended to introduce less bias and maintain more of a phage population.
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Ahlawat S, Kumar P, Mohan H, Goyal S, Sharma KK. Inflammatory bowel disease: tri-directional relationship between microbiota, immune system and intestinal epithelium. Crit Rev Microbiol 2021; 47:254-273. [PMID: 33576711 DOI: 10.1080/1040841x.2021.1876631] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human gut microbiota contributes to host nutrition and metabolism, sustains intestinal cell proliferation and differentiation, and modulates host immune system. The alterations in their composition lead to severe gut disorders, including inflammatory bowel disease (IBD) or inflammatory bowel syndrome (IBS). IBD including ulcerative colitis (UC) and Crohn's disease (CD) are gamut of chronic inflammatory disorders of gut, mediated by complex interrelations among genetic, environmental, and internal factors. IBD has debateable aetiology, however in recent years, exploring the central role of a tri-directional relationship between gut microbiota, mucosal immune system, and intestinal epithelium in pathogenesis is getting the most attention. Increasing incidences and early onset explains the exponential rise in IBD burden on health-care systems. Industrialization, hypersensitivity to allergens, lifestyle, hygiene hypothesis, loss of intestinal worms, and gut microbial composition, explains this shifted rise. Hitherto, the interventions modulating gut microbiota composition, microfluidics-based in vitro gastrointestinal models, non-allergic functional foods, nutraceuticals, and faecal microbiota transplantation (FMT) from healthy donors are some of the futuristic approaches for the disease management.
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Affiliation(s)
- Shruti Ahlawat
- Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Pramod Kumar
- Ministry of Health and Family Welfare, Government of India, Indian Council of Medical Research, New Delhi, India
| | - Hari Mohan
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Sandeep Goyal
- Department of Medicine, Pt. BD Sharma Post-graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Krishna Kant Sharma
- Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
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Gregory AC, Zablocki O, Zayed AA, Howell A, Bolduc B, Sullivan MB. The Gut Virome Database Reveals Age-Dependent Patterns of Virome Diversity in the Human Gut. Cell Host Microbe 2020; 28:724-740.e8. [PMID: 32841606 PMCID: PMC7443397 DOI: 10.1016/j.chom.2020.08.003] [Citation(s) in RCA: 365] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/14/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022]
Abstract
The gut microbiome profoundly affects human health and disease, and their infecting viruses are likely as important, but often missed because of reference database limitations. Here, we (1) built a human Gut Virome Database (GVD) from 2,697 viral particle or microbial metagenomes from 1,986 individuals representing 16 countries, (2) assess its effectiveness, and (3) report a meta-analysis that reveals age-dependent patterns across healthy Westerners. The GVD contains 33,242 unique viral populations (approximately species-level taxa) and improves average viral detection rates over viral RefSeq and IMG/VR nearly 182-fold and 2.6-fold, respectively. GVD meta-analyses show highly personalized viromes, reveal that inter-study variability from technical artifacts is larger than any "disease" effect at the population level, and document how viral diversity changes from human infancy into senescence. Together, this compact foundational resource, these standardization guidelines, and these meta-analysis findings provide a systematic toolkit to help maximize our understanding of viral roles in health and disease.
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Affiliation(s)
- Ann C Gregory
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA
| | - Olivier Zablocki
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA; Center of Microbiome Science, Ohio State University, Columbus, OH 43210, USA
| | - Ahmed A Zayed
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA; Center of Microbiome Science, Ohio State University, Columbus, OH 43210, USA
| | - Allison Howell
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA
| | - Benjamin Bolduc
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA; Center of Microbiome Science, Ohio State University, Columbus, OH 43210, USA
| | - Matthew B Sullivan
- Department of Microbiology, Ohio State University, Columbus, OH 43210, USA; Department of Civil, Environmental and Geodetic Engineering, Ohio State University, Columbus, OH 43210, USA; Center of Microbiome Science, Ohio State University, Columbus, OH 43210, USA.
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Blanco-Picazo P, Fernández-Orth D, Brown-Jaque M, Miró E, Espinal P, Rodríguez-Rubio L, Muniesa M, Navarro F. Unravelling the consequences of the bacteriophages in human samples. Sci Rep 2020; 10:6737. [PMID: 32317653 PMCID: PMC7174282 DOI: 10.1038/s41598-020-63432-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/31/2020] [Indexed: 12/26/2022] Open
Abstract
Bacteriophages are abundant in human biomes and therefore in human clinical samples. Although this is usually not considered, they might interfere with the recovery of bacterial pathogens at two levels: 1) by propagating in the enrichment cultures used to isolate the infectious agent, causing the lysis of the bacterial host and 2) by the detection of bacterial genes inside the phage capsids that mislead the presence of the bacterial pathogen. To unravel these interferences, human samples (n = 271) were analyzed and infectious phages were observed in 11% of blood culture, 28% of serum, 45% of ascitic fluid, 14% of cerebrospinal fluid and 23% of urine samples. The genetic content of phage particles from a pool of urine and ascitic fluid samples corresponded to bacteriophages infecting different bacterial genera. In addition, many bacterial genes packaged in the phage capsids, including antibiotic resistance genes and 16S rRNA genes, were detected in the viromes. Phage interference can be minimized applying a simple procedure that reduced the content of phages up to 3 logs while maintaining the bacterial load. This method reduced the detection of phage genes avoiding the interference with molecular detection of bacteria and reduced the phage propagation in the cultures, enhancing the recovery of bacteria up to 6 logs.
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Affiliation(s)
- Pedro Blanco-Picazo
- Department of Genetics, Microbiology and Statistics, University of Barcelona, Diagonal 643, Annex, Floor 0, 08028, Barcelona, Spain
| | - Dietmar Fernández-Orth
- European Genome-phenome Archive, Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003, Barcelona, Spain
| | - Maryury Brown-Jaque
- Department of Genetics, Microbiology and Statistics, University of Barcelona, Diagonal 643, Annex, Floor 0, 08028, Barcelona, Spain
| | - Elisenda Miró
- Servei de Microbiologia, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau, Sant Quintí 89, 08041, Barcelona, Spain
| | - Paula Espinal
- Servei de Microbiologia, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau, Sant Quintí 89, 08041, Barcelona, Spain
| | - Lorena Rodríguez-Rubio
- Department of Genetics, Microbiology and Statistics, University of Barcelona, Diagonal 643, Annex, Floor 0, 08028, Barcelona, Spain
| | - Maite Muniesa
- Department of Genetics, Microbiology and Statistics, University of Barcelona, Diagonal 643, Annex, Floor 0, 08028, Barcelona, Spain.
| | - Ferran Navarro
- Servei de Microbiologia, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau, Sant Quintí 89, 08041, Barcelona, Spain.,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Barcelona, Spain
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37
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Maronek M, Link R, Ambro L, Gardlik R. Phages and Their Role in Gastrointestinal Disease: Focus on Inflammatory Bowel Disease. Cells 2020; 9:E1013. [PMID: 32325706 PMCID: PMC7226564 DOI: 10.3390/cells9041013] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/09/2020] [Accepted: 04/16/2020] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of chronic autoinflammatory diseases including Crohn's disease and ulcerative colitis. Although the molecular mechanisms governing the pathogenesis of gastrointestinal inflammation are not completely clear, the main factors are presumed to be genetic predisposition, environmental exposure, and the intestinal microbiome. Hitherto, most of the studies focusing on the role of the microbiome studied the action and effect of bacteria. However, the intestinal microbiome comprises other members of the microbial community as well, namely, fungi, protozoa, and viruses. We believe that bacteriophages are among the main orchestrators of the effect of microbiota on the gut mucosa. Therefore, this review aims to summarize the knowledge of the role of intestinal phageome in IBD and to discuss the concept of phage therapy and its future applications.
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Affiliation(s)
- Martin Maronek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Rene Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (R.L.); (L.A.)
| | - Lubos Ambro
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (R.L.); (L.A.)
| | - Roman Gardlik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
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Abstract
Crohn's disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in incidence worldwide. Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. The onset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn's disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.
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Pittayanon R, Lau JT, Leontiadis GI, Tse F, Yuan Y, Surette M, Moayyedi P. Differences in Gut Microbiota in Patients With vs Without Inflammatory Bowel Diseases: A Systematic Review. Gastroenterology 2020; 158:930-946.e1. [PMID: 31812509 DOI: 10.1053/j.gastro.2019.11.294] [Citation(s) in RCA: 383] [Impact Index Per Article: 76.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 11/05/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Altering the intestinal microbiota has been proposed as a treatment for inflammatory bowel diseases (IBDs), but there are no established associations between specific microbes and IBD. We performed a systematic review to identify frequent associations. METHODS We searched the MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases, through April 2, 2018 for studies that compared intestinal microbiota (from fecal or colonic or ileal tissue samples) among patients (adult or pediatric) with IBD vs healthy individuals (controls). The primary outcome was difference in specific taxa in fecal or intestinal tissue samples from patients with IBD vs controls. We used the Newcastle-Ottawa scale to assess the quality of studies included in the review. RESULTS We identified 2631 citations; 48 studies from 45 articles were included in the analysis. Most studies evaluated adults with Crohn's disease or ulcerative colitis. All 3 studies of Christensenellaceae and Coriobacteriaceae and 6 of 11 studies of Faecalibacterium prausnitzii reported a decreased amount of those organisms compared with controls, whereas 2 studies each of Actinomyces, Veillonella, and Escherichia coli revealed an increased amount in patients with Crohn's disease. For patients with ulcerative colitis, Eubacterium rectale and Akkermansia were decreased in all 3 studies, whereas E coli was increased in 4 of 9 studies. The microbiota diversity was either decreased or not different in patients with IBD vs controls. Fewer than 50% of the studies stated comparable sexes and ages of cases and controls. CONCLUSIONS In a systematic review, we found evidence for differences in abundances of some bacteria in patients with IBD vs controls, but we cannot make conclusions due to inconsistent results and methods among studies. Further large-scale studies, with better methods of assessing microbe populations, are needed.
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Affiliation(s)
- Rapat Pittayanon
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; King Chulalongkorn Memorial Hospital, The Thai Red Cross, Bangkok, Thailand
| | - Jennifer T Lau
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Grigorios I Leontiadis
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Frances Tse
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Yuhong Yuan
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Michael Surette
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Paul Moayyedi
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
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40
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Sutton TDS, Hill C. Gut Bacteriophage: Current Understanding and Challenges. Front Endocrinol (Lausanne) 2019; 10:784. [PMID: 31849833 PMCID: PMC6895007 DOI: 10.3389/fendo.2019.00784] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/28/2019] [Indexed: 12/13/2022] Open
Abstract
The gut microbiome is widely accepted to have a significant impact on human health yet, despite years of research on this complex ecosystem, the contributions of different forces driving microbial population structure remain to be fully elucidated. The viral component of the human gut microbiome is dominated by bacteriophage, which are known to play crucial roles in shaping microbial composition, driving bacterial diversity, and facilitating horizontal gene transfer. Bacteriophage are also one of the most poorly understood components of the human gut microbiome, with the vast majority of viral sequences sharing little to no homology to reference databases. If we are to understand the dynamics of bacteriophage populations, their interaction with the human microbiome and ultimately their influence on human health, we will depend heavily on sequence based approaches and in silico tools. This is complicated by the fact that, as with any research field in its infancy, methods of analyses vary and this can impede our ability to compare the outputs of different studies. Here, we discuss the major findings to date regarding the human virome and reflect on our current understanding of how gut bacteriophage shape the microbiome. We consider whether or not the virome field is built on unstable foundations and if so, how can we provide a solid basis for future experimentation. The virome is a challenging yet crucial piece of the human microbiome puzzle. In order to develop our understanding, we will discuss the need to underpin future studies with robust research methods and suggest some solutions to existing challenges.
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Affiliation(s)
| | - Colin Hill
- APC Microbiome Ireland and School of Microbiology, University College Cork, Cork, Ireland
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41
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Lin DM, Koskella B, Ritz NL, Lin D, Carroll-Portillo A, Lin HC. Transplanting Fecal Virus-Like Particles Reduces High-Fat Diet-Induced Small Intestinal Bacterial Overgrowth in Mice. Front Cell Infect Microbiol 2019; 9:348. [PMID: 31750259 PMCID: PMC6843071 DOI: 10.3389/fcimb.2019.00348] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/30/2019] [Indexed: 12/30/2022] Open
Abstract
Fecal microbiota transplantation (FMT) is an effective tool for treating Clostridium difficile infection in the setting of dysbiosis of the intestinal microbiome. FMT for other forms of human disorders linked to dysbiosis have been less effective. The fecal microbiota contains a high density of virus-like particles (VLP), up to 90% of which are bacteriophages, thought to have a role in regulating gut bacterial populations. We hypothesized that transplantation of the phage-containing fecal VLP fraction may reduce bacterial density in the dysbiotic setting of small intestinal bacterial overgrowth (SIBO). In an experiment using fecal transplantation, we compared the effect of the fecal VLP fraction (bacteria removed) against “Whole” FMT (bacteria intact) on the ileal microbiome. Recipients were either treated with a 30-day high-fat diet (HFD) as a model of dysbiosis to induce SIBO or were on a standard diet (SD). We observed that transplantation of fecal VLPs from donors on a HFD was sufficient to alter the ileal microbiota, but the effect was dependent on diet of the recipient. In recipients on a HFD, ileal bacterial density was reduced. In recipients on a SD, the ileal microbiome transitioned toward the composition associated with a HFD. In both recipient groups, transplantation of fecal VLP fraction alone produced the same outcome as whole FMT. Neither treatment altered expression of antimicrobial peptides. These findings demonstrated a potential role of VLPs, likely phages, for modifying the gut microbiome during dysbiosis.
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Affiliation(s)
- Derek M Lin
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, United States
| | - Britt Koskella
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States
| | - Nathaniel L Ritz
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, United States
| | - Dongdong Lin
- Mind Research Network, University of New Mexico, Albuquerque, NM, United States
| | | | - Henry C Lin
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, United States.,Division of Gastroenterology and Hepatology, The University of New Mexico, Albuquerque, NM, United States
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42
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García-López R, Pérez-Brocal V, Moya A. Beyond cells - The virome in the human holobiont. MICROBIAL CELL (GRAZ, AUSTRIA) 2019; 6:373-396. [PMID: 31528630 PMCID: PMC6717880 DOI: 10.15698/mic2019.09.689] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/14/2019] [Accepted: 04/03/2019] [Indexed: 01/01/2023]
Abstract
Viromics, or viral metagenomics, is a relatively new and burgeoning field of research that studies the complete collection of viruses forming part of the microbiota in any given niche. It has strong foundations rooted in over a century of discoveries in the field of virology and recent advances in molecular biology and sequencing technologies. Historically, most studies have deconstructed the concept of viruses into a simplified perception of viral agents as mere pathogens, which demerits the scope of large-scale viromic analyses. Viruses are, in fact, much more than regular parasites. They are by far the most dynamic and abundant entity and the greatest killers on the planet, as well as the most effective geo-transforming genetic engineers and resource recyclers, acting on all life strata in any habitat. Yet, most of this uncanny viral world remains vastly unexplored to date, greatly hindered by the bewildering complexity inherent to such studies and the methodological and conceptual limitations. Viromic studies are just starting to address some of these issues but they still lag behind microbial metagenomics. In recent years, however, higher-throughput analysis and resequencing have rekindled interest in a field that is just starting to show its true potential. In this review, we take a look at the scientific and technological developments that led to the advent of viral and bacterial metagenomics with a particular, but not exclusive, focus on human viromics from an ecological perspective. We also address some of the most relevant challenges that current viral studies face and ponder on the future directions of the field.
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Affiliation(s)
- Rodrigo García-López
- Institute of Evolutionary Systems Biology (I2Sysbio), Universitat de València and CSIC, València, Spain
- CIBER in Epidemiology and Public Health (CIBEResp), Madrid, Spain
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), València, Spain
| | - Vicente Pérez-Brocal
- Institute of Evolutionary Systems Biology (I2Sysbio), Universitat de València and CSIC, València, Spain
- CIBER in Epidemiology and Public Health (CIBEResp), Madrid, Spain
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), València, Spain
| | - Andrés Moya
- Institute of Evolutionary Systems Biology (I2Sysbio), Universitat de València and CSIC, València, Spain
- CIBER in Epidemiology and Public Health (CIBEResp), Madrid, Spain
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), València, Spain
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Mukhopadhya I, Segal JP, Carding SR, Hart AL, Hold GL. The gut virome: the 'missing link' between gut bacteria and host immunity? Therap Adv Gastroenterol 2019; 12:1756284819836620. [PMID: 30936943 PMCID: PMC6435874 DOI: 10.1177/1756284819836620] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 02/14/2019] [Indexed: 02/04/2023] Open
Abstract
The human gut virome includes a diverse collection of viruses that infect our own cells as well as other commensal organisms, directly impacting on our well-being. Despite its predominance, the virome remains one of the least understood components of the gut microbiota, with appropriate analysis toolkits still in development. Based on its interconnectivity with all living cells, it is clear that the virome cannot be studied in isolation. Here we review the current understanding of the human gut virome, specifically in relation to other constituents of the microbiome, its evolution and life-long association with its host, and our current understanding in the context of inflammatory bowel disease and associated therapies. We propose that the gut virome and the gut bacterial microbiome share similar trajectories and interact in both health and disease and that future microbiota studies should in parallel characterize the gut virome to uncover its role in health and disease.
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Affiliation(s)
- Indrani Mukhopadhya
- Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, UK Gut Health Group, The Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen, UK
| | - Jonathan P. Segal
- St. Mark’s Hospital, Watford Road, Harrow, UK Imperial College London, South Kensington Campus, Department of Surgery and Cancer, London, UK
| | - Simon R. Carding
- Gut Microbes and Health Research Programme, The Quadram Institute, Norwich Research Park, Norwich, Norfolk, UK Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Ailsa L. Hart
- St. Mark’s Hospital, Watford Road, Harrow, UK Imperial College London, South Kensington Campus, Department of Surgery and Cancer, London, UK
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Rowan-Nash AD, Korry BJ, Mylonakis E, Belenky P. Cross-Domain and Viral Interactions in the Microbiome. Microbiol Mol Biol Rev 2019; 83:e00044-18. [PMID: 30626617 PMCID: PMC6383444 DOI: 10.1128/mmbr.00044-18] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The importance of the microbiome to human health is increasingly recognized and has become a major focus of recent research. However, much of the work has focused on a few aspects, particularly the bacterial component of the microbiome, most frequently in the gastrointestinal tract. Yet humans and other animals can be colonized by a wide array of organisms spanning all domains of life, including bacteria and archaea, unicellular eukaryotes such as fungi, multicellular eukaryotes such as helminths, and viruses. As they share the same host niches, they can compete with, synergize with, and antagonize each other, with potential impacts on their host. Here, we discuss these major groups making up the human microbiome, with a focus on how they interact with each other and their multicellular host.
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Affiliation(s)
- Aislinn D Rowan-Nash
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA
| | - Benjamin J Korry
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA
| | - Eleftherios Mylonakis
- Infectious Diseases Division, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA
| | - Peter Belenky
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA
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Yao Y, Jin Z, Lee JH. An improved statistical model for taxonomic assignment of metagenomics. BMC Genet 2018; 19:98. [PMID: 30373533 PMCID: PMC6206629 DOI: 10.1186/s12863-018-0680-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 10/02/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND With the advances in the next-generation sequencing technologies, researchers can now rapidly examine the composition of samples from humans and their surroundings. To enhance the accuracy of taxonomy assignments in metagenomic samples, we developed a method that allows multiple mismatch probabilities from different genomes. RESULTS We extended the algorithm of taxonomic assignment of metagenomic sequence reads (TAMER) by developing an improved method that can set a different mismatch probability for each genome rather than imposing a single parameter for all genomes, thereby obtaining a greater degree of accuracy. This method, which we call TADIP (Taxonomic Assignment of metagenomics based on DIfferent Probabilities), was comprehensively tested in simulated and real datasets. The results support that TADIP improved the performance of TAMER especially in large sample size datasets with high complexity. CONCLUSIONS TADIP was developed as a statistical model to improve the estimate accuracy of taxonomy assignments. Based on its varying mismatch probability setting and correlated variance matrix setting, its performance was enhanced for high complexity samples when compared with TAMER.
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Affiliation(s)
- Yujing Yao
- Department of Biostatistics, Columbia University, New York, NY, USA
| | - Zhezhen Jin
- Department of Biostatistics, Columbia University, New York, NY, USA
| | - Joseph H Lee
- Sergievsky Center, Taub Institute, and Departments of Epidemiology and Neurology, Columbia University, New York, NY, USA. .,Sergievsky Center, Columbia University, 630 West 168th Street, P&S Unit 16, New York, NY, 10032, USA.
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Microbiota and Phage Therapy: Future Challenges in Medicine. Med Sci (Basel) 2018; 6:medsci6040086. [PMID: 30301167 PMCID: PMC6313512 DOI: 10.3390/medsci6040086] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/01/2018] [Accepted: 10/01/2018] [Indexed: 12/26/2022] Open
Abstract
An imbalance of bacterial quantity and quality of gut microbiota has been linked to several pathologies. New strategies of microbiota manipulation have been developed such as fecal microbiota transplantation (FMT); the use of pre/probiotics; an appropriate diet; and phage therapy. The presence of bacteriophages has been largely underestimated and their presence is a relevant component for the microbiome equilibrium. As a promising treatment, phage therapy has been extensively used in Eastern Europe to reduce pathogenic bacteria and has arisen as a new method to modulate microbiota diversity. Phages have been selected and “trained” to infect a wide spectrum of bacteria or tailored to infect specific antibiotic resistant bacteria present in patients. The new development of genetically modified phages may be an efficient tool to treat the gut microbiota dysbiosis associated with different pathologies and increased production of bacterial metabolites and subsequently decrease systemic low-grade chronic inflammation associated with chronic diseases. Microbiota quality and mitochondria dynamics can be remodulated and manipulated by phages to restore the equilibrium and homeostasis of the system. Our aim is to highlight the great interest for phages not only to eliminate and control pathogenic bacterial infection but also in the near future to modulate the microbiota by adding new functions to selected bacteria species and rebalance the dynamic among phages and bacteria. The challenge for the medicine of tomorrow is to re-think and redesign strategies differently and far from our traditional thinking.
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Zuo T, Ng SC. The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Front Microbiol 2018; 9:2247. [PMID: 30319571 PMCID: PMC6167487 DOI: 10.3389/fmicb.2018.02247] [Citation(s) in RCA: 396] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022] Open
Abstract
In the twenty first century, the changing epidemiology of inflammatory bowel disease (IBD) globally with increasing disease incidence across many countries relates to the altered gut microbiota, due to a combinatorial effect of environmental factors, human immune responses and genetics. IBD is a gastrointestinal disease associated with a gut microbial dysbiosis, including an expansion of facultative anaerobic bacteria of the family Enterobacteriaceae. Advances in high-throughput sequencing enable us to entangle the gut microbiota in human health and IBD beyond the gut bacterial microbiota, expanding insights into the mycobiota, virobiota and helminthes. Caudovirales (viruses) and Basidiomycota, Ascomycota, and Candida albicans (fungi) are revealed to be increased in IBD. The deconvolution of the gut microbiota in IBD lays the basis for unveiling the roles of these various gut microbiota components in IBD pathogenesis and being conductive to instructing on future IBD diagnosis and therapeutics. Here we comprehensively elucidate the alterations in the gut microbiota in IBD, discuss the effect of diets in the gut microbiota in relation to IBD, and illustrate the potential of manipulation of gut microbiota for IBD therapeutics. The therapeutic strategy of antibiotics, prebiotics, probiotics and fecal microbiota transplantation will benefit the effective application of precision microbiome manipulation in IBD.
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Affiliation(s)
- Tao Zuo
- Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
- Faculty of Medicine, Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China
| | - Siew C. Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
- Faculty of Medicine, Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China
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48
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Gregory AC, Sullivan MB, Segal LN, Keller BC. Smoking is associated with quantifiable differences in the human lung DNA virome and metabolome. Respir Res 2018; 19:174. [PMID: 30208886 PMCID: PMC6136173 DOI: 10.1186/s12931-018-0878-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 09/03/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The role of commensal viruses in humans is poorly understood, and the impact of the virome on lung health and smoking-related disease is particularly understudied. METHODS Genetic material from acellular bronchoalveolar lavage fluid was sequenced to identify and quantify viral members of the lower respiratory tract which were compared against concurrent bronchoalveolar lavage bacterial, metabolite, cytokine and cellular profiles, and clinical data. Twenty smoker and 10 nonsmoker participants with no significant comorbidities were studied. RESULTS Viruses that infect bacteria (phages) represented the vast majority of viruses in the lung. Though bacterial communities were statistically indistinguishable across smokers and nonsmokers as observed in previous studies, lung viromes and metabolic profiles were significantly different between groups. Statistical analyses revealed that changes in viral communities correlate most with changes in levels of arachidonic acid and IL-8, both potentially relevant for chronic obstructive pulmonary disease (COPD) pathogenesis based on prior studies. CONCLUSIONS Our assessment of human lung DNA viral communities reveals that commensal viruses are present in the lower respiratory tract and differ between smokers and nonsmokers. The associations between viral populations and local immune and metabolic tone suggest a significant role for virome-host interaction in smoking related lung disease.
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Affiliation(s)
- Ann C. Gregory
- Department of Microbiology, The Ohio State University, Columbus, OH 43210 USA
| | - Matthew B. Sullivan
- Department of Microbiology, The Ohio State University, Columbus, OH 43210 USA
- Department of Civil, Environmental and Geodetic Engineering, The Ohio State University, Columbus, OH 43210 USA
| | - Leopoldo N. Segal
- Division of Pulmonary, Critical Care & Sleep Medicine, New York University School of Medicine, New York, NY 10016 USA
| | - Brian C. Keller
- Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, 201 Davis Heart & Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210 USA
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Garcia-Nuñez M, Gallego M, Monton C, Capilla S, Millares L, Pomares X, Espasa M, Ferrari R, Moya A, Monsó E, Perez-Brocal V. The Respiratory Virome in Chronic Obstructive Pulmonary Disease. Future Virol 2018; 13:457-466. [DOI: 10.2217/fvl-2018-0027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/19/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Marian Garcia-Nuñez
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
- Centro de Investigación en Red de Enfermedades Respiratorias CIBERES
Bunyola
Spain
- Fundació Insitut d’Investigació GermansTrias i Pujol
Badalona
Spain
| | - Miguel Gallego
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
- Centro de Investigación en Red de Enfermedades Respiratorias CIBERES
Bunyola
Spain
| | - Concepción Monton
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
| | - Silvia Capilla
- Department of Microbiology Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
| | - Laura Millares
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
- Centro de Investigación en Red de Enfermedades Respiratorias CIBERES
Bunyola
Spain
- Fundació Insitut d’Investigació GermansTrias i Pujol
Badalona
Spain
| | - Xavier Pomares
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
- Centro de Investigación en Red de Enfermedades Respiratorias CIBERES
Bunyola
Spain
| | - Mateu Espasa
- Department of Microbiology Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
| | - Rafaella Ferrari
- Genomics & Health Area Centro Superior de Investigación en Salud Pública – Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (CSISP-FISABIO)
Valencia
Spain
| | - Andres Moya
- Genomics & Health Area Centro Superior de Investigación en Salud Pública – Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (CSISP-FISABIO)
Valencia
Spain
- Department of Genetics Institut Cavanilles de Biodiversitat i Biologia Evolutiva (ICBiBE) Universitat de València
València
Spain
- CIBER Epidemiología y Salud Pública (CIBERESP)
Barcelona
Spain
| | - Eduard Monsó
- Department of Respiratory Medicine Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autonoma de Barcelona
Sabadell
Spain
- Centro de Investigación en Red de Enfermedades Respiratorias CIBERES
Bunyola
Spain
| | - Vicente Perez-Brocal
- Genomics & Health Area Centro Superior de Investigación en Salud Pública – Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (CSISP-FISABIO)
Valencia
Spain
- Department of Genetics Institut Cavanilles de Biodiversitat i Biologia Evolutiva (ICBiBE) Universitat de València
València
Spain
- CIBER Epidemiología y Salud Pública (CIBERESP)
Barcelona
Spain
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Abstract
In the 21st century, urbanization represents a major demographic shift in developed and developing countries. Rapid urbanization in the developing world has been associated with an increasing incidence of several autoimmune diseases, including IBD. Patients with IBD exhibit a decrease in the diversity and richness of the gut microbiota, while urbanization attenuates the gut microbial diversity and might have a role in the pathogenesis of IBD. Environmental exposures during urbanization, including Westernization of diet, increased antibiotic use, pollution, improved hygiene status and early-life microbial exposure, have been shown to affect the gut microbiota. The disparate patterns of the gut microbiota composition in rural and urban areas offer an opportunity to understand the contribution of a 'rural microbiome' in potentially protecting against the development of IBD. This Perspective discusses the effect of urbanization and its surrogates on the gut microbiome (bacteriome, virome, mycobiome and helminths) in both human health and IBD and how such changes might be associated with the development of IBD.
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