|
1
|
Caruso R, Lo BC, Chen GY, Núñez G. Host-pathobiont interactions in Crohn's disease. Nat Rev Gastroenterol Hepatol 2024:10.1038/s41575-024-00997-y. [PMID: 39448837 DOI: 10.1038/s41575-024-00997-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/26/2024]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.
Collapse
Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Grace Y Chen
- Department of Internal Medicine and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
2
|
Ahn EH, Liu X, Alam AM, Kang SS, Ye K. Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson's disease. Mol Psychiatry 2023; 28:1337-1350. [PMID: 36543925 DOI: 10.1038/s41380-022-01910-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 11/30/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
Gut dysbiosis contributes to Parkinson's disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.
Collapse
Affiliation(s)
- Eun Hee Ahn
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Department of Physiology, College of Medicine, Hallym University, Hallymdaehak-gil, Chuncheon-si, Gangwon-Do, 24252, South Korea
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ashfaqul M Alam
- Microbiology, Immunology & Molecular Genetics, University of Kentucky, Office - MN 376, Medical Science Building, 800 Rose Street, Lexington, KY, USA
| | - Seong Su Kang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. .,Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, Guangdong, China.
| |
Collapse
|
|
3
|
Tanaka R, Imai J, Tsugawa H, Eap KB, Yazawa M, Kaneko M, Ohno M, Sugihara K, Kitamoto S, Nagao-Kitamoto H, Barnich N, Matsushima M, Suzuki T, Kagawa T, Nishizaki Y, Suzuki H, Kamada N, Hozumi K. Adherent-invasive E. coli - induced specific IgA limits pathobiont localization to the epithelial niche in the gut. Front Microbiol 2023; 14:1031997. [PMID: 36910191 PMCID: PMC9995611 DOI: 10.3389/fmicb.2023.1031997] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Background and aim Adherent-invasive E. coli (AIEC) has been identified as a pathobiont associated with Crohn's disease (CD), that prefers to grow in inflammatory conditions. Although the colonization by AIEC is implicated in the progression of the disease and exacerbates inflammation in murine colitis models, the recognition and response of host immunity to AIEC remains elusive. Methods Antibiotic treated female C57BL/6 mice were inoculated by commensal E. coli and LF82 AIEC strains. Luminal-IgA fractions were prepared from feces and their binding to AIEC and other strains was assessed to confirm specificity. IgA binding to isogenic mutant strains was performed to identify the functional molecules that are recognized by AIEC specific IgA. The effect of IgA on epithelial invasion of LF82 strain was confirmed using in vitro invasion assay and in vivo colonization of the colonic epithelium. Results Persistent colonization by AIEC LF82 induced secretion of luminal IgA, while commensal E. coli strain did not. Induced anti-LF82 IgA showed specific binding to other AIEC strains but not to the commensal, non-AIEC E. coli strains. Induced IgA showed decreased binding to LF82 strains with mutated adhesin and outer membrane proteins which are involved in AIEC - epithelial cell interaction. Consistently, LF82-specific IgA limited the adhesion and invasion of LF82 in cultured epithelial cells, which seems to be required for the elimination in the colonic epithelium in mice. Conclusion These results demonstrate that host immunity selectively recognizes pathobiont E. coli, such as AIEC, and develop specific IgA. The induced IgA specific to pathobiont E. coli, in turn, contributes to preventing the pathobionts from accessing the epithelium.
Collapse
Affiliation(s)
- Rika Tanaka
- Department of Immunology, Tokai University School of Medicine, Isehara, Japan
| | - Jin Imai
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.,Department of Clinical Health Science, Tokai University School of Medicine, Isehara, Japan
| | - Hitoshi Tsugawa
- Transkingdom Signaling Research Unit, Division of Host Defense, Tokai University School of Medicine, Isehara, Japan
| | - Karl Bil Eap
- Department of Immunology, Tokai University School of Medicine, Isehara, Japan
| | - Masaki Yazawa
- Department of Immunology, Tokai University School of Medicine, Isehara, Japan
| | - Motoki Kaneko
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masashi Ohno
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Kohei Sugihara
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Sho Kitamoto
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.,WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Hiroko Nagao-Kitamoto
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.,WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Nicolas Barnich
- UMR1071 Inserm/University Clermont Auvergne, INRAE USC2018, M2iSH, CRNH Auvergne, Clermont-Ferrand, France
| | - Masashi Matsushima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Yasuhiro Nishizaki
- Department of Clinical Health Science, Tokai University School of Medicine, Isehara, Japan
| | - Hidekazu Suzuki
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.,WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Katsuto Hozumi
- Department of Immunology, Tokai University School of Medicine, Isehara, Japan
| |
Collapse
|
|
4
|
Akuzum B, Lee JY. Context-Dependent Regulation of Type17 Immunity by Microbiota at the Intestinal Barrier. Immune Netw 2022; 22:e46. [PMID: 36627936 PMCID: PMC9807962 DOI: 10.4110/in.2022.22.e46] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 07/26/2022] [Accepted: 08/01/2022] [Indexed: 12/30/2022] Open
Abstract
T-helper-17 (Th17) cells and related IL-17-producing (type17) lymphocytes are abundant at the epithelial barrier. In response to bacterial and fungal infection, the signature cytokines IL-17A/F and IL-22 mediate the antimicrobial immune response and contribute to wound healing of injured tissues. Despite their protective function, type17 lymphocytes are also responsible for various chronic inflammatory disorders, including inflammatory bowel disease (IBD) and colitis associated cancer (CAC). A deeper understanding of type17 regulatory mechanisms could ultimately lead to the discovery of therapeutic strategies for the treatment of chronic inflammatory disorders and the prevention of cancer. In this review, we discuss the current understanding of the development and function of type17 immune cells at the intestinal barrier, focusing on the impact of microbiota-immune interactions on intestinal barrier homeostasis and disease etiology.
Collapse
Affiliation(s)
- Begum Akuzum
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
| | - June-Yong Lee
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
| |
Collapse
|
|
5
|
Harada Y, Miyamoto K, Chida A, Okuzawa AT, Yoshimatsu Y, Kudo Y, Sujino T. Localization and movement of Tregs in gastrointestinal tract: a systematic review. Inflamm Regen 2022; 42:47. [PMID: 36329556 PMCID: PMC9632047 DOI: 10.1186/s41232-022-00232-8] [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: 08/04/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The intestine is rich in food-derived and microbe-derived antigens. Regulatory T cells (Tregs) are an essential T-cell population that prevents systemic autoimmune diseases and inhibits inflammation by encountering antigens. Previously, it was reported that the functional loss of Tregs induces systemic inflammation, including inflammatory bowel disease and graft-versus-host disease in human and murine models. However, there is a dearth of information about how Tregs localize in different tissues and suppress effector cells. MAIN BODY The development of Tregs and their molecular mechanism in the digestive tract have been elucidated earlier using murine genetic models, infectious models, and human samples. Tregs suppress immune and other nonimmune cells through direct effect and cytokine production. The recent development of in vivo imaging technology allows us to visualize how Tregs localize and move in the settings of inflammation and homeostasis. This is important because, according to a recent report, Treg characterization and function are regulated by their location. Tregs located in the proximal intestine and its draining lymph nodes induce tolerance against food antigens, and those located in the distal intestine suppress the inflammation induced by microbial antigens. Taken together, various Tregs are induced in a location-specific manner in the gastrointestinal tract and influence the homeostasis of the gut. CONCLUSION In this review, we summarize how Tregs are induced in the digestive tract and the application of in vivo Treg imaging to elucidate immune homeostasis in the digestive tract.
Collapse
Affiliation(s)
- Yosuke Harada
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Kentaro Miyamoto
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan.,Miyarisan Pharm. Co. Ltd, Tokyo, Japan
| | - Akihiko Chida
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Anna Tojo Okuzawa
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Yusuke Yoshimatsu
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Yumi Kudo
- Department of Pediatric Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tomohisa Sujino
- Center for the Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan.
| |
Collapse
|
|
6
|
Khan R, Shah MD, Shah L, Lee PC, Khan I. Bacterial polysaccharides-A big source for prebiotics and therapeutics. Front Nutr 2022; 9:1031935. [PMID: 36407542 PMCID: PMC9671505 DOI: 10.3389/fnut.2022.1031935] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/11/2022] [Indexed: 07/29/2023] Open
Abstract
Bacterial polysaccharides are unique due to their higher purity, hydrophilic nature, and a finer three-dimensional fibrous structure. Primarily, these polymers provide protection, support, and energy to the microorganism, however, more recently several auxiliary properties of these biopolymers have been unmasked. Microbial polysaccharides have shown therapeutic abilities against various illnesses, augmented the healing abilities of the herbal and Western medicines, improved overall health of the host, and have exerted positive impact on the growth of gut dwelling beneficial bacteria. Specifically, the review is discussing the mechanism through which bacterial polysaccharides exert anti-inflammatory, antioxidant, anti-cancer, and anti-microbial properties. In addition, they are holding promising application in the 3D printing. The review is also discussing a perspective about the metagenome-based screening of polysaccharides, their integration with other cutting-edge tools, and synthetic microbiome base intervention of polysaccharides as a strategy for prebiotic intervention. This review has collected interesting information about the bacterial polysaccharides from Google Scholar, PubMed, Scopus, and Web of Science databases. Up to our knowledge, this is the first of its kind review article that is summarizing therapeutic, prebiotics, and commercial application of bacterial polysaccharides.
Collapse
Affiliation(s)
- Raees Khan
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Muhammad Dawood Shah
- Borneo Marine Research Institute, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
| | - Luqman Shah
- Department of Biochemistry, Faculty of Biological and Health Sciences, Hazara University, Mansehra, Pakistan
| | - Ping-Chin Lee
- Biotechnology Research Institute, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
- Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
| | - Imran Khan
- Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University Mardan, Mardan, Pakistan
| |
Collapse
|
|
7
|
Fraschilla I, Amatullah H, Rahman RU, Jeffrey KL. Immune chromatin reader SP140 regulates microbiota and risk for inflammatory bowel disease. Cell Host Microbe 2022; 30:1370-1381.e5. [PMID: 36130593 PMCID: PMC10266544 DOI: 10.1016/j.chom.2022.08.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/30/2022] [Accepted: 08/30/2022] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Speckled Protein 140 (SP140) is an immune-restricted chromatin "reader" that is associated with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the disease-causing mechanisms of SP140 remain undefined. Here, we identify an immune-intrinsic role for SP140 in regulating phagocytic defense responses to prevent the expansion of inflammatory bacteria. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis that was transmissible upon cohousing and ameliorated with antibiotics. Loss of SP140 results in blooms of Proteobacteria, including Helicobacter in Sp140-/- mice and Enterobacteriaceae in humans bearing the CD-associated SP140 loss-of-function variant. Phagocytes from patients with the SP140 loss-of-function variant and Sp140-/- mice exhibited altered antimicrobial defense programs required for control of pathobionts. Thus, mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by microbiota.
Collapse
Affiliation(s)
- Isabella Fraschilla
- Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Hajera Amatullah
- Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Raza-Ur Rahman
- Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Kate L Jeffrey
- Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Massachusetts Institute of Technology Center for Microbiome, Informatics and Therapeutics, Cambridge, MA 02139, USA.
| |
Collapse
|
|
8
|
Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis. mBio 2022; 13:e0190422. [PMID: 35900107 PMCID: PMC9426610 DOI: 10.1128/mbio.01904-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10-/- mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germfree animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients. IMPORTANCE Patients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germfree mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile.
Collapse
|
|
9
|
Fecal Microbiota Transplants for Inflammatory Bowel Disease Treatment: Synthetic- and Engineered Communities-Based Microbiota Transplants Are the Future. Gastroenterol Res Pract 2022; 2022:9999925. [PMID: 35140783 PMCID: PMC8820897 DOI: 10.1155/2022/9999925] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 01/12/2022] [Indexed: 12/21/2022] Open
Abstract
The human intestine harbors a huge number of diverse microorganisms where a variety of complex interactions take place between the microbes as well as the host and gut microbiota. Significant long-term variations in the gut microbiota (dysbiosis) have been associated with a variety of health conditions including inflammatory bowel disease (IBD). Conventional fecal microbiota transplantations (FMTs) have been utilized to treat IBD and have been proved promising. However, various limitations such as transient results, pathogen transfer, storage, and reproducibility render conventional FMT less safe and less sustainable. Defined synthetic microbial communities (SynCom) have been used to dissect the host-microbiota-associated functions using gnotobiotic animals or in vitro cell models. This review focuses on the potential use of SynCom in IBD and its advantages and relative safety over conventional FMT. Additionally, this review reinforces how various technological advances could be combined with SynCom to have a better understanding of the complex microbial interactions in various gut inflammatory diseases including IBD. Some technological advances including the availability of a gut-on-a-chip system, intestinal organoids, ex vivo intestinal cultures, AI-based refining of the microbiome structural and functional data, and multiomic approaches may help in making more practical in vitro models of the human host. Additionally, an increase in the cultured diversity from gut microbiota and the availability of their genomic information would further make the design and utilization of SynCom more feasible. Taken together, the combined use of the available knowledge of the gut microbiota in health and disease and recent technological advances and the development of defined SynCom seem to be a promising, safe, and sustainable alternative to conventional FMT in treating IBD.
Collapse
|
|
10
|
Chandra H, Sharma KK, Tuovinen OH, Sun X, Shukla P. Pathobionts: mechanisms of survival, expansion, and interaction with host with a focus on Clostridioides difficile. Gut Microbes 2022; 13:1979882. [PMID: 34724858 PMCID: PMC8565823 DOI: 10.1080/19490976.2021.1979882] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [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
Pathobionts are opportunistic microbes that emerge as a result of perturbations in the healthy microbiome due to complex interactions of various genetic, exposomal, microbial, and host factors that lead to their selection and expansion. Their proliferations can aggravate inflammatory manifestations, trigger autoimmune diseases, and lead to severe life-threatening conditions. Current surge in microbiome research is unwinding these complex interplays between disease development and protection against pathobionts. This review summarizes the current knowledge of pathobiont emergence with a focus on Clostridioides difficile and the recent findings on the roles of immune cells such as iTreg cells, Th17 cells, innate lymphoid cells, and cytokines in protection against pathobionts. The review calls for adoption of innovative tools and cutting-edge technologies in clinical diagnostics and therapeutics to provide insights in identification and quantification of pathobionts.
Collapse
Affiliation(s)
- Harish Chandra
- Department of Environmental Microbiology, School of Earth and Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India,Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Krishna Kant Sharma
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Olli H. Tuovinen
- Department of Microbiology, Ohio State University, Columbus, OH, USA
| | - Xingmin Sun
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA,Xingmin Sun Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Pratyoosh Shukla
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India,Enzyme Technology and Protein Bioinformatics Laboratory, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India,CONTACT Pratyoosh Shukla School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| |
Collapse
|
|
11
|
Friedrich V, Forné I, Matzek D, Ring D, Popper B, Jochum L, Spriewald S, Straub T, Imhof A, Krug A, Stecher B, Brocker T. Helicobacter hepaticus is required for immune targeting of bacterial heat shock protein 60 and fatal colitis in mice. Gut Microbes 2022; 13:1-20. [PMID: 33550886 PMCID: PMC7889221 DOI: 10.1080/19490976.2021.1882928] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Gut microbiota and the immune system are in constant exchange shaping both host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40-CD40L axis showed promising results as these molecules are deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals with a constitutive CD40-signal in CD11c+ cells, causing a lack of intestinal CD103+ dendritic cells (DCs) and failure to induce regulatory T (iTreg) cells. These mice rapidly develop spontaneous fatal colitis, accompanied by dysbiosis and increased inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ + Th1 cells. In the present study, we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria, and by proteome analysis, we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in the absence of iTregs. When re-derived to a different Hh-free specific-pathogen-free (SPF) microbiota, mice showed few signs of disease, normal microbiota, and no fatality. Upon recolonization of mice with Hh, the disease developed rapidly. Thus, the present work identifies GroEL/Hsp60 as a major Hh-antigen and its role in disease onset, progression, and outcome in this colitis model. Our results highlight the importance of CD103+ DC- and iTreg-mediated immune tolerance to specific pathobionts to maintain healthy intestinal balance.
Collapse
Affiliation(s)
- Verena Friedrich
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Ignasi Forné
- Protein Analysis Unit, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Dana Matzek
- Core Facility Animal Models, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Diana Ring
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Bastian Popper
- Core Facility Animal Models, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Lara Jochum
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Stefanie Spriewald
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Tobias Straub
- Core Facility Bioinformatics, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Axel Imhof
- Protein Analysis Unit, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Anne Krug
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany,German Center for Infection Research (DZIF), Partner Site, Munich, Germany
| | - Thomas Brocker
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany,CONTACT Thomas Brocker Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich82152, Germany
| |
Collapse
|
|
12
|
Jeffery R, Ilott NE, Powrie F. Genetic and environmental factors shape the host response to Helicobacter hepaticus: insights into IBD pathogenesis. Curr Opin Microbiol 2021; 65:145-155. [PMID: 34883389 DOI: 10.1016/j.mib.2021.10.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 11/03/2022]
Abstract
Pathobionts are members of the gut microbiota with the capacity to cause disease when there is malfunctioning intestinal homeostasis. These organisms are thought to be major contributors to the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders driven by dysregulated responses towards the microbiota. Over two decades have passed since the discovery of Helicobacter hepaticus, a mouse pathobiont which causes colitis in the context of immune deficiency. During this time, we have developed a detailed understanding of the cellular players and cytokine networks which drive H. hepaticus immunopathology. However, we are just beginning to understand the microbial factors that enable H. hepaticus to interact with the host and influence colonic health and disease. Here we review key H. hepaticus-host interactions, their relevance to other exemplar pathobionts and how when maladapted they drive colitis. Further understanding of these pathways may offer new therapeutic approaches for IBD.
Collapse
Affiliation(s)
- Rebecca Jeffery
- Kennedy Institute of Rheumatology, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom
| | - Nicholas E Ilott
- Kennedy Institute of Rheumatology, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.
| |
Collapse
|
|
13
|
Jergens AE, Parvinroo S, Kopper J, Wannemuehler MJ. Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease. Front Med (Lausanne) 2021; 8:669913. [PMID: 34513862 PMCID: PMC8432614 DOI: 10.3389/fmed.2021.669913] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex, multifactorial disorders that lead to chronic and relapsing intestinal inflammation. The exact etiology remains unknown, however multiple factors including the environment, genetic, dietary, mucosal immunity, and altered microbiome structure and function play important roles in disease onset and progression. Supporting this notion that the gut microbiota plays a pivotal role in IBD pathogenesis, studies in gnotobiotic mice have shown that mouse models of intestinal inflammation require a microbial community to develop colitis. Additionally, antimicrobial therapy in some IBD patients will temporarily induce remission further demonstrating an association between gut microbes and intestinal inflammation. Finally, a dysfunctional intestinal epithelial barrier is also recognized as a key pathogenic factor in IBD. The intestinal epithelium serves as a barrier between the luminal environment and the mucosal immune system and guards against harmful molecules and microorganisms while being permeable to essential nutrients and solutes. Beneficial (i.e., mutualists) bacteria promote mucosal health by strengthening barrier integrity, increasing local defenses (mucin and IgA production) and inhibiting pro-inflammatory immune responses and apoptosis to promote mucosal homeostasis. In contrast, pathogenic bacteria and pathobionts suppress expression and localization of tight junction proteins, cause dysregulation of apoptosis/proliferation and increase pro-inflammatory signaling that directly damages the intestinal mucosa. This review article will focus on the role of intestinal epithelial cells (IECs) and the luminal environment acting as mediators of barrier function in IBD. We will also share some of our translational observations of interactions between IECs, immune cells, and environmental factors contributing to maintenance of mucosal homeostasis, as it relates to GI inflammation and IBD in different animal models.
Collapse
Affiliation(s)
- Albert E. Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Shadi Parvinroo
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Jamie Kopper
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Michael J. Wannemuehler
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| |
Collapse
|
|
14
|
Saha P, Golonka RM, Abokor AA, Yeoh BS, Vijay-Kumar M. IL-10 Receptor Neutralization-Induced Colitis in Mice: A Comprehensive Guide. Curr Protoc 2021; 1:e227. [PMID: 34399038 DOI: 10.1002/cpz1.227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Interleukin-10 (IL-10) and its receptor (IL-10R) have been foremost targets to understand inflammatory bowel disease (IBD) pathogenesis. For the past several decades, IL-10-deficient (Il10-/- ) mice were considered one of the best models to study immune-mediated colitis. Several physiologic limitations with this model, e.g., delayed and varied disease onset, have hindered investigators in testing new clinical therapies for IBD. In this article, we provide comprehensive guidance for using anti-IL-10R monoclonal antibody (αIL-10R mAb) neutralization as a superior alternative model to study IBD. This article describes the feasibility of using αIL-10R mAb to induce chronic colitis (within 4 weeks), perform time-dependent mechanistic studies, and assess the efficacy of IBD therapeutics. This article also delineates protocols for in-house assays to critically assess colitis and associated inflammatory parameters. Overall, we underscore αIL-10R mAb neutralization as a relevant immune-mediated murine colitis model to study human Crohn's disease. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Induction of chronic colitis in mice via αIL-10R mAb neutralization Basic Protocol 2: Biochemical evaluation of αIL-10R mAb neutralization-induced chronic colitis Support Protocol 1: Stool analysis and scoring Support Protocol 2: Swiss roll method.
Collapse
Affiliation(s)
- Piu Saha
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Rachel M Golonka
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Ahmed A Abokor
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Beng San Yeoh
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Matam Vijay-Kumar
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| |
Collapse
|
|
15
|
Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
Collapse
Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
| |
Collapse
|
|
16
|
Zeng XY, Li M. Looking into key bacterial proteins involved in gut dysbiosis. World J Methodol 2021; 11:130-143. [PMID: 34322365 PMCID: PMC8299906 DOI: 10.5662/wjm.v11.i4.130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal microbiota plays a pivotal role in health and has been linked to many diseases. With the rapid accumulation of pyrosequencing data of the bacterial composition, the causal-effect relationship between specific dysbiosis features and diseases is now being explored. The aim of this review is to describe the key functional bacterial proteins and antigens in the context of dysbiosis related-diseases. We subjectively classify the key functional proteins into two categories: Primary key proteins and secondary key proteins. The primary key proteins mainly act by themselves and include biofilm inhibitors, toxin degraders, oncogene degraders, adipose metabolism modulators, anti-inflammatory peptides, bacteriocins, host cell regulators, adhesion and invasion molecules, and intestinal barrier regulators. The secondary key proteins mainly act by eliciting host immune responses and include flagellin, outer membrane proteins, and other autoantibody-related antigens. Knowledge of key bacterial proteins is limited compared to the rich microbiome data. Understanding and focusing on these key proteins will pave the way for future mechanistic level cause-effect studies of gut dysbiosis and diseases.
Collapse
Affiliation(s)
- Xin-Yu Zeng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Ming Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumors, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| |
Collapse
|
|
17
|
Ochoa S, Collado L. Enterohepatic Helicobacter species - clinical importance, host range, and zoonotic potential. Crit Rev Microbiol 2021; 47:728-761. [PMID: 34153195 DOI: 10.1080/1040841x.2021.1924117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The genus Helicobacter defined just over 30 years ago, is a highly diverse and fast-growing group of bacteria that are able to persistently colonize a wide range of animals. The members of this genus are subdivided into two groups with different ecological niches, associated pathologies, and phylogenetic relationships: the gastric Helicobacter (GH) and the enterohepatic Helicobacter (EHH) species. Although GH have been mostly studied, EHH species have become increasingly important as emerging human pathogens and potential zoonotic agents in the last years. This group of bacteria has been associated with the development of several diseases in humans from acute pathologies like gastroenteritis to chronic pathologies that include inflammatory bowel disease, and liver and gallbladder diseases. However, their reservoirs, as well as their routes of transmission, have not been well established yet. Therefore, this review summarizes the current knowledge of taxonomy, epidemiology, and clinical role of the EHH group.
Collapse
Affiliation(s)
- Sofia Ochoa
- Faculty of Sciences, Institute of Biochemistry and Microbiology, Universidad Austral de Chile, Valdivia, Chile.,ANID - Millennium Science Initiative Program - Millennium Nucleus in the Biology of the Intestinal Microbiota, Santiago, Chile
| | - Luis Collado
- Faculty of Sciences, Institute of Biochemistry and Microbiology, Universidad Austral de Chile, Valdivia, Chile.,ANID - Millennium Science Initiative Program - Millennium Nucleus in the Biology of the Intestinal Microbiota, Santiago, Chile
| |
Collapse
|
|
18
|
Intestinal Inflammation and Altered Gut Microbiota Associated with Inflammatory Bowel Disease Render Mice Susceptible to Clostridioides difficile Colonization and Infection. mBio 2021; 12:e0273320. [PMID: 34126769 PMCID: PMC8262858 DOI: 10.1128/mbio.02733-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Clostridioides difficile is a noteworthy pathogen in patients with inflammatory bowel disease (IBD). Patients with IBD who develop concurrent C. difficile infection (CDI) experience increased morbidity and mortality. IBD is associated with intestinal inflammation and alterations of the gut microbiota, both of which can diminish colonization resistance to C. difficile. Here, we describe the development of a mouse model to explore the role that IBD-induced changes of the gut microbiome play in susceptibility to C. difficile. Helicobacter hepaticus, a normal member of the mouse gut microbiota, triggers pathological inflammation in the distal intestine akin to human IBD in mice that lack intact interleukin 10 (IL-10) signaling. We demonstrate that mice with H. hepaticus-induced IBD were susceptible to C. difficile colonization in the absence of other perturbations, such as antibiotic treatment. Concomitant IBD and CDI were associated with significantly worse disease than observed in animals with colitis alone. Development of IBD resulted in a distinct intestinal microbiota community compared to that of non-IBD controls. Inflammation played a critical role in the susceptibility of animals with IBD to C. difficile colonization, as mice colonized with an isogenic mutant of H. hepaticus that triggers an attenuated intestinal inflammation maintained full colonization resistance. These studies with a novel mouse model of IBD and CDI emphasize the importance of host responses and alterations of the gut microbiota in susceptibility to C. difficile colonization and infection in the setting of IBD.
Collapse
|
|
19
|
Xu Z, Liu W, Zhang Y, Zhang D, Qiu B, Wang X, Liu J, Liu L. Therapeutic and Prebiotic Effects of Five Different Native Starches on Dextran Sulfate Sodium-Induced Mice Model of Colonic Colitis. Mol Nutr Food Res 2021; 65:e2000922. [PMID: 33629501 DOI: 10.1002/mnfr.202000922] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/14/2021] [Indexed: 12/12/2022]
Abstract
SCOPE The availability of studies related to the effects of natural macronutrients on inflammatory bowel disease (IBD) remain relatively limited. This study investigates whether and to what extent the consumption of five different native starches alleviate the clinical symptoms and dysbiosis of gut microbiota associated with colitis. METHODS AND RESULTS Using dextran sodium sulfate (DSS)-induced mouse model of colitis, the potential effects of native potato starch (PS), pea starch (PEAS), corn starch (CS), Chinese yam starch (CYS), and red sorghum starch (RSS) on the clinical manifestations and dysbiosis of gut microbiota are studied. Compared to CS and RSS, the consumption of PEAS, PS, and CYS significantly diminishes clinical enteritis symptoms, including reduced disease activity index, and the alleviated degree of colonic histological damage. Furthermore, the analysis of gut microbiota reveals the significant prebiotic characteristics of PEAS, PS and CYS, as indicated by the maintenance of gut microbiota hemostasis and the inhibition of typically pathogenic bacteria, including Escherichia coli and Helicobacter hepaticus. CONCLUSION Starches from potato, pea, and Chinese yam alleviate colitis symptoms in a mouse model, and also show significant prebiotic characteristics. These findings suggest a cost-effective and convenient dietary strategy for the management of IBD.
Collapse
Affiliation(s)
- Zhenzhen Xu
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| | - Wei Liu
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| | - Yuhan Zhang
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| | - Di Zhang
- Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Bin Qiu
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| | - Xianshu Wang
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| | - Jie Liu
- Beijing Technology and Business University (BTBU), Beijing, 10048, China
| | - Lina Liu
- Shandong Academy of Agricultural Sciences, Institute of Agro-Food Science and Technology, Jinan, 250100, China
| |
Collapse
|
|
20
|
Zhu L, Zhu C, Cao S, Zhang Q. Helicobacter hepaticus Induce Colitis in Male IL-10 -/- Mice Dependent by Cytolethal Distending Toxin B and via the Activation of Jak/Stat Signaling Pathway. Front Cell Infect Microbiol 2021; 11:616218. [PMID: 33777833 PMCID: PMC7994616 DOI: 10.3389/fcimb.2021.616218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 02/09/2021] [Indexed: 01/08/2023] Open
Abstract
It has been well documented that cytolethal distending toxin (CDT) from Helicobacter hepaticus (H. hepaticus), Campylobacter jejuni (C. jejuni) and other Gram-negative intestinal pathogens is linked to the inflammatory bowel disease (IBD). However, the mechanisms underlying the progression of H. hepaticus induced colitis remains unclear. In this study, male B6.129P2-IL10tm1Cgn/J mice were infected by H. hepaticus and ΔCdtB H. hepaticus for 6, 12, 18, and 24 weeks. Histopathology, H. hepaticus colonization levels, expression of inflammatory cytokines, signaling pathways, and content of NO in proximal colon were examined. We found that Cytolethal distending toxin subunit B (CdtB) deletion had no influence on colonization ability of H. hepaticus in colon of B6.129P2-IL10tm1cgn/J mice, and there was no significant difference in abundance of colonic H. hepaticus over infection duration. H. hepaticus aggravated rectocele and proximal colonic inflammation, especially at 24 WPI, while ΔCdtB H. hepaticus could not cause significant symptom. Furthermore, mRNA levels of Il-6, Tnf-α, Il-1β, and iNOS significantly increased in the proximal colon of H. hepaticus-infected mice compared to ΔCdtB H. hepaticus infected group from 12 WPI to 24 WPI. In addition, the elevated content of NO and activated Stat3 and Jak2 in colon were observed in H. hepaticus infected mice. These data demonstrated that CdtB promote colitis development in male B6.129P2-IL10tm1Cgn/J mice by induction of inflammatory response and activation of Jak-Stat signaling pathway.
Collapse
Affiliation(s)
- Liqi Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Chen Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Shuyang Cao
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Quan Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| |
Collapse
|
|
21
|
Gill T, Rosenbaum JT. Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy. Front Immunol 2021; 11:586494. [PMID: 33537028 PMCID: PMC7848169 DOI: 10.3389/fimmu.2020.586494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
Collapse
Affiliation(s)
- Tejpal Gill
- Division of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - James T Rosenbaum
- Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University, Portland, OR, United States.,Legacy Devers Eye Institute, Portland, OR, United States
| |
Collapse
|
|
22
|
Maschmeyer P, Zimmermann J, Kühl AA. Murine T-Cell Transfer Colitis as a Model for Inflammatory Bowel Disease. Methods Mol Biol 2021; 2285:349-373. [PMID: 33928564 DOI: 10.1007/978-1-0716-1311-5_26] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of severe chronic inflammatory conditions of the human gastrointestinal tract. Murine models of colitis have been invaluable tools to improve the understanding of IBD development and pathogenesis. While the disease etiology of IBD is complex and multifactorial, CD4+ T helper cells have been shown to strongly contribute to the disease pathogenesis of IBD. Here, we present a detailed protocol of the preclinical model of T-cell transfer colitis, which can easily be utilized in the laboratory to study T helper cell functions in intestinal inflammation.
Collapse
Affiliation(s)
- Patrick Maschmeyer
- Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, an Institute of the Leibniz Association, Berlin, Germany.
| | - Jakob Zimmermann
- Maurice Müller Laboratories (Department of Biomedical Research), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Bern, Switzerland
| | - Anja Andrea Kühl
- iPATH.Berlin - Core Unit of the Charité, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
23
|
Label or Concept – What Is a Pathobiont? Trends Microbiol 2020; 28:789-792. [DOI: 10.1016/j.tim.2020.04.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023]
|
|
24
|
Enriquez J, Mims BMD, Trasti S, Furr KL, Grisham MB. Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery. BMC Immunol 2020; 21:50. [PMID: 32878597 PMCID: PMC7464063 DOI: 10.1186/s12865-020-00380-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
Background The use of inbred mice housed under standardized environmental conditions has been critical in identifying immuno-pathological mechanisms in different infectious and inflammatory diseases as well as revealing new therapeutic targets for clinical trials. Unfortunately, only a small percentage of preclinical intervention studies using well-defined mouse models of disease have progressed to clinically-effective treatments in patients. The reasons for this lack of bench-to-bedside transition are not completely understood; however, emerging data suggest that genetic diversity and housing environment may greatly influence muring immunity and inflammation. Results Accumulating evidence suggests that certain immune responses and/or disease phenotypes observed in inbred mice may be quite different than those observed in their outbred counterparts. These differences have been thought to contribute to differing immune responses to foreign and/or auto-antigens in mice vs. humans. There is also a growing literature demonstrating that mice housed under specific pathogen free conditions possess an immature immune system that remarkably affects their ability to respond to pathogens and/or inflammation when compared with mice exposed to a more diverse spectrum of microorganisms. Furthermore, recent studies demonstrate that mice develop chronic cold stress when housed at standard animal care facility temperatures (i.e. 22–24 °C). These temperatures have been shown alter immune responses to foreign and auto-antigens when compared with mice housed at their thermo-neutral body temperature of 30–32 °C. Conclusions Exposure of genetically diverse mice to a spectrum of environmentally-relevant microorganisms at housing temperatures that approximate their thermo-neutral zone may improve the chances of identifying new and more potent therapeutics to treat infectious and inflammatory diseases.
Collapse
Affiliation(s)
- Josue Enriquez
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Brianyell Mc Daniel Mims
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Scott Trasti
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA.,Laboratory Animal Research Center, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Kathryn L Furr
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Matthew B Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA.
| |
Collapse
|
|
25
|
Cao S, Zhu C, Feng J, Zhu L, Yin J, Xu Y, Yang H, Huang Y, Zhang Q. Helicobacter hepaticus infection induces chronic hepatitis and fibrosis in male BALB/c mice via the activation of NF-κB, Stat3, and MAPK signaling pathways. Helicobacter 2020; 25:e12677. [PMID: 31881556 DOI: 10.1111/hel.12677] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND It has been documented that Helicobacter hepaticus (H hepaticus) infection is linked to chronic hepatitis and liver cancer. However, our understanding of the molecular mechanisms underlying progression of the H hepaticus-induced hepatic inflammation to cellular hepatocarcinoma is still limited. MATERIALS AND METHODS In our study, male BALB/c mice were infected by H hepaticus for 8, 12, 16, 20, and 24 weeks. Histopathology, H hepaticus colonization dynamics, select signaling pathways, and expression of key inflammatory cytokines in the liver were examined. RESULTS We found that H hepaticus was detectible in feces of mice at 7 days postinfection (DPI) by PCR, but it was not detected in the livers by PCR until 8 weeks postinfection (WPI). In addition, abundance of colonic and hepatic H hepaticus was progressively increased over the infection duration. H hepaticus-induced hepatic inflammation and fibrosis were aggravated over the infection duration, and necrosis or cirrhosis developed in the infected liver at 24 WPI H hepaticus infection increased levels of alanine aminotransferase and aspartate aminotransferase. Moreover, mRNA levels of Il-6 and Tnf-α were significantly elevated in the livers of H hepaticus-infected mice compared to uninfected control from 8 WPI to 24 WPI. Furthermore, Stat3, nuclear factor-κB (p65), and MAPK (Erk1/2 and p38) were activated by H hepaticus infection. CONCLUSIONS These data demonstrated that male BALB/c mice can be used as a new mouse model of H hepaticus-induced liver diseases and that the H hepaticus-induced liver injury is triggered by NF-κB, Jak-Stat, and MAPK signaling pathways.
Collapse
Affiliation(s)
- Shuyang Cao
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| | - Chen Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jie Feng
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Shanghai Lab Animal Center, Shanghai, China
| | - Liqi Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jun Yin
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yongliang Xu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, China.,Public Health Research Center, Jiangnan University, Wuxi, Jiangsu Province, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haitao Yang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, China.,Public Health Research Center, Jiangnan University, Wuxi, Jiangsu Province, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuzheng Huang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, China.,Public Health Research Center, Jiangnan University, Wuxi, Jiangsu Province, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Quan Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China
| |
Collapse
|
|
26
|
Benoit SL, Maier RJ, Sawers RG, Greening C. Molecular Hydrogen Metabolism: a Widespread Trait of Pathogenic Bacteria and Protists. Microbiol Mol Biol Rev 2020; 84:e00092-19. [PMID: 31996394 PMCID: PMC7167206 DOI: 10.1128/mmbr.00092-19] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pathogenic microorganisms use various mechanisms to conserve energy in host tissues and environmental reservoirs. One widespread but often overlooked means of energy conservation is through the consumption or production of molecular hydrogen (H2). Here, we comprehensively review the distribution, biochemistry, and physiology of H2 metabolism in pathogens. Over 200 pathogens and pathobionts carry genes for hydrogenases, the enzymes responsible for H2 oxidation and/or production. Furthermore, at least 46 of these species have been experimentally shown to consume or produce H2 Several major human pathogens use the large amounts of H2 produced by colonic microbiota as an energy source for aerobic or anaerobic respiration. This process has been shown to be critical for growth and virulence of the gastrointestinal bacteria Salmonella enterica serovar Typhimurium, Campylobacter jejuni, Campylobacter concisus, and Helicobacter pylori (including carcinogenic strains). H2 oxidation is generally a facultative trait controlled by central regulators in response to energy and oxidant availability. Other bacterial and protist pathogens produce H2 as a diffusible end product of fermentation processes. These include facultative anaerobes such as Escherichia coli, S Typhimurium, and Giardia intestinalis, which persist by fermentation when limited for respiratory electron acceptors, as well as obligate anaerobes, such as Clostridium perfringens, Clostridioides difficile, and Trichomonas vaginalis, that produce large amounts of H2 during growth. Overall, there is a rich literature on hydrogenases in growth, survival, and virulence in some pathogens. However, we lack a detailed understanding of H2 metabolism in most pathogens, especially obligately anaerobic bacteria, as well as a holistic understanding of gastrointestinal H2 transactions overall. Based on these findings, we also evaluate H2 metabolism as a possible target for drug development or other therapies.
Collapse
Affiliation(s)
- Stéphane L Benoit
- Department of Microbiology, University of Georgia, Athens, Georgia, USA
| | - Robert J Maier
- Department of Microbiology, University of Georgia, Athens, Georgia, USA
| | - R Gary Sawers
- Institute of Microbiology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Chris Greening
- School of Biological Sciences, Monash University, Clayton, VIC, Australia
- Department of Microbiology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| |
Collapse
|
|
27
|
Hsu CC, Patil K, Seamons A, Brabb TL, Treuting PM, Paik J, Meeker SM, Maggio-Price L. Lack of Effect of Murine Norovirus Infection on the CD4 + CD45RB high T-cell Adoptive Transfer Mouse Model of Inflammatory Bowel Disease. Comp Med 2020; 70:16-24. [PMID: 31937392 PMCID: PMC7024779 DOI: 10.30802/aalas-cm-19-000009] [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: 01/10/2019] [Revised: 02/24/2019] [Accepted: 04/22/2019] [Indexed: 11/05/2022]
Abstract
Murine norovirus (MNV) infection is highly prevalent in laboratory mice. Although MNV infection does not typically induce clinical disease in most laboratory mice, infection may nonetheless affect mouse models of disease by altering immune responses. We previously reported that MNV altered the bacterial-induced mouse model of inflammatory bowel disease (IBD) using Helicobacter-infected Mdr1a-/- mice. Therefore, we hypothesized that MNV infection would exacerbate another mouse model of IBD, the T-cell adoptive transfer (AT) model. In this model, Helicobacter infection is used to accelerate the progression of IBD induced by AT of naïve CD4+CD45RBhigh T cells into B6.129S7- Rag1tm1Mom/J (Rag1-/-) mice. We evaluated the effects of MNV infection in both Helicobacter-accelerated as well as Helicobacter-free AT models. In our studies, Helicobacter-infected Rag1-/- mice that received CD4+CD45RBhigh T cells through AT rapidly developed weight loss and typhlocolitis; MNV infection had no effect on disease severity or rate of progression. In the absence of Helicobacter infection, progression of IBD caused by AT of CD4+CD45RBhigh T cells was slower and typhlocolitis was less severe; this inflammation likewise was unaltered by MNV infection. These results indicate that MNV infection does not alter IBD progression and severity in the CD4+CD45RBhigh T-cell AT model in Rag1-/- mice.
Collapse
Affiliation(s)
- Charlie C Hsu
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington;,
| | | | - Audrey Seamons
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - Thea L Brabb
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - Piper M Treuting
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - Jisun Paik
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - Stacey M Meeker
- University Laboratory Animal Resources, Department of Veterinary Preventive Medicine, Ohio State University, Columbus, Ohio
| | - Lillian Maggio-Price
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington
| |
Collapse
|
|
28
|
The Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut. Microbiol Mol Biol Rev 2019; 83:83/2/e00054-18. [PMID: 30867232 DOI: 10.1128/mmbr.00054-18] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The human intestinal ecosystem is characterized by a complex interplay between different microorganisms and the host. The high variation within the human population further complicates the quest toward an adequate understanding of this complex system that is so relevant to human health and well-being. To study host-microbe interactions, defined synthetic bacterial communities have been introduced in gnotobiotic animals or in sophisticated in vitro cell models. This review reinforces that our limited understanding has often hampered the appropriate design of defined communities that represent the human gut microbiota. On top of this, some communities have been applied to in vivo models that differ appreciably from the human host. In this review, the advantages and disadvantages of using defined microbial communities are outlined, and suggestions for future improvement of host-microbe interaction models are provided. With respect to the host, technological advances, such as the development of a gut-on-a-chip system and intestinal organoids, may contribute to more-accurate in vitro models of the human host. With respect to the microbiota, due to the increasing availability of representative cultured isolates and their genomic sequences, our understanding and controllability of the human gut "core microbiota" are likely to increase. Taken together, these advancements could further unravel the molecular mechanisms underlying the human gut microbiota superorganism. Such a gain of insight would provide a solid basis for the improvement of pre-, pro-, and synbiotics as well as the development of new therapeutic microbes.
Collapse
|
|
29
|
Mueller C, Kwong Chung CKC, Faderl MR, Brasseit J, Zysset D. Helicobacter spp. in Experimental Models of Colitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1197:97-105. [DOI: 10.1007/978-3-030-28524-1_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
30
|
Hrncir T, Hrncirova L, Kverka M, Tlaskalova-Hogenova H. The role of gut microbiota in intestinal and liver diseases. Lab Anim 2018; 53:271-280. [PMID: 30580671 DOI: 10.1177/0023677218818605] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The world-wide incidence of many immune-mediated and metabolic diseases, including those of the intestines and liver, is steadily increasing. Gut microbiota plays a central role in the pathogenesis of these diseases as it mediates environmental changes to the intestinal immune system. Various environmental factors including diet, food additives and medication also trigger the compositional and functional alterations of microbiota, that is, dysbiosis, and this dysbiosis is closely associated with many chronic inflammatory diseases. However, the causal relationship remains unclear for the majority of these diseases. In this review, we discuss essential epidemiological data, known pathogenetic factors including those of genetic and environmental nature, while mainly focusing on the role of gut microbiota in the development of selected intestinal and liver diseases. Using specific examples, we also briefly describe some of the most widely-used animal models including gnotobiotic models and their contribution to the research of pathogenetic mechanisms of the host-microbiota relationship.
Collapse
Affiliation(s)
- Tomas Hrncir
- 1 Institute of Microbiology, The Czech Academy of Sciences, Czech Republic
| | - Lucia Hrncirova
- 1 Institute of Microbiology, The Czech Academy of Sciences, Czech Republic.,2 Faculty of Medicine, Charles University, Czech Republic
| | - Miloslav Kverka
- 1 Institute of Microbiology, The Czech Academy of Sciences, Czech Republic
| | | |
Collapse
|
|
31
|
Sundberg JP, Schofield PN. Living inside the box: environmental effects on mouse models of human disease. Dis Model Mech 2018; 11:dmm.035360. [PMID: 30194139 PMCID: PMC6215423 DOI: 10.1242/dmm.035360] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The impact of the laboratory environment on animal models of human disease, particularly the mouse, has recently come under intense scrutiny regarding both the reproducibility of such environments and their ability to accurately recapitulate elements of human environmental conditions. One common objection to the use of mice in highly controlled facilities is that humans live in much more diverse and stressful environments, which affects the expression and characteristics of disease phenotypes. In this Special Article, we review some of the known effects of the laboratory environment on mouse phenotypes and compare them with environmental effects on humans that modify phenotypes or, in some cases, have driven genetic adaptation. We conclude that the 'boxes' inhabited by mice and humans have much in common, but that, when attempting to tease out the effects of environment on phenotype, a controlled and, importantly, well-characterized environment is essential.
Collapse
Affiliation(s)
| | - Paul N Schofield
- The Jackson Laboratory, Bar Harbor, ME 04609-1500, USA.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| |
Collapse
|
|
32
|
Casey KM, Johnson AL, Hunrath MN, Fraser JK, McCowan NC, Wasson K, Doty RA, Griffey SM, Imai DM. Proliferative Typhlocolitis With Multinucleated Giant Cells: A Nonspecific Enteropathy in Immunodeficient Sentinel Mice. Vet Pathol 2018; 56:157-168. [PMID: 30222063 DOI: 10.1177/0300985818798106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Beginning in 2015, athymic nude sentinel mice from conventional, medium-, and high-security facilities presented to the Comparative Pathology Laboratory (CPL) with weight loss, diarrhea, and/or rectal prolapse. Regardless of whether clinical signs were present or absent, the gross observation of ceco-colonic thickening corresponded histologically to pleocellular typhlocolitis with mucosal hyperplasia and lamina proprial multinucleated cells. A subset of affected sentinels exhibited granulomatous serositis and hepatosplenic necrosis with multinucleated cells. Initial suspicion of mouse hepatitis virus infection was excluded by polymerase chain reaction, electron microscopy, and serology. Multinucleated giant cells were confirmed as macrophages by positive immunoreactivity to Mac-3 and Iba-1 and negative immunoreactivity to pancytokeratin. From conventional and medium-security facilities, Helicobacter species were identified in 40 of 143 (27.9%) mice, with H. hepaticus accounting for 72.5% of identified Helicobacter species. Other agents included opportunistic bacterial infection (41/145, 28.3%), murine norovirus (16/106, 15.1%), and pinworms (2/146, 1.4%). From high-security facilities, only Enterobacter cloacae was identified (2/13, 15.4%), and no evidence of Helicobacter sp., murine norovirus, or pinworms was present. No potentially infectious disease agent(s) was identified in 71 of 146 (48.6%) affected nude sentinels from conventional and medium-security facilities and 11 of 13 (84.6%) affected nude sentinels from high-security facilities. No statistically significant differences in histologic lesion scores were identified between Helicobacter-positive and Helicobacter-negative mice. Thus, proliferative typhlocolitis with multinucleated giant cells was considered a nonspecific histologic pattern associated with a variety of primary and opportunistic pathogens in athymic nude mice.
Collapse
Affiliation(s)
- Kerriann M Casey
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA.,2 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Amanda L Johnson
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Melea N Hunrath
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Jenelle K Fraser
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Nicole C McCowan
- 3 Campus Veterinary Services, University of California, Davis, CA, USA
| | - Katherine Wasson
- 4 Office of Research and Economic Development, University of California, Merced, CA, USA
| | | | - Stephen M Griffey
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Denise M Imai
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| |
Collapse
|
|
33
|
Danne C, Ryzhakov G, Martínez-López M, Ilott NE, Franchini F, Cuskin F, Lowe EC, Bullers SJ, Arthur JSC, Powrie F. A Large Polysaccharide Produced by Helicobacter hepaticus Induces an Anti-inflammatory Gene Signature in Macrophages. Cell Host Microbe 2018; 22:733-745.e5. [PMID: 29241040 PMCID: PMC5734933 DOI: 10.1016/j.chom.2017.11.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/22/2017] [Accepted: 10/06/2017] [Indexed: 12/19/2022]
Abstract
Interactions between the host and its microbiota are of mutual benefit and promote health. Complex molecular pathways underlie this dialog, but the identity of microbe-derived molecules that mediate the mutualistic state remains elusive. Helicobacter hepaticus is a member of the mouse intestinal microbiota that is tolerated by the host. In the absence of an intact IL-10 signaling, H. hepaticus induces an IL-23-driven inflammatory response in the intestine. Here we investigate the interactions between H. hepaticus and host immune cells that may promote mutualism, and the microbe-derived molecule(s) involved. Our results show that H. hepaticus triggers early IL-10 induction in intestinal macrophages and produces a large soluble polysaccharide that activates a specific MSK/CREB-dependent anti-inflammatory and repair gene signature via the receptor TLR2. These data identify a host-bacterial interaction that promotes mutualistic mechanisms at the intestinal interface. Further understanding of this pathway may provide novel prevention and treatment strategies for inflammatory bowel disease.
Helicobacter hepaticus (Hh) activates a specific anti-inflammatory program in macrophages This activity is driven by an Hh polysaccharide inducing high IL-10/IL-6 ratio in BMDMs The polysaccharide-specific response is dependent on the TLR2/MSK/CREB pathway
Collapse
Affiliation(s)
- Camille Danne
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
| | - Grigory Ryzhakov
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Maria Martínez-López
- Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid, Spain
| | | | - Fanny Franchini
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Fiona Cuskin
- Institute for Cell and Molecular Biosciences, Medical School Newcastle University, Newcastle upon Tyne, UK
| | - Elisabeth C Lowe
- Institute for Cell and Molecular Biosciences, Medical School Newcastle University, Newcastle upon Tyne, UK
| | - Samuel J Bullers
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - J Simon C Arthur
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
| |
Collapse
|
|
34
|
Kim M, Galan C, Hill AA, Wu WJ, Fehlner-Peach H, Song HW, Schady D, Bettini ML, Simpson KW, Longman RS, Littman DR, Diehl GE. Critical Role for the Microbiota in CX 3CR1 + Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses. Immunity 2018; 49:151-163.e5. [PMID: 29980437 PMCID: PMC6051886 DOI: 10.1016/j.immuni.2018.05.009] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 02/20/2018] [Accepted: 05/22/2018] [Indexed: 12/11/2022]
Abstract
The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.
Collapse
Affiliation(s)
- Myunghoo Kim
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Carolina Galan
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Andrea A Hill
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Wan-Jung Wu
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hannah Fehlner-Peach
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Hyo Won Song
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Deborah Schady
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew L Bettini
- Department of Pediatrics, Section of Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA; Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kenneth W Simpson
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Randy S Longman
- Jill Roberts Center for IBD Research and Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Dan R Littman
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York, NY 10016, USA
| | - Gretchen E Diehl
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
| |
Collapse
|
|
35
|
Chiaranunt P, Tometich JT, Ji J, Hand TW. T Cell Proliferation and Colitis Are Initiated by Defined Intestinal Microbes. THE JOURNAL OF IMMUNOLOGY 2018; 201:243-250. [PMID: 29777027 DOI: 10.4049/jimmunol.1800236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 04/23/2018] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease has been associated with the dysregulation of T cells specific to Ags derived from the intestinal microbiota. How microbiota-specific T cells are regulated is not completely clear but is believed to be mediated by a combination of IgA, regulatory T cells, and type 3 innate lymphoid cells. To test the role of these regulatory components on microbiota-specific T cells, we bred CBir1 TCR transgenic (CBir1Tg) mice (specific to flagellin from common intestinal bacteria) onto a lymphopenic Rag1-/- background. Surprisingly, T cells from CBir1Tg mice bred onto a Rag1-/- background could not induce colitis and did not differentiate to become effectors under lymphopenic conditions, despite deficits in immunoregulatory factors, such as IgA, regulatory T cells, and type 3 innate lymphoid cells. In fact, upon transfer of conventional CBir1Tg T cells into lymphopenic mice, the vast majority of proliferating T cells responded to Ags other than CBir1 flagellin, including those found on other bacteria, such as Helicobacter spp. Thus, we discovered a caveat in the CBir1Tg model within our animal facility that illustrates the limitations of using TCR transgenics at mucosal surfaces, where multiple TCR specificities can respond to the plethora of foreign Ags. Our findings also indicate that T cell specificity to the microbiota alone is not sufficient to induce T cell activation and colitis. Instead, other interrelated factors, such as the composition and ecology of the intestinal microbiota and host access to Ag, are paramount in controlling the activation of microbiota-specific T cell clones.
Collapse
Affiliation(s)
- Pailin Chiaranunt
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224
| | - Justin T Tometich
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224
| | - Junyi Ji
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224.,School of Medicine, Tsinghua University, Beijing 100084, China; and
| | - Timothy W Hand
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224; .,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224.,Department of Immunology, University of Pittsburgh Medical School, Pittsburgh, PA 15213
| |
Collapse
|
|
36
|
Reinoso Webb C, den Bakker H, Koboziev I, Jones-Hall Y, Rao Kottapalli K, Ostanin D, Furr KL, Mu Q, Luo XM, Grisham MB. Differential Susceptibility to T Cell-Induced Colitis in Mice: Role of the Intestinal Microbiota. Inflamm Bowel Dis 2018; 24:361-379. [PMID: 29361089 PMCID: PMC6176899 DOI: 10.1093/ibd/izx014] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Indexed: 12/12/2022]
Abstract
One of the best characterized mouse models of the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) is the CD4+CD45RBhigh T cell transfer model of chronic colitis. Following our relocation to Texas Tech University Health Sciences Center (TTUHSC), we observed a dramatic reduction in the incidence of moderate-to-severe colitis from a 16-year historical average of 90% at Louisiana State University Health Sciences Center (LSUHSC) to <30% at TTUHSC. We hypothesized that differences in the commensal microbiota at the 2 institutions may account for the differences in susceptibility to T cell-induced colitis. Using bioinformatic analyses of 16S rRNA amplicon sequence data, we quantified and compared the major microbial populations in feces from healthy and colitic mice housed at the 2 institutions. We found that the bacterial composition differed greatly between mice housed at LSUHSC vs TTUHSC. We identified several genera strongly associated with, and signficantly overrepresented in high responding RAG-/- mice housed at LSUHSC. In addition, we found that colonization of healthy TTUHSC RAG-/- mice with feces obtained from healthy or colitic RAG-/- mice housed at LSUHSC transferred susceptibility to T cell-induced colitis such that the recipients developed chronic colitis with incidence and severity similar to mice generated at LSUHSC. Finally, we found that the treatment of mice with preexisting colitis with antibiotics remarkably attenuated disease. Taken together, our data demonstrate that specific microbial communities determine disease susceptibility and that manipulation of the intestinal microbiota alters the induction and/or perpetuation of chronic colitis.
Collapse
Affiliation(s)
- Cynthia Reinoso Webb
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX
| | | | - Iurii Koboziev
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Yava Jones-Hall
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN
| | | | - Dmitry Ostanin
- Immunology Discovery, Translational Research and Development, Bristol Myers Squibb, Princeton, NJ
| | - Kathryn L Furr
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Qinghui Mu
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA
| | - Xin M Luo
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA
| | - Matthew B Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX,Correspondence address. Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, Texas 79430-6591. E-mail:
| |
Collapse
|
|
37
|
Zhang L, Wu W, Lee YK, Xie J, Zhang H. Spatial Heterogeneity and Co-occurrence of Mucosal and Luminal Microbiome across Swine Intestinal Tract. Front Microbiol 2018; 9:48. [PMID: 29472900 PMCID: PMC5810300 DOI: 10.3389/fmicb.2018.00048] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/10/2018] [Indexed: 01/17/2023] Open
Abstract
Pigs are one of the most important economic livestock. Gut microbiota is not only critical to the health but also the production efficiency of pigs. Manipulating gut microbiota relies on the full view of gut microbiome and the understanding of drive forces shaping microbial communities. 16s rDNA sequencing was used to profile microbiota along the longitudinal and radical axes to obtain the topographical map of microbiome in different intestinal compartments in young pigs. Alpha and beta-diversities revealed distinct differences in microbial compositions between the distal ileum and cecum and colon, as well as between the lumen and mucosa. Firmicutes and Proteobacteria dominated in the ileum, constituting 95 and 80% of the luminal and mucosa-attached microbiome. Transitioning from the small intestine to the large intestine, luminal Bacteroidetes increased from 1.69 to 45.98% in the cecum and 40.09% in the colon, while mucosal Bacteroidetes raised from 9 to 35.36% and 27.96%. Concurrently, luminal Firmicutes and Proteobacteria and mucosal-attached Proteobacteria remarkably decreased. By co-occurrence network analyses, Prevotellaceae, Ruminococcaceae, Lachnospiraceae and Veillonellaceae were recognized as the central nodes of luminal microbial network, and Prevotellaceae and Enterobacteriaceae, Caulobacteraceae, Enterococcaceae, Xanthomonadaceae, Pseudomonadaceae were identified as mucosal central nodes. Co-abundance was uncovered among Prevotellaceae, Lachnospiraceae, and Veillonellaceae in the luminal and mucosal microbiome, while opportunistic pathogens from γ-Proteobacteria in the mucosa. Strong co-exclusion was shown between Enterobacteriaceae with Prevotellaceae-centered microbial groups in the lumen. Redundancy analysis found bile acids and short chain fatty acids explained 37.1 and 41% of variations in the luminal microbial composition, respectively. Primary bile acid, taurine- and glycine- conjugated bile acids were positively correlated with Lactobacillaceae, Enterobacteriaceae, Clostridiaceae_1, Peptostreptococcaceae, whereas secondary bile acids, acetate, propionate, butyrate, and valerate were positively correlated with Prevotellaceae, Acidaminococcaceae, Ruminococcaceae, Lachnospiraceae, Desulfovibronaceae, Veillonellaceae. Functional analyses demonstrated that Prevotella, Veillonellaceae, Lachnospiraceae, and Ruminococcaceae were positively correlated with gene functions related to amino acids, energy, cofactors and vitamins metabolism, which are indispensable for the hosts. These results suggested site specific colonization and co-occurrence of swine gut microbiome closely relate to the microenvironment in each niche. Interactions of core gut microbiome greatly contributed to metabolism and/or immunity in the swine intestine.
Collapse
Affiliation(s)
- Li Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Weida Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yuan-Kun Lee
- Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
| | - Jingjing Xie
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| |
Collapse
|
|
38
|
Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun 2017; 89:41-52. [PMID: 29183643 PMCID: PMC5916452 DOI: 10.1016/j.jaut.2017.11.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 12/02/2022]
Abstract
In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
Th1 cells expressing miR-148a mediate colitis in a murine model of IBD. Antagomir-148a inhibits colitis by selectively depleting Th1 cells from the colon. Antagomir-148a does not affect the protective immunological memory.
Collapse
Affiliation(s)
| | - Georg Petkau
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | | | | | - Anja Andrea Kühl
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Katrin Lehmann
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - Melanie Weber
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - René Riedel
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | - Markus Bardua
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - Cam Loan Tran
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | - Bimba Franziska Hoyer
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany; Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Falk Hiepe
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany; Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Sebastian Herzog
- Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria
| | - Jürgen Wittmann
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany
| | | | | | | | | | | |
Collapse
|
|
39
|
Abstract
A general consensus exists that IBD is associated with compositional and metabolic changes in the intestinal microbiota (dysbiosis). However, a direct causal relationship between dysbiosis and IBD has not been definitively established in humans. Findings from animal models have revealed diverse and context-specific roles of the gut microbiota in health and disease, ranging from protective to pro-inflammatory actions. Moreover, evidence from these experimental models suggest that although gut bacteria often drive immune activation, chronic inflammation in turn shapes the gut microbiota and contributes to dysbiosis. The purpose of this Review is to summarize current associations between IBD and dysbiosis, describe the role of the gut microbiota in the context of specific animal models of colitis, and discuss the potential role of microbiota-focused interventions in the treatment of human IBD. Ultimately, more studies will be needed to define host-microbial relationships relevant to human disease and amenable to therapeutic interventions.
Collapse
Affiliation(s)
- Josephine Ni
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, 914 BRB II/III, Philadeplhia, Pennsylvania 19104, USA
| | - Gary D Wu
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, 914 BRB II/III, Philadeplhia, Pennsylvania 19104, USA
| | - Lindsey Albenberg
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Vesselin T Tomov
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, 914 BRB II/III, Philadeplhia, Pennsylvania 19104, USA
| |
Collapse
|
|
40
|
Zimmermann J, Durek P, Kühl AA, Schattenberg F, Maschmeyer P, Siracusa F, Lehmann K, Westendorf K, Weber M, Riedel R, Müller S, Radbruch A, Chang HD. The intestinal microbiota determines the colitis-inducing potential of T-bet-deficient Th cells in mice. Eur J Immunol 2017; 48:161-167. [PMID: 28875499 PMCID: PMC5813160 DOI: 10.1002/eji.201747100] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/28/2017] [Accepted: 08/31/2017] [Indexed: 12/16/2022]
Abstract
Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naïve T cells into Rag-/- mice requires expression of the transcription factor T-bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag-/- recipient determines whether or not T-bet-deficient Th cells can induce colitis and we have resolved the differences of the two microbiomes, permissive or non-permissive to T-bet-independent colitis. Our data highlight the dominance of the microbiota over particular T cell differentiation programs in the pathogenesis of chronic intestinal inflammation.
Collapse
Affiliation(s)
- Jakob Zimmermann
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.,Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie & Medizin Inselspital, University of Bern, Bern, Switzerland
| | - Pawel Durek
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Anja A Kühl
- Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin, Germany
| | - Florian Schattenberg
- Helmholtzzentrum für Umweltforschung (UFZ) Leipzig, Department Umweltmikrobiologie, Leipzig, Germany
| | - Patrick Maschmeyer
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Francesco Siracusa
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Katrin Lehmann
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Kerstin Westendorf
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Melanie Weber
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - René Riedel
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.,Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Susann Müller
- Helmholtzzentrum für Umweltforschung (UFZ) Leipzig, Department Umweltmikrobiologie, Leipzig, Germany
| | - Andreas Radbruch
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Hyun-Dong Chang
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| |
Collapse
|
|
41
|
Microbiota and reproducibility of rodent models. Lab Anim (NY) 2017; 46:114-122. [PMID: 28328896 DOI: 10.1038/laban.1222] [Citation(s) in RCA: 162] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 01/27/2017] [Indexed: 02/07/2023]
Abstract
The gut microbiota (GM) plays a critical role in human health and disease. Likewise, it is becoming increasingly evident that changes or disruptions to the GM can have significant effects on animal models and their expressed phenotypes, adding a complex and important variable into basic research and preclinical studies. In this article, we review some of the most common sources of GM variability in rodent models, and discuss measures to address this variability for improved reproducibility.
Collapse
|
|
42
|
Vyshenska D, Lam KC, Shulzhenko N, Morgun A. Interplay between viruses and bacterial microbiota in cancer development. Semin Immunol 2017; 32:14-24. [PMID: 28602713 DOI: 10.1016/j.smim.2017.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 05/03/2017] [Accepted: 05/30/2017] [Indexed: 12/29/2022]
Abstract
During the last few decades we have become accustomed to the idea that viruses can cause tumors. It is much less considered and discussed, however, that most people infected with oncoviruses will never develop cancer. Therefore, the genetic and environmental factors that tip the scales from clearance of viral infection to development of cancer are currently an area of active investigation. Microbiota has recently emerged as a potentially critical factor that would affect this balance by increasing or decreasing the ability of viral infection to promote carcinogenesis. In this review, we provide a model of microbiome contribution to the development of oncogenic viral infections and viral associated cancers, give examples of this process in human tumors, and describe the challenges that prevent progress in the field as well as their potential solutions.
Collapse
Affiliation(s)
- Dariia Vyshenska
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA
| | - Khiem C Lam
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA
| | - Natalia Shulzhenko
- College of Veterinary Medicine, Oregon State University, 208 Dryden Hall, Corvallis, OR 97331, USA.
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA.
| |
Collapse
|
|
43
|
Abstract
Commensal bacteria live intimately and in constant dialogue with skin immune cells. Regulating our immune response to these bacteria is critical for skin homeostasis. Using a new murine model to track Staphylococcus epidermidis-specific T cells, we found that colonization during neonatal but not adult life led to S.epidermidis-specific immune tolerance. This tolerance protected against skin inflammation and was mediated by a wave of regulatory T cells entering neonatal skin. These findings provide new insight into how we establish a healthy symbiosis with commensal microbes and highlight avenues for future research to identify novel therapies for inflammatory skin disease.
Collapse
Affiliation(s)
- Tiffany C Scharschmidt
- Department of Dermatology, University of California, San Francisco, 1701 Divisadero Street, 3rd Floor, San Francisco, CA 94115, USA.
| |
Collapse
|
|
44
|
Lifestyle and Horizontal Gene Transfer-Mediated Evolution of Mucispirillum schaedleri, a Core Member of the Murine Gut Microbiota. mSystems 2017; 2:mSystems00171-16. [PMID: 28168224 PMCID: PMC5285517 DOI: 10.1128/msystems.00171-16] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 01/04/2017] [Indexed: 01/01/2023] Open
Abstract
Shifts in gut microbiota composition have been associated with intestinal inflammation, but it remains unclear whether inflammation-associated bacteria are commensal or detrimental to their host. Here, we studied the lifestyle of the gut bacterium Mucispirillum schaedleri, which is associated with inflammation in widely used mouse models. We found that M. schaedleri has specialized systems to handle oxidative stress during inflammation. Additionally, it expresses secretion systems and effector proteins and can modify the mucosal gene expression of its host. This suggests that M. schaedleri undergoes intimate interactions with its host and may play a role in inflammation. The insights presented here aid our understanding of how commensal gut bacteria may be involved in altering susceptibility to disease. Mucispirillum schaedleri is an abundant inhabitant of the intestinal mucus layer of rodents and other animals and has been suggested to be a pathobiont, a commensal that plays a role in disease. In order to gain insights into its lifestyle, we analyzed the genome and transcriptome of M. schaedleri ASF 457 and performed physiological experiments to test traits predicted by its genome. Although described as a mucus inhabitant, M. schaedleri has limited capacity for degrading host-derived mucosal glycans and other complex polysaccharides. Additionally, M. schaedleri reduces nitrate and expresses systems for scavenging oxygen and reactive oxygen species in vivo, which may account for its localization close to the mucosal tissue and expansion during inflammation. Also of note, M. schaedleri harbors a type VI secretion system and putative effector proteins and can modify gene expression in mucosal tissue, suggesting intimate interactions with its host and a possible role in inflammation. The M. schaedleri genome has been shaped by extensive horizontal gene transfer, primarily from intestinal Epsilon- and Deltaproteobacteria, indicating that horizontal gene transfer has played a key role in defining its niche in the gut ecosystem. IMPORTANCE Shifts in gut microbiota composition have been associated with intestinal inflammation, but it remains unclear whether inflammation-associated bacteria are commensal or detrimental to their host. Here, we studied the lifestyle of the gut bacterium Mucispirillum schaedleri, which is associated with inflammation in widely used mouse models. We found that M. schaedleri has specialized systems to handle oxidative stress during inflammation. Additionally, it expresses secretion systems and effector proteins and can modify the mucosal gene expression of its host. This suggests that M. schaedleri undergoes intimate interactions with its host and may play a role in inflammation. The insights presented here aid our understanding of how commensal gut bacteria may be involved in altering susceptibility to disease.
Collapse
|
|
45
|
Abstract
Report of the Working Group on Hygiene of the Gesellschaft für Versuchstierkunde–Society for Laboratory Animal Science (GV-SOLAS) GV-SOLAS Working Group on Hygiene: Werner Nicklas (Chairman), Felix R. Homberger, Brunhilde Illgen-Wilcke, Karin Jacobi, Volker Kraft, Ivo Kunstyr, Michael Mähler, Herbert Meyer & Gabi Pohlmeyer-Esch
Collapse
|
|
46
|
Zimmermann J, Kühl AA, Weber M, Grün JR, Löffler J, Haftmann C, Riedel R, Maschmeyer P, Lehmann K, Westendorf K, Mashreghi MF, Löhning M, Mack M, Radbruch A, Chang HD. T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis. Mucosal Immunol 2016; 9:1487-1499. [PMID: 26883725 DOI: 10.1038/mi.2016.5] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 01/03/2016] [Indexed: 02/04/2023]
Abstract
The transcription factor T-bet is highly expressed by Th cells isolated from the inflamed intestine of Crohn's disease patients, and has been regarded a critical driver of murine T cell-induced colitis. However, we show here that T-bet expression by Th cells is not required for the manifestation of T-cell-induced colitis in the presence of segmented filamentous bacteria and Helicobacter hepaticus. T-bet expression by Th cells controls their survival and localization, their repertoire of chemokine and chemokine receptor expression, the accumulation of monocytes and macrophages in the inflamed colon, and their differentiation to the M1 type, i.e., type 1 inflammation. Nevertheless, T-bet-deficient Th cells efficiently induce colitis, as reflected by weight loss, diarrhea, and colon histopathology. T-bet-deficient Th cells differentiate into Th1/17 cells, able to express IFN-γ and IL-17A upon restimulation. While neutralization of IL-17A exacerbated colitis induced by wild-type or T-bet-deficient Th cells, neutralization of IFN-γ completely abolished colitis.
Collapse
Affiliation(s)
- J Zimmermann
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - A A Kühl
- Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin, Germany
| | - M Weber
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - J R Grün
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - J Löffler
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - C Haftmann
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - R Riedel
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - P Maschmeyer
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - K Lehmann
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - K Westendorf
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - M-F Mashreghi
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - M Löhning
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - M Mack
- Universitätsklinikum Regensburg, Regensburg, Germany
| | - A Radbruch
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - H D Chang
- Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| |
Collapse
|
|
47
|
Wymore Brand M, Wannemuehler MJ, Phillips GJ, Proctor A, Overstreet AM, Jergens AE, Orcutt RP, Fox JG. The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community. ILAR J 2016; 56:169-78. [PMID: 26323627 DOI: 10.1093/ilar/ilv012] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal (GI) microbiota forms a mutualistic relationship with the host through complex and dynamic interactions. Because of the complexity and interindividual variation of the GI microbiota, investigating how members of the microbiota interact with each other, as well as with the host, is daunting. The altered Schaedler flora (ASF) is a model community of eight microorganisms that was developed by R.P. Orcutt and has been in use since the late 1970s. The eight microorganisms composing the ASF were all derived from mice, can be cultured in vitro, and are stably passed through multiple generations (at least 15 years or more by the authors) in gnotobiotic mice continually bred in isolator facilities. With the limitations associated with conventional, mono- or biassociated, and germfree mice, use of mice colonized with a consortium of known bacteria that naturally inhabit the murine gut offers a powerful system to investigate mechanisms governing host-microbiota relationships, and how members of the GI microbiota interact with one another. The ASF community offers significant advantages to study homeostatic as well as disease-related interactions by taking advantage of a well-defined, limited community of microorganisms. For example, quantification and spatial distribution of individual members, microbial genetic manipulation, genomic-scale analysis, and identification of microorganism-specific host immune responses are all achievable using the ASF model. This review compiles highlights associated with the 37-year history of the ASF, including descriptions of its continued use in biomedical research to elucidate the complexities of host-microbiome interactions in health and disease.
Collapse
Affiliation(s)
- Meghan Wymore Brand
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Michael J Wannemuehler
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Gregory J Phillips
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Alexandra Proctor
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Anne-Marie Overstreet
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Albert E Jergens
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - Roger P Orcutt
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| | - James G Fox
- Meghan Wymore Brand, DVM, is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Michael J. Wannemuehler, MS, PhD, is Professor and Chair in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Gregory J. Phillips, MA, PhD, is a professor in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Alexandra Proctor is a graduate student in the Department of Veterinary Microbiology and Preventive Medicine at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Anne-Marie Overstreet, PhD, is a postdoctoral fellow in the Department of Microbiology and Immunology at Indiana University School of Medicine-South Bend in South Bend, Indiana. Albert E. Jergens, DVM, MS, PhD, is Professor and Associate Chair for Research and Graduate Studies in the Department of Veterinary Clinical Sciences at the College of Veterinary Medicine at Iowa State University in Ames, Iowa. Roger P. Orcutt, PhD, is a consultant at Biomedical Research Associates in Dunkirk, New York. James G. Fox, MS, DVM, is Director of the Division of Comparative Medicine and Professor in the Department of Biological Engineering at Massachusetts Institute of Technology in Cambridge, Massachusetts
| |
Collapse
|
|
48
|
Zhang Q, Wu Y, Wang J, Wu G, Long W, Xue Z, Wang L, Zhang X, Pang X, Zhao Y, Zhao L, Zhang C. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium. Sci Rep 2016; 6:27572. [PMID: 27264309 PMCID: PMC4893749 DOI: 10.1038/srep27572] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 05/23/2016] [Indexed: 12/13/2022] Open
Abstract
Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn't induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates.
Collapse
Affiliation(s)
- Qianpeng Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Yanqiu Wu
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Jing Wang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Guojun Wu
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Wenmin Long
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Zhengsheng Xue
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Linghua Wang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Xiaojun Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Xiaoyan Pang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Yufeng Zhao
- Ministry of Education Key Laboratory for Systems Biomedicine, Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Liping Zhao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240.,Ministry of Education Key Laboratory for Systems Biomedicine, Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China, 200240
| |
Collapse
|
|
49
|
Woods SE, Ek C, Shen Z, Feng Y, Ge Z, Muthupalani S, Whary MT, Fox JG. Male Syrian Hamsters Experimentally Infected with Helicobacter spp. of the H. bilis Cluster Develop MALT-Associated Gastrointestinal Lymphomas. Helicobacter 2016; 21:201-17. [PMID: 26348390 PMCID: PMC4783298 DOI: 10.1111/hel.12265] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Aged hamsters naturally infected with novel Helicobacter spp. classified in the H. bilis cluster develop hepatobiliary lesions and typhlocolitis. METHODS To determine whether enterohepatic H. spp. contribute to disease, Helicobacter-free hamsters were experimentally infected with H. spp. after suppression of intestinal bacteria by tetracycline treatment of dams and pups. After antibiotic withdrawal, weanlings were gavaged with four H. bilis-like Helicobacter spp. isolated from hamsters or H. bilis ATCC 43879 isolated from human feces and compared to controls (n = 7 per group). RESULTS Helicobacter bilis 43879-dosed hamsters were necropsied at 33 weeks postinfection (WPI) due to the lack of detectable infection by fecal PCR; at necropsy, 5 of 7 were weakly PCR positive but lacked intestinal lesions. The remaining hamsters were maintained for ~95 WPI; chronic H. spp. infection in hamsters (6/7) was confirmed by PCR, bacterial culture, fluorescent in situ hybridization, and ELISA. Hamsters had mild-to-moderate typhlitis, and three of the male H. spp.-infected hamsters developed small intestinal lymphoma, in contrast to one control. Of the three lymphomas in H. spp.-infected hamsters, one was a focal ileal mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, while the other two were multicentric small intestinal large B-cell lymphomas involving both the MALT and extra-MALT mucosal sites with lymphoepithelial lesions. The lymphoma in the control hamster was a diffuse small intestinal lymphoma with a mixed population of T and B cells. CONCLUSIONS Results suggest persistent H. spp. infection may augment risk for gastrointestinal MALT origin lymphomas. This model is consistent with H. pylori/heilmannii-associated MALT lymphoma in humans and could be further utilized to investigate the mechanisms of intestinal lymphoma development.
Collapse
Affiliation(s)
- Stephanie E Woods
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Courtney Ek
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Mark T Whary
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| |
Collapse
|
|
50
|
The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection. Microbiol Spectr 2016; 3. [PMID: 26185088 DOI: 10.1128/microbiolspec.mbp-0008-2014] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The healthy human intestine is colonized by as many as 1014 bacteria belonging to more than 500 different species forming a microbial ecosystem of unsurpassed diversity, termed the microbiota. The microbiota's various bacterial members engage in a physiological network of cooperation and competition within several layers of complexity. Within the last 10 years, technological progress in the field of next-generation sequencing technologies has tremendously advanced our understanding of the wide variety of physiological and pathological processes that are influenced by the commensal microbiota (1, 2). An increasing number of human disease conditions, such as inflammatory bowel diseases (IBD), type 2 diabetes, obesity, allergies and colorectal cancer are linked with altered microbiota composition (3). Moreover, a clearer picture is emerging of the composition of the human microbiota in healthy individuals, its variability over time and between different persons and how the microbiota is shaped by environmental factors (i.e., diet) and the host's genetic background (4). A general feature of a normal, healthy gut microbiota can generate conditions in the gut that disfavor colonization of enteric pathogens. This is termed colonization-resistance (CR). Upon disturbance of the microbiota, CR can be transiently disrupted, and pathogens can gain the opportunity to grow to high levels. This disruption can be caused by exposure to antibiotics (5, 6), changes in diet (7, 8), application of probiotics and drugs (9), and a variety of diseases (3). Breakdown of CR can boost colonization by intrinsic pathogens or increase susceptibility to infections (10). One consequence of pathogen expansion is the triggering of inflammatory host responses and pathogen-mediated disease. Interestingly, human enteric pathogens are part of a small group of bacterial families that belong to the Proteobacteria: the Enterobacteriaceae (E. coli, Yersinia spp., Salmonella spp., Shigella spp.), the Vibrionaceae (Vibrio cholerae) and the Campylobacteriaceae (Campylobacter spp.). In general, members of these families (be it commensals or pathogens) only constitute a minority of the intestinal microbiota. However, proteobacterial "blooms" are a characteristic trait of an abnormal microbiota such as in the course of antibiotic therapy, dietary changes or inflammation (11). It has become clear that the gut microbiota not only plays a major role in priming and regulating mucosal and systemic immunity, but that the immune system also contributes to host control over microbiota composition. These two ways of mutual communication between the microbiota and the immune system were coined as "outside-in" and "inside-out," respectively (12). The significance of those interactions for human health is particularly evident in Crohn's disease (CD) and Ulcerative Colitis (UC). The symptoms of these recurrent, chronic types of gut inflammation are caused by an excessive immune response against one's own commensal microbiota (13). It is assumed that deregulated immune responses can be caused by a genetic predisposition, leading to, for example, the impairment of intestinal barrier function or disruption of mucosal T-cell homeostasis. In CD or UC patients, an abnormally composed microbiota, referred to as "dysbiosis," is commonly observed (discussed later). This is often characterized by an increased relative abundance of facultative anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time, depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia. So far, it is unclear whether dysbiosis is a cause or a consequence of inflammatory bowel disease (IBD). In fact, both scenarios are equally conceivable. Recent work suggests that inflammatory immune responses in the gut (both IBD and pathogen-induced) can alter the gut luminal milieu in a way that favors dysbiosis (14). In this chapter, I present a survey on our current state of understanding of the characteristics and mechanisms underlying gut inflammation-associated dysbiosis. The role of dysbiosis in enteric infections and human IBD is discussed. In addition, I will focus on competition of enteric pathogens and the gut microbiota in the inflamed gut and the role of dysbiotic microbiota alterations (e.g., "Enterobacterial blooms" (11)) for the evolution of pathogenicity.
Collapse
|