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1
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Rahaman MM, Wangchuk P, Sarker S. A systematic review on the role of gut microbiome in inflammatory bowel disease: Spotlight on virome and plant metabolites. Microb Pathog 2025; 205:107608. [PMID: 40250496 DOI: 10.1016/j.micpath.2025.107608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/20/2025]
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, arise from various factors such as dietary, genetic, immunological, and microbiological influences. The gut microbiota plays a crucial role in the development and treatment of IBD, though the exact mechanisms remain uncertain. Current research has yet to definitively establish the beneficial effects of the microbiome on IBD. Bacteria and viruses (both prokaryotic and eukaryotic) are key components of the microbiome uniquely related to IBD. Numerous studies suggest that dysbiosis of the microbiota, including bacteria, viruses, and bacteriophages, contributes to IBD pathogenesis. Conversely, some research indicates that bacteria and bacteriophages may positively impact IBD outcomes. Additionally, plant metabolites play a crucial role in alleviating IBD due to their anti-inflammatory and microbiome-modulating properties. This systematic review discusses the role of the microbiome in IBD pathogenesis and evaluates the potential connection between plant metabolites and the microbiome in the context of IBD pathophysiology.
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Affiliation(s)
- Md Mizanur Rahaman
- Biomedical Sciences and Molecular Biology, College of Medicine and Dentistry, James Cook University, Townsville, QLD, 4811, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, 4811, Australia
| | - Phurpa Wangchuk
- College of Science and Engineering, James Cook University, Nguma Bada campus, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Nguma Bada campus, McGregor Rd, Smithfield, Cairns, QLD, 4878, Australia
| | - Subir Sarker
- Biomedical Sciences and Molecular Biology, College of Medicine and Dentistry, James Cook University, Townsville, QLD, 4811, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, 4811, Australia.
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2
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Bonazzi E, De Barba C, Lorenzon G, Maniero D, Bertin L, Barberio B, Facciotti F, Caprioli F, Scaldaferri F, Zingone F, Savarino EV. Recent developments in managing luminal microbial ecology in patients with inflammatory bowel disease: from evidence to microbiome-based diagnostic and personalized therapy. Expert Rev Gastroenterol Hepatol 2025; 19:563-576. [PMID: 40247656 DOI: 10.1080/17474124.2025.2495087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/21/2025] [Accepted: 04/15/2025] [Indexed: 04/19/2025]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic condition characterized by abnormal immune responses and intestinal inflammation. Emerging evidence highlights the vital role of gut microbiota in IBD's onset and progression. Recent advances have shaped diagnostic and therapeutic strategies, increasingly focusing on microbiome-based personalized care. Methodology: this review covers studies from 2004 to 2024, reflecting the surge in research on luminal microbial ecology in IBD. Human studies were prioritized, with select animal studies included for mechanistic insights. Only English-language, peer-reviewed articles - clinical trials, systematic reviews, and meta-analyses - were considered. Studies without clinical validation were excluded unless offering essential insights. Searches were conducted using PubMed, Scopus, and Web of Science. AREAS COVERED we explore mechanisms for managing IBD-related microbiota, including microbial markers for diagnosis and novel therapies such as fecal microbiota transplantation, metabolite-based treatments, and precision microbiome modulation. Additionally, we review technologies and diagnostic tools used to analyze gut microbiota composition and function in clinical settings. Emerging data supporting personalized therapeutic strategies based on individual microbial profiles are discussed. EXPERT OPINION Standardized microbiome research integration into clinical practice will enhance precision in IBD care, signaling a shift toward microbiota-based personalized medicine.
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Affiliation(s)
- Erica Bonazzi
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Caterina De Barba
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Greta Lorenzon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Daria Maniero
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale-Università Padova, Padua, Italy
| | - Brigida Barberio
- Gastroenterology Unit, Azienda Ospedale-Università Padova, Padua, Italy
| | - Federica Facciotti
- INGM-National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi', Milan, Italy
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
- Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Franco Scaldaferri
- Department of Gastroenterological Area, "A. Gemelli" Hospital, Catholic University of the Sacred Heart, Rome, Italy
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale-Università Padova, Padua, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale-Università Padova, Padua, Italy
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Li Q, Wang J. The Effect of Protein Nutritional Support on Inflammatory Bowel Disease and Its Potential Mechanisms. Nutrients 2024; 16:2302. [PMID: 39064745 PMCID: PMC11280054 DOI: 10.3390/nu16142302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/11/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn's disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.
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Affiliation(s)
| | - Jing Wang
- Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China;
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Tian Y, Xu P, Wu X, Gong Z, Yang X, Zhu H, Zhang J, Hu Y, Li G, Sang N, Yue H. Lung injuries induced by ozone exposure in female mice: Potential roles of the gut and lung microbes. ENVIRONMENT INTERNATIONAL 2024; 183:108422. [PMID: 38217903 DOI: 10.1016/j.envint.2024.108422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024]
Abstract
Ozone (O3) is one of the most harmful pollutants affecting health. However, the potential effects of O3 exposure on microbes in the gut-lung axis related to lung injuries remain elusive. In this study, female mice were exposed to 0-, 0.5- and 1-ppm O3 for 28 days, followed by routine blood tests, lung function tests and histopathological examination of the colon, nasal cavity and lung. Mouse faeces and lungs were collected for 16s rRNA sequencing to assess the overall microbiological profile and screen for key differential enriched microbes (DEMs). The key DEMs in faecal samples were Butyricimonas, Rikenellaceae RC9 and Escherichia-Shigella, whereas those in lung samples were DNF00809, Fluviicola, Bryobacter, Family XII AD3011 group, Sharpea, MND1 and unclassified Phycisphaeraceae. After a search in microbe-disease databases, these key DEMs were found to be associated with lung diseases such as lung neoplasms, cystic fibrosis, pneumonia, chronic obstructive pulmonary disease, respiratory distress syndrome and bronchiectasis. Subsequently, we used transcriptomic data from Gene Expression Omnibus (GEO) with exposure conditions similar to those in this study to cross-reference with Comparative Toxicogenomic Database (CTD). Il-6 and Ccl2 were identified as the key causative genes and were validated. The findings of this study suggest that exposure to O3 leads to significant changes in the microbial composition of the gut and lungs. These changes are associated with increased levels of inflammatory factors in the lungs and impaired lung function, resulting in an increased risk of lung disease. Altogether, this study provides novel insights into the role of microbes present in the gut-lung axis in O3 exposure-induced lung injury.
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Affiliation(s)
- Yuchai Tian
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Pengchong Xu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Xiaoyun Wu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Zhihua Gong
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China; Department of Clinical Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tong ji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, PR China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Xiaowen Yang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Huizhen Zhu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Jiyue Zhang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Yangcheng Hu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Guangke Li
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Nan Sang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Huifeng Yue
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
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Zhou X, Wang L, Wang Z, Zhu P, Chen Y, Yu C, Chen S, Xie Y. Impacts of Eimeria coinfection on growth performance, intestinal health and immune responses of broiler chickens. Vet Parasitol 2023; 322:110019. [PMID: 37666058 DOI: 10.1016/j.vetpar.2023.110019] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/16/2023] [Accepted: 08/24/2023] [Indexed: 09/06/2023]
Abstract
Coccidiosis caused by Eimeria is one of the most severe chicken diseases and imposes huge economic losses to the poultry industry globally. Multi-Eimeria species coinfections are common with the most prevalent combination being mixtures of Eimeria acervulina and Eimeria tenella. Although detrimental impacts of either E. acervulina or E. tenella on chicken health are well recognized, no information is available regarding their coinfection effects so far. This study was designed to investigate the influence of coinfection with E. acervulina and E. tenella on broiler chickens. 144 one-day-old broiler chickens within each of trials (trial I or II) were divided into four groups, namely, control group (CG), E. acervulina infection group (EAIG), E. tenella infection group (ETIG) and dual (E. acervulina and E. tenella) infection group (DIG). Then, chickens were measured for weight loss, lesion scores, oocyst outputs, histological changes and expressions of pro-inflammatory (interleukin [IL]-6, IL-8 and IL-18), regulatory (IL-10 and IL-22) cytokines and Toll-like receptors (TLR; TLR2 and TLR4) as well as intestinal barrier (mucin 2 [MUC2] and fattey acid-bingding proteins 2 and 6 [FABP2 and FABP6])- and tight junction (TJ; zonula occluden-1 [ZO-1], occludin [OCLN], and claudins 1 and 5 [CLDN1 and CLDN5])-related proteins at 3, 5, 7, 10, 14 and 21 days post-infection, respectively. Our results consistently showed that although ETIG and DIG exhibited a higher level of weight loss and a more amount of oocyst excretion than EAIG, DIG had lighter lesions than EAIG in the early phase because of coinfection with E. tenella. A higher (P < 0.05) ratio of duodenal villous height to crypt depth was also observed in DIG than EAIG. Moreover, histological changes in the duodenum and cecum varied by single and dual Eimeria infections. Expressions of the intestinal barrier- and TJ-related genes of EAIG, ETIG and DIG were significantly (P < 0.05) upregulated but their levels exhibited differential changes among infected chickens. Similarly, the infected chickens showed significant (P < 0.05) inflammatory responses and higher (P < 0.05) expressions of TLRs in the intestines in comparison to CG. These results presented a comprehensive physiological, pathological and immunological characterization of E. acervulina and E. tenella coinfection in broiler chickens and also shed insights into pathogenesis of multi-coccidia coinfections.
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Affiliation(s)
- Xuan Zhou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Lidan Wang
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Zhao Wang
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Pengchen Zhu
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yijun Chen
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Chunlin Yu
- Sichuan Animal Science Academy, Chengdu 610065, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Yue Xie
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
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Tu KC, Yu RY, Lin YH, Chien CC, Lu CL. Bidirectional association between infectious gastroenteritis and inflammatory bowel disease: a population-based study. Eur J Med Res 2023; 28:337. [PMID: 37697336 PMCID: PMC10494362 DOI: 10.1186/s40001-023-01324-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 08/27/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Intertwined association between infectious gastroenteritis (IGE) and inflammatory bowel disease (IBD) has not been investigated clearly. We aimed to examine the bidirectional association between IGE and IBD. METHODS A bidirectional study using the Taiwan National Health Insurance Research Database was designed. Through a case-control design, we identified 2899 new IBD cases during 2006-2017 and matched to 28,990 non-IBD controls. We used conditional logistic regression model to estimate odds ratios (OR) of IBD for previous IGE in different exposure time-windows within 5-years before IBD diagnosis and Poisson regression model to estimate incidence rate ratio (IRR) of subsequent IGE for IBD group to non-IBD group. RESULTS The mean age at the initial IBD diagnosis was 41 years. More IBD patients (21.49%) than controls (12.60%) had been exposed to IGE during > 6 months to 5 years before IBD diagnosis, the OR of IBD for IGE was 1.89 [95% confidence interval: 1.69-2.11]. Excess OR decreased as IGE exposure time before the index date increased. More IGE episodes were associated with additional increase in IBD risk (OR: 1.64, 2.19, 2.57, 3.50, and 4.57 in patients with 1, 2, 3, 4, and ≥ 5 IGE episodes, respectively). The IRR of having IGE for IBD group to non-IBD group was 2.42 before IBD diagnosis and increased to 5.74 after IBD diagnosis. CONCLUSIONS These findings suggested an IGE-IBD bidirectional association. More attention is needed for physicians to develop preventive strategies and be aware of the higher risk of subsequent IGE in IBD patients.
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Affiliation(s)
- Kuan-Chieh Tu
- Department of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Ru-Yi Yu
- Graduate Institute of Food Safety, College of Agriculture and Natural Resources, South District, National Chung Hsing University, 145 Xingda Road, Taichung, 402, Taiwan
| | - Yu-Hsuan Lin
- Graduate Institute of Food Safety, College of Agriculture and Natural Resources, South District, National Chung Hsing University, 145 Xingda Road, Taichung, 402, Taiwan
| | | | - Chin-Li Lu
- Graduate Institute of Food Safety, College of Agriculture and Natural Resources, South District, National Chung Hsing University, 145 Xingda Road, Taichung, 402, Taiwan.
- Department of Food Science and Biotechnology, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan.
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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7
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Feilstrecker Balani G, dos Santos Cortez M, Picasky da Silveira Freitas JE, Freire de Melo F, Zarpelon-Schutz AC, Teixeira KN. Immune response modulation in inflammatory bowel diseases by Helicobacter pylori infection. World J Gastroenterol 2023; 29:4604-4615. [PMID: 37662864 PMCID: PMC10472898 DOI: 10.3748/wjg.v29.i30.4604] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/01/2023] [Accepted: 07/24/2023] [Indexed: 08/10/2023] Open
Abstract
Many studies point to an association between Helicobacter pylori (H. pylori) infection and inflammatory bowel diseases (IBD). Although controversial, this association indicates that the presence of the bacterium somehow affects the course of IBD. It appears that H. pylori infection influences IBD through changes in the diversity of the gut microbiota, and hence in local chemical characteristics, and alteration in the pattern of gut immune response. The gut immune response appears to be modulated by H. pylori infection towards a less aggressive inflammatory response and the establishment of a targeted response to tissue repair. Therefore, a T helper 2 (Th2)/macrophage M2 response is stimulated, while the Th1/macrophage M1 response is suppressed. The immunomodulation appears to be associated with intrinsic factors of the bacteria, such as virulence factors - such oncogenic protein cytotoxin-associated antigen A, proteins such H. pylori neutrophil-activating protein, but also with microenvironmental changes that favor permanence of H. pylori in the stomach. These changes include the increase of gastric mucosal pH by urease activity, and suppression of the stomach immune response promoted by evasion mechanisms of the bacterium. Furthermore, there is a causal relationship between H. pylori infection and components of the innate immunity such as the NLR family pyrin domain containing 3 inflammasome that directs IBD toward a better prognosis.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Campus Anísio Teixeira, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa de Pós-graduação em Biotecnologia - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
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8
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Sun W, Gao J, Yang B, Chen X, Kang N, Liu W. Protocol for colitis-associated colorectal cancer murine model induced by AOM and DSS. STAR Protoc 2023; 4:102105. [PMID: 36853726 PMCID: PMC9929628 DOI: 10.1016/j.xpro.2023.102105] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/06/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) contribute to the tumorigenesis of colorectal cancer (CRC). Here, we describe a step-by-step protocol for the construction of colitis-associated CRC murine model by sequential utilization of azoxymethane and dextran sulfate sodium. We also detail steps to determine the degree of murine intestinal inflammation and to generate colorectum Swiss roll for further histopathological analyses. This is a convenient and reproducible protocol for colitis-associated CRC murine model by the induction of general chemical reagents. For complete details on the use and execution of this protocol, please refer to Yang et al. (2022).1.
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Affiliation(s)
- Wenbo Sun
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Ji Gao
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China
| | - Bing Yang
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China
| | - Xiangjun Chen
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China
| | - Na Kang
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
| | - Wanli Liu
- School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
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9
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Zhang W, Lyu M, Bessman NJ, Xie Z, Arifuzzaman M, Yano H, Parkhurst CN, Chu C, Zhou L, Putzel GG, Li TT, Jin WB, Zhou J, Hu H, Tsou AM, Guo CJ, Artis D. Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection. Cell 2022; 185:4170-4189.e20. [PMID: 36240781 PMCID: PMC9617796 DOI: 10.1016/j.cell.2022.09.008] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/14/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022]
Abstract
Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.
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Affiliation(s)
- Wen Zhang
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Mengze Lyu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Nicholas J Bessman
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Zili Xie
- Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
| | - Mohammad Arifuzzaman
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Hiroshi Yano
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Christopher N Parkhurst
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Coco Chu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Lei Zhou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Gregory G Putzel
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Ting-Ting Li
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Wen-Bing Jin
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Jordan Zhou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Hongzhen Hu
- Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
| | - Amy M Tsou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Weill Cornell Medical College, New York, NY, USA
| | - Chun-Jun Guo
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
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10
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Cong J, Wu D, Dai H, Ma Y, Liao C, Li L, Ye L, Huang Z. Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion. Theranostics 2022; 12:5204-5219. [PMID: 35836813 PMCID: PMC9274733 DOI: 10.7150/thno.69616] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 06/14/2022] [Indexed: 01/12/2023] Open
Abstract
Background: Inflammatory bowel disease (IBD) involves complicated crosstalk between host immunity and the gut microbiome, whereas the mechanics of how they govern intestinal inflammation remain poorly understood. In this study, we investigated the contribution of environmental factors to shaping gut microbiota composition in colitis mice that were transgenic for human IL-37, a natural anti-inflammatory cytokine possessing pathogenic and protective functions related to microbiota alterations. Methods: Mice transgenic expressing human IL-37 (IL-37tg) were housed under conventional and specific pathogen-free (SPF) conditions to develop a mouse model of dextran sulfate sodium (DSS)-induced colitis. 16S ribosomal RNA sequencing was used for analyzing fecal microbial communities. The efficacy of microbiota in the development of colitis in IL-37tg mice was investigated after antibiotic treatment and fecal microbiota transplantation (FMT). The mechanism by which IL-37 worsened colitis was studied by evaluating intestinal epithelial barrier function, immune cell infiltration, the expression of diverse cytokines and chemokines, as well as activated signaling pathways. Results: We found that IL-37 overexpression aggravated DSS-induced colitis in conventional mice but protected against colitis in SPF mice. These conflicting results from IL-37tg colitis mice are ascribed to a dysbiosis of the gut microbiota in which detrimental bacteria increased in IL-37tg conventional mice. We further identified that the outcome of IL-37-caused colon inflammation is strongly related to intestinal epithelial barrier impairment caused by pathogenic bacteria, neutrophils, and NK cells recruitment in colon lamina propria and mesenteric lymph node to enhance inflammatory responses in IL-37tg conventional mice. Conclusions: The immunoregulatory properties of IL-37 are detrimental in the face of dysbiosis of the intestinal microbiota, which contributes to exacerbated IBD occurrences that are uncontrollable by the immune system, suggesting that depleting gut pathogenic bacteria or maintaining intestinal microbial and immune homeostasis could be a promising therapeutic strategy for IBD.
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Affiliation(s)
- Junxiao Cong
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Dandan Wu
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Hanying Dai
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Yanmei Ma
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Chenghui Liao
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Lingyun Li
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Liang Ye
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.,✉ Corresponding authors: Zhong Huang, Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Center, 518055 Shenzhen, China. Phone: +86-0755-86671943. . Liang Ye, Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, 518055 Shenzhen, China. Phone: +86-0755-26631420.
| | - Zhong Huang
- Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.,✉ Corresponding authors: Zhong Huang, Department of Immunology, Biological Therapy Institute of Shenzhen University, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Center, 518055 Shenzhen, China. Phone: +86-0755-86671943. . Liang Ye, Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, 518055 Shenzhen, China. Phone: +86-0755-26631420.
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11
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GPP (composition of Ganoderma lucidum polysaccharides and Polyporus umbellatus polysaccharides) protects against DSS-induced murine colitis by enhancing immune function and regulating intestinal flora. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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12
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Shi L, Zhang P, Jin R, Chen X, Dong L, Chen W. Dioscin ameliorates inflammatory bowel disease by up-regulating miR-125a-5p to regulate macrophage polarization. J Clin Lab Anal 2022; 36:e24455. [PMID: 35524480 PMCID: PMC9169194 DOI: 10.1002/jcla.24455] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 04/13/2022] [Accepted: 04/16/2022] [Indexed: 11/08/2022] Open
Abstract
PURPOSE Dioscin has been proven to have anti-cancer, anti-inflammatory, and anti-infection roles. However, the role of Dioscin in inflammatory bowel disease (IBD) and its related mechanisms is unclear and needs further study. METHODS The colitis model in mice was established. After Dioscin (20, 40, or 80 mg/kg) treatment, the colon length was measured by a ruler. Histopathology, inflammatory cytokines, gut permeability, tight junction proteins, macrophage infiltration, macrophage polarization, and miR-125a-5p level were detected by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), FITC-dextran, Western blot, and flow cytometry. In vitro experiments, after RAW264.7 cells induced by lipopolysaccharide (LPS)/interleukin-4 (IL-4), were treated with Dioscin and miR-125a-5p inhibitor, miR-125a-5p level, cell vitality, inflammatory cytokines, and M1/M2 marker genes were measured by qRT-PCR and MTT assay. RESULTS Dioscin (20, 40, or 80 mg/kg) relieved DSS-triggered colitis and restrained the serum and colon of pro-inflammatory cytokines expression. Meanwhile, different concentrations' Dioscin weakened M1 macrophage polarization but facilitated tight junction protein expressions, M2 macrophage polarization, and miR-125a-5p level in colitic mice. Moreover, miR-125a-5p inhibitor reversed the modulation of Dioscin on miR-125a-5p expression, cell vitality, and inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW264.7 cells. We further discovered that Dioscin restrained M1 marker gene (CD16) expression while intensifying M2 marker genes (CD206 and Arginase-1) expressions in vitro, which was reversed by miR-125a-5p inhibitor. CONCLUSION Dioscin modulated macrophage polarization by increasing miR-125a-5p, thereby improving the intestinal epithelial barrier function and reducing IBD.
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Affiliation(s)
- Lingyan Shi
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Peichen Zhang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ruifang Jin
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Xiaowei Chen
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Lemei Dong
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Weichang Chen
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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Sottoriva K, Paik NY, White Z, Bandara T, Shao L, Sano T, Pajcini KV. A Notch/IL-21 signaling axis primes bone marrow T cell progenitor expansion. JCI Insight 2022; 7:e157015. [PMID: 35349492 PMCID: PMC9090257 DOI: 10.1172/jci.insight.157015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
Long-term impairment in T cell-mediated adaptive immunity is a major clinical obstacle following treatment of blood disorders with hematopoietic stem cell transplantation. Although T cell development in the thymus has been extensively characterized, there are significant gaps in our understanding of prethymic processes that influence early T cell potential. We have uncovered a Notch/IL-21 signaling axis in bone marrow common lymphoid progenitor (CLP) cells. IL-21 receptor expression was driven by Notch activation in CLPs, and in vivo treatment with IL-21 induced Notch-dependent CLP proliferation. Taking advantage of this potentially novel signaling axis, we generated T cell progenitors ex vivo, which improved repopulation of the thymus and peripheral lymphoid organs of mice in an allogeneic transplant model. Importantly, Notch and IL-21 activation were equally effective in the priming and expansion of human cord blood cells toward the T cell fate, confirming the translational potential of the combined treatment.
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Affiliation(s)
| | - Na Yoon Paik
- Department of Pharmacology and Regenerative Medicine and
| | - Zachary White
- Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA
| | | | - Lijian Shao
- Department of Pharmacology and Regenerative Medicine and
| | - Teruyuki Sano
- Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA
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14
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Shehata AA, Yalçın S, Latorre JD, Basiouni S, Attia YA, Abd El-Wahab A, Visscher C, El-Seedi HR, Huber C, Hafez HM, Eisenreich W, Tellez-Isaias G. Probiotics, Prebiotics, and Phytogenic Substances for Optimizing Gut Health in Poultry. Microorganisms 2022; 10:microorganisms10020395. [PMID: 35208851 PMCID: PMC8877156 DOI: 10.3390/microorganisms10020395] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 02/05/2022] [Indexed: 02/06/2023] Open
Abstract
The gut microbiota has been designated as a hidden metabolic ‘organ’ because of its enormous impact on host metabolism, physiology, nutrition, and immune function. The connection between the intestinal microbiota and their respective host animals is dynamic and, in general, mutually beneficial. This complicated interaction is seen as a determinant of health and disease; thus, intestinal dysbiosis is linked with several metabolic diseases. Therefore, tractable strategies targeting the regulation of intestinal microbiota can control several diseases that are closely related to inflammatory and metabolic disorders. As a result, animal health and performance are improved. One of these strategies is related to dietary supplementation with prebiotics, probiotics, and phytogenic substances. These supplements exert their effects indirectly through manipulation of gut microbiota quality and improvement in intestinal epithelial barrier. Several phytogenic substances, such as berberine, resveratrol, curcumin, carvacrol, thymol, isoflavones and hydrolyzed fibers, have been identified as potential supplements that may also act as welcome means to reduce the usage of antibiotics in feedstock, including poultry farming, through manipulation of the gut microbiome. In addition, these compounds may improve the integrity of tight junctions by controlling tight junction-related proteins and inflammatory signaling pathways in the host animals. In this review, we discuss the role of probiotics, prebiotics, and phytogenic substances in optimizing gut function in poultry.
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Affiliation(s)
- Awad A. Shehata
- Research and Development Section, PerNaturam GmbH, 56290 Gödenroth, Germany
- Avian and Rabbit Diseases Department, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
- Correspondence: (A.A.S.); (G.T.-I.)
| | - Sakine Yalçın
- Department of Animal Nutrition and Nutritional Diseases, Faculty of Veterinary Medicine, Ankara University (AU), 06110 Ankara, Turkey;
| | - Juan D. Latorre
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA;
| | - Shereen Basiouni
- Clinical Pathology Department, Faculty of Veterinary Medicine, Benha University, Benha 13518, Egypt;
| | - Youssef A. Attia
- Department of Agriculture, Faculty of Environmental Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Amr Abd El-Wahab
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, 30173 Hannover, Germany; (A.A.E.-W.); (C.V.)
- Department of Nutrition and Nutritional Deficiency Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Christian Visscher
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, 30173 Hannover, Germany; (A.A.E.-W.); (C.V.)
| | - Hesham R. El-Seedi
- Pharmacognosy Group, Biomedical Centre, Department of Pharmaceutical Biosciences, Uppsala University, SE 75124 Uppsala, Sweden;
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu Education Department, Jiangsu University, Zhenjiang 212013, China
| | - Claudia Huber
- Bavarian NMR Center, Structural Membrane Biochemistry, Department of Chemistry, Technische Universität München, Lichtenbegstr. 4, 85748 Garching, Germany; (C.H.); (W.E.)
| | - Hafez M. Hafez
- Institute of Poultry Diseases, Faculty of Veterinary Medicine, Free University of Berlin, 14163 Berlin, Germany;
| | - Wolfgang Eisenreich
- Bavarian NMR Center, Structural Membrane Biochemistry, Department of Chemistry, Technische Universität München, Lichtenbegstr. 4, 85748 Garching, Germany; (C.H.); (W.E.)
| | - Guillermo Tellez-Isaias
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA;
- Correspondence: (A.A.S.); (G.T.-I.)
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15
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Chen L, Wang Z, Wang P, Yu X, Ding H, Wang Z, Feng J. Effect of Long-Term and Short-Term Imbalanced Zn Manipulation on Gut Microbiota and Screening for Microbial Markers Sensitive to Zinc Status. Microbiol Spectr 2021; 9:e0048321. [PMID: 34730437 PMCID: PMC8567254 DOI: 10.1128/spectrum.00483-21] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/23/2021] [Indexed: 12/20/2022] Open
Abstract
Zinc (Zn) imbalance is a common single-nutrient disorder worldwide, but little is known about the short-term and long-term effects of imbalanced dietary zinc in the intestinal microbiome. Here, 3-week-old C57BL/6 mice were fed diets supplemented with Zn at the doses of 0 (low Zn), 30 (control Zn), 150 (high Zn), and 600 mg/kg of body weight (excess Zn) for 4 weeks (short term) and 8 weeks (long term). The gut bacterial composition at the phyla, genus, and species levels were changed as the result of the imbalanced Zn diet (e.g., Lactobacillus reuteri and Akkermansia muciniphila). Moreover, pathways including carbohydrate, glycan, and nucleotide metabolism were decreased by a short-term low-Zn diet. Valeriate production was suppressed by a long-term low-Zn diet. Pathways such as drug resistance and infectious diseases were upregulated in high- and excess-Zn diets over 4-week and 8-week intervals. Long-term zinc fortification doses, especially at the high-Zn level, suppressed the abundance of short-chain fatty acids (SCFAs)-producing genera as well as the concentrations of metabolites. Finally, Melainabacteria (phylum) and Desulfovibrio sp. strain ABHU2SB (species) were identified to be potential markers for Zn status with high accuracy (area under the curve [AUC], >0.8). Collectively, this study identified significant changes in gut microbial composition and its metabolite concentration in altered Zn-fed mice and the relevant microbial markers for Zn status. IMPORTANCE Zn insufficiency is an essential health problem in developing countries. To prevent the occurrence of zinc deficit, zinc fortification and supplementation are widely used. However, in developed countries, the amounts of Zn consumed often exceed the tolerable upper intake limit. Our results demonstrated that dietary Zn is an essential mediator of microbial community structure and that both Zn deficiency and Zn overdose can generate a dysbiosis in the gut microbiota. Moreover, specific microbial biomarkers of Zn status were identified and correlated with serum Zn level. Our study found that a short-term low-Zn diet (0 mg/kg) and a long-term high-zinc diet (150 mg/kg) had obvious negative effects in a mouse model. Thus, these results indicate that the provision and duration of supplemental Zn should be approached with caution.
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Affiliation(s)
- Lingjun Chen
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Zhonghang Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Peng Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xiaonan Yu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Haoxuan Ding
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Zinan Wang
- Elpida Institute of Life Sciences, Hangzhou, Zhejiang, China
| | - Jie Feng
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
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16
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Mo Q, Liu T, Fu A, Ruan S, Zhong H, Tang J, Zhao M, Li Y, Zhu S, Cai H, Feng F. Novel Gut Microbiota Patterns Involved in the Attenuation of Dextran Sodium Sulfate-Induced Mouse Colitis Mediated by Glycerol Monolaurate via Inducing Anti-inflammatory Responses. mBio 2021; 12:e0214821. [PMID: 34634946 PMCID: PMC8510546 DOI: 10.1128/mbio.02148-21] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/27/2021] [Indexed: 01/11/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a type of immune-mediated chronic and relapsing inflammatory gastrointestinal symptoms. IBD cannot be completely cured because of the complex pathogenesis. Glycerol monolaurate (GML), naturally found in breast milk and coconut oil, has excellent antimicrobial, anti-inflammatory, and immunoregulatory functions. Here, the protective effect of GML on dextran sodium sulfate (DSS)-induced mouse colitis and the underlying gut microbiota-dependent mechanism were assessed in C57BL/6 mice pretreated or cotreated with GML and in antibiotic-treated mice transplanted with GML-modulated microbiota. Results showed that GML pretreatment has an advantage over GML cotreatment in alleviating weight loss and reducing disease activity index (DAI), colonic histological scores, and proinflammatory responses. Moreover, the amounts of Lactobacillus and Bifidobacterium and fecal propionic acid and butyric acid were elevated only in mice pretreated with GML upon DSS induction. Of note, fecal microbiota transplantation (FMT) from GML-pretreated mice achieved faster and more significant remission of DSS-induced colitis, manifested as reduced DAI, longer colon, decreased histological scores, and enhanced colonic Foxp3+ regulatory T cells (Tregs) and ratio of serum anti-inflammatory/proinflammatory cytokines, as well as the reconstruction of microbial communities, including elevated Helicobacter ganmani and decreased pathogenic microbes. In conclusion, GML-mediated enhancement of Bifidobacterium and fecal short-chain fatty acids (SCFAs) could be responsible for the anticolitis effect. FMT assay confirmed that gut microbiota modulated by GML was more resistant to DSS-induced colitis via elevating beneficial H. ganmani and establishing Treg tolerant phenotype. Importantly, colitis remission induced by GML is associated with novel gut microbiota patterns, even though different microbial contexts were involved. IMPORTANCE The gut microbiota, which can be highly and dynamically affected by dietary components, is closely related to IBD pathogenesis. Here, we demonstrated that food-grade glycerol monolaurate (GML)-mediated enhancement of Bifidobacterium and fecal SCFAs could be responsible for the anticolitis effect. FMT assay confirmed that gut microbiota modulated by GML was more resistant to DSS-induced colitis via elevating beneficial H. ganmani and establishing Treg tolerant phenotype. Collectively, colitis remission induced by GML is associated with novel gut microbiota patterns, even though different microbial contexts were involved, which further provided a perspective to identify specific microbial members and those responsible for the anticolitis effect, such as Bifidobacterium and Helicobacter.
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Affiliation(s)
- Qiufen Mo
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Tao Liu
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Aikun Fu
- Institute of Biology, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, China
| | - Shengyue Ruan
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Hao Zhong
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Jun Tang
- Institute of Biology, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, China
| | - Minjie Zhao
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Yang Li
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
| | - Songming Zhu
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
| | - Haiying Cai
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang, China
| | - Fengqin Feng
- College of Biosystems Engineering and Food Science, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou, Zhejiang, China
- Ningbo Institute of Zhejiang University, Ningbo, Zhejiang, China
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Hyun CK. Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22179139. [PMID: 34502047 PMCID: PMC8430512 DOI: 10.3390/ijms22179139] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023] Open
Abstract
Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
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Affiliation(s)
- Chang-Kee Hyun
- School of Life Science, Handong Global University, Pohang 37554, Gyungbuk, Korea
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Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS-Challenged Piglets. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6634821. [PMID: 33833852 PMCID: PMC8018853 DOI: 10.1155/2021/6634821] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 12/11/2022]
Abstract
Bacterial infections are among the major factors that cause stress and intestinal diseases in piglets. Lipopolysaccharide (LPS), a major component of the Gram-negative bacteria outer membrane, is commonly employed for inducing an immune response in normal organisms for convenience. The association between LPS stimulation and gut immunity has been reported. However, the effects of gut immunity on microbial homeostasis and metabolism of host, especially bile acid and lipid metabolism in piglets, remain unclear. Hence, in the current study, we elucidated the effect of gut immunity on microbial balance and host metabolism. Twenty-one-day-old healthy piglets (male) were randomly assigned into the CON and LPS groups. After 4 hours of treatment, related tissues and cecal contents were obtained for further analysis. The obtained results showed that stimulated LPS considerably damaged the morphology of intestinal villi and enhanced the relative expression of proinflammatory cytokines. Besides, LPS partially changed the microbial structure as indicated by β-diversity and increased operational taxonomic units (OTUs) related to Oxalobacter and Ileibacterium. Furthermore, bile acid, a large class of gut microbiota metabolites, was also assessed by many proteins related to the enterohepatic circulation of bile acids. It was also revealed that LPS markedly inhibited the mRNA and protein expression of TGR5 and FXR (bile acid receptors) in the ileum, which expressed negative feedback on bile acid de novo synthesis. Additionally, results indicated upregulated mRNA of genes associated with the production of bile acid in the liver tissues. Moreover, LPS reduced the expression of bile acid transporters in the ileum and liver tissues and further disturbed the normal enterohepatic circulation. Taken together, gut immunity and microbial dysbiosis are associated with altered bile acid metabolism in LPS-challenged piglets, which provided theoretical basis for revealing the potential mechanism of intestinal inflammation in swine and seeking nutrients to resist intestinal damage.
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19
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Jean-Pierre F, Henson MA, O’Toole GA. Metabolic Modeling to Interrogate Microbial Disease: A Tale for Experimentalists. Front Mol Biosci 2021; 8:634479. [PMID: 33681294 PMCID: PMC7930556 DOI: 10.3389/fmolb.2021.634479] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 01/19/2021] [Indexed: 12/14/2022] Open
Abstract
The explosion of microbiome analyses has helped identify individual microorganisms and microbial communities driving human health and disease, but how these communities function is still an open question. For example, the role for the incredibly complex metabolic interactions among microbial species cannot easily be resolved by current experimental approaches such as 16S rRNA gene sequencing, metagenomics and/or metabolomics. Resolving such metabolic interactions is particularly challenging in the context of polymicrobial communities where metabolite exchange has been reported to impact key bacterial traits such as virulence and antibiotic treatment efficacy. As novel approaches are needed to pinpoint microbial determinants responsible for impacting community function in the context of human health and to facilitate the development of novel anti-infective and antimicrobial drugs, here we review, from the viewpoint of experimentalists, the latest advances in metabolic modeling, a computational method capable of predicting metabolic capabilities and interactions from individual microorganisms to complex ecological systems. We use selected examples from the literature to illustrate how metabolic modeling has been utilized, in combination with experiments, to better understand microbial community function. Finally, we propose how such combined, cross-disciplinary efforts can be utilized to drive laboratory work and drug discovery moving forward.
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Affiliation(s)
- Fabrice Jean-Pierre
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Michael A. Henson
- Department of Chemical Engineering and Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, United States
| | - George A. O’Toole
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
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20
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Mohan S, Mok S, Judge T. Identification of Novel Therapeutic Molecular Targets in Inflammatory Bowel Disease by Using Genetic Databases. Clin Exp Gastroenterol 2020; 13:467-473. [PMID: 33116744 PMCID: PMC7585167 DOI: 10.2147/ceg.s264812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/09/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose Utilization of genetic databases to identify genes involved in ulcerative colitis (UC), Crohn’s disease (CD), and their extra-intestinal manifestations. Methods Protein coding genes involved in ulcerative colitis (3783 genes), Crohn’s disease (3980 genes), uveitis (1043 genes), arthritis (5583 genes), primary sclerosing cholangitis (PSC) (1313 genes), and pyoderma gangrenosum (119 genes) were categorized using four genetic databases. These include Genecards: The Human Gene Database (www.genecards.org), DisGeNET (https://www.disgenet.org/), The Comparative Toxicogenomics Database (http://ctdbase.org/) and the Universal Protein Resource (https://www.uniprot.org/). NDex, Network Data Exchange (http://www.ndexbio.org/), was then utilized for mapping a unique signal pathway from the identified shared genes involved in the above disease processes. Results We have detected a unique array of 20 genes with the highest probability of overlay in UC, CD, uveitis, arthritis, pyoderma gangrenosum, and PSC. Figure 1 represents the interactome of these 20 protein coding genes. Of note, unique immune modulators in different disease processes are also noted. Interleukin-25 (IL-25) and monensin-resistant homolog 2 (MON-2) are only noted in UC, CD, pyoderma gangrenosum, and arthritis. Arachidonate 5-lipoxygenase (ALOX5) is involved in UC, CD, and arthritis. SLCO1B3 is exclusively involved with pyoderma gangrenosum, UC, and CD. As expected, TNF involvement is noted in CD, UC, PSC, and arthritis. Table 1 depicts the detailed result. Conclusion Our work has identified a distinctive set of genes involved in IBD and its associated extra-intestinal disease processes. These genes play crucial roles in mechanisms of immune response, inflammation, and apoptosis and further our understanding of this complex disease process. We postulate that these genes play a critical role at intersecting pathways involved in inflammatory bowel disease, and these novel molecules, their upstream and downstream effectors, are potential targets for future therapeutic agents.
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Affiliation(s)
- Sachin Mohan
- Department of Gastroenterology and Hepatology, University of Minnesota School of Medicine, St Paul, MN, USA.,Regions Hospital, Department of Gastroenterology and Hepatology, St Paul, MN, USA.,Health Partners Digestive Care Center, St Paul, MN, 55130, USA
| | - Shaffer Mok
- Division of Gastroenterology and Hepatology, University Hospital Digestive Health Institute, Westlake, OH 44145, USA
| | - Thomas Judge
- Division of Gastroenterology and Liver Diseases, Cooper University Hospital, Mount Laurel, NJ 08054, USA
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21
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Musson R, Szukała W, Jura J. MCPIP1 RNase and Its Multifaceted Role. Int J Mol Sci 2020; 21:ijms21197183. [PMID: 33003343 PMCID: PMC7582464 DOI: 10.3390/ijms21197183] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/27/2020] [Accepted: 09/28/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation is regulated at many levels, and one of these levels is post-transcriptional regulation, which controls the half-life of transcripts that encode inflammatory mediators. One of the proteins responsible for controlling the amount of mRNA in a cell is the RNase monocyte chemoattractant protein-induced protein 1 (MCPIP1). The studies conducted so far have shown that MCPIP1 is involved not only in the regulation of inflammation but also in many other physiological and pathological processes. This paper provides a summary of the information on the role of MCPIP1 in adipogenesis, angiogenesis, cell differentiation, cancer, and skin inflammation obtained to date.
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22
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Interactions between Gut Microbiota and Immunomodulatory Cells in Rheumatoid Arthritis. Mediators Inflamm 2020; 2020:1430605. [PMID: 32963490 PMCID: PMC7499318 DOI: 10.1155/2020/1430605] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.
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23
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YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis. Cell Rep 2020; 27:1176-1189.e5. [PMID: 31018132 DOI: 10.1016/j.celrep.2019.03.028] [Citation(s) in RCA: 261] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 12/17/2018] [Accepted: 03/07/2019] [Indexed: 12/30/2022] Open
Abstract
Inflammation, epithelial cell regeneration, macrophage polarization, and gut microbial homeostasis are critical for the pathological processes associated with inflammatory bowel disease (IBD). YAP (Yes-associated protein) is a key component of the Hippo pathway and was recently suggested to promote epithelial cell regeneration for IBD recovery. However, it is unclear how YAP regulates macrophage polarization, inflammation, and gut microbial homeostasis. Although YAP has been shown to promote epithelial regeneration and alleviate IBD, here we show that YAP in macrophages aggravates IBD, accompanied by the production of antimicrobial peptides and changes in gut microbiota. YAP impairs interleukin-4 (IL-4)/IL-13-induced M2 macrophage polarization while promoting lipopolysaccharide (LPS)/interferon γ (IFN-γ)-triggered M1 macrophage activation for IL-6 production. In addition, YAP expression is differently regulated during the induction of M2 versus M1 macrophages. This study suggests that fully understanding the multiple functions of YAP in different cell types is crucial for IBD therapy.
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24
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Anti-inflammatory properties and gut microbiota modulation of an alkali-soluble polysaccharide from purple sweet potato in DSS-induced colitis mice. Int J Biol Macromol 2020; 153:708-722. [DOI: 10.1016/j.ijbiomac.2020.03.053] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/08/2020] [Accepted: 03/09/2020] [Indexed: 12/19/2022]
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25
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Agliata I, Fernandez-Jimenez N, Goldsmith C, Marie JC, Bilbao JR, Dante R, Hernandez-Vargas H. The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells. Epigenetics 2020; 15:1068-1082. [PMID: 32281463 PMCID: PMC7518701 DOI: 10.1080/15592294.2020.1748916] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abnormal DNA methylation has been described in human inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD). As other complex diseases, IBD results from the balance between genetic predisposition and environmental exposures. As such, DNA methylation may be the consequence (and potential effector) of both, genetic susceptibility variants and/or environmental signals such as cytokine exposure. We attempted to discern between these two non-excluding possibilities by performing a combined analysis of published DNA methylation data in intestinal mucosal cells of IBD and control samples. We identified abnormal DNA methylation at different levels: deviation from mean methylation signals at site and region levels, and differential variability. A fraction of such changes is associated with genetic polymorphisms linked to IBD susceptibility. In addition, by comparing with another intestinal inflammatory condition (i.e., coeliac disease) we propose that aberrant DNA methylation can also be the result of unspecific processes such as chronic inflammation. Our characterization suggests that IBD methylomes combine intrinsic and extrinsic responses in intestinal mucosal cells, and could point to knowledge-based biomarkers of IBD detection and progression.
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Affiliation(s)
- Iolanda Agliata
- Department of Medicine and Health Sciences, University of Molise , Campobasso, Italy
| | - Nora Fernandez-Jimenez
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute , Leioa, Spain
| | - Chloe Goldsmith
- Department of Immunity, Virus and Inflammation, Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard , Lyon, France
| | - Julien C Marie
- Department of Immunity, Virus and Inflammation, Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard , Lyon, France
| | - Jose R Bilbao
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute , Leioa, Spain.,Ciber de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) , Madrid, Spain
| | - Robert Dante
- Department of Signaling of Tumoral Escape, Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon , Lyon, France
| | - Hector Hernandez-Vargas
- Department of Immunity, Virus and Inflammation, Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard , Lyon, France.,Department of Translational Research and Innovation, Centre Léon Bérard , Lyon, France
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26
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Lian Q, Yan S, Yin Q, Yan C, Zheng W, Gu W, Zhao X, Fan W, Li X, Ma L, Ling Z, Zhang Y, Liu J, Li J, Sun B. TRIM34 attenuates colon inflammation and tumorigenesis by sustaining barrier integrity. Cell Mol Immunol 2020; 18:350-362. [PMID: 32094504 DOI: 10.1038/s41423-020-0366-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 01/19/2020] [Indexed: 12/26/2022] Open
Abstract
Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer. However, key host factors that may control the generation of the inner mucus layer are rarely reported. Here, we identify a novel function of TRIM34 in goblet cells (GCs) in controlling inner mucus layer generation. Upon DSS treatment, TRIM34 deficiency led to a reduction in Muc2 secretion by GCs and subsequent defects in the inner mucus layer. This outcome rendered TRIM34-deficient mice more susceptible to DSS-induced colitis and colitis-associated colorectal cancer. Mechanistic experiments demonstrated that TRIM34 controlled TLR signaling-induced Nox/Duox-dependent ROS synthesis, thereby promoting the compound exocytosis of Muc2 by colonic GCs that were exposed to bacterial TLR ligands. Clinical analysis revealed that TRIM34 levels in patient samples were correlated with the outcome of ulcerative colitis (UC) and the prognosis of rectal adenocarcinoma. This study indicates that TRIM34 expression in GCs plays an essential role in generating the inner mucus layer and preventing excessive colon inflammation and tumorigenesis.
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Affiliation(s)
- Qiaoshi Lian
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Shanshan Yan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,School of Life Sciences, University of Science and Technology of China, Hefei, 230022, China
| | - Qi Yin
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Chenghua Yan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Wanwei Zheng
- Department of Digestive Diseases, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Wangpeng Gu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,School of Life Sciences, University of Science and Technology of China, Hefei, 230022, China
| | - Xinhao Zhao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Weiguo Fan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Xuezhen Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Liyan Ma
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Zhiyang Ling
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
| | - Jie Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China. .,Institutes of Biomedical Sciences and Department of Immunology, Shanghai Medical School, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, China.
| | - Jinsong Li
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
| | - Bing Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
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27
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Ferrer-Font L, Mehta P, Harmos P, Schmidt AJ, Chappell S, Price KM, Hermans IF, Ronchese F, le Gros G, Mayer JU. High-dimensional analysis of intestinal immune cells during helminth infection. eLife 2020; 9:51678. [PMID: 32041687 PMCID: PMC7012606 DOI: 10.7554/elife.51678] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022] Open
Abstract
Single cell isolation from helminth-infected murine intestines has been notoriously difficult, due to the strong anti-parasite type 2 immune responses that drive mucus production, tissue remodeling and immune cell infiltration. Through the systematic optimization of a standard intestinal digestion protocol, we were able to successfully isolate millions of immune cells from the heavily infected duodenum. To validate that these cells gave an accurate representation of intestinal immune responses, we analyzed them using a high-dimensional spectral flow cytometry panel and confirmed our findings by confocal microscopy. Our cell isolation protocol and high-dimensional analysis allowed us to identify many known hallmarks of anti-parasite immune responses throughout the entire course of helminth infection and has the potential to accelerate single-cell discoveries of local helminth immune responses that have previously been unfeasible.
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Affiliation(s)
| | - Palak Mehta
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Phoebe Harmos
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | | | - Sally Chappell
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Kylie M Price
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Ian F Hermans
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Franca Ronchese
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Graham le Gros
- Malaghan Institute of Medical Research, Wellington, New Zealand
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28
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Chu H, Tao X, Sun Z, Hao W, Wei X. Galactooligosaccharides protects against DSS-induced murine colitis through regulating intestinal flora and inhibiting NF-κB pathway. Life Sci 2020; 242:117220. [DOI: 10.1016/j.lfs.2019.117220] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/12/2019] [Accepted: 12/22/2019] [Indexed: 02/08/2023]
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29
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Yu G, Wang F, You M, Xu T, Shao C, Liu Y, Liu R, Deng M, Qi Z, Wang Z, Liu J, Yao Y, Chen J, Sun Z, Hao S, Guo W, Zhao T, Yu Z, Zhang Q, Zhao Y, Chen F, Yu S. TCF-1 deficiency influences the composition of intestinal microbiota and enhances susceptibility to colonic inflammation. Protein Cell 2020; 11:380-386. [PMID: 31970666 PMCID: PMC7196568 DOI: 10.1007/s13238-020-00689-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Guotao Yu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Fang Wang
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Menghao You
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Tiansong Xu
- Central Laboratory, School of Stomatology, Peking University, Beijing, 100081, China
| | - Chunlei Shao
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yuning Liu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Ruiqi Liu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Min Deng
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Zhihong Qi
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Zhao Wang
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Jingjing Liu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yingpeng Yao
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Jingjing Chen
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Zhen Sun
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Shanshan Hao
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Wenhui Guo
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Tianyan Zhao
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Zhengquan Yu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Qian Zhang
- Central Laboratory, School of Stomatology, Peking University, Beijing, 100081, China
| | - Yaofeng Zhao
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Feng Chen
- Central Laboratory, School of Stomatology, Peking University, Beijing, 100081, China.
| | - Shuyang Yu
- State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
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30
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Wu H, Liu H, Zhao X, Zheng Y, Liu B, Zhang L, Gao C. IKIP Negatively Regulates NF-κB Activation and Inflammation through Inhibition of IKKα/β Phosphorylation. THE JOURNAL OF IMMUNOLOGY 2019; 204:418-427. [PMID: 31826938 DOI: 10.4049/jimmunol.1900626] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 11/07/2019] [Indexed: 01/27/2023]
Abstract
Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/β to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/β and the activation of NF-κB. Upon LPS, TNF-α, and IL-1β stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/β phosphorylation, IκB, and p65 phosphorylation and production of NF-κB-responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate-induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/β phosphorylation through the disruption of IKK complex formation.
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Affiliation(s)
- Haifeng Wu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
| | - Hansen Liu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
| | - Xueying Zhao
- Department of Transfusion, The Second Hospital of Shandong University, Jinan 250000, China
| | - Yi Zheng
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
| | - Bingyu Liu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
| | - Lei Zhang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
| | - Chengjiang Gao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, China; and
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A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res 2019; 2019:7247238. [PMID: 31886308 PMCID: PMC6914932 DOI: 10.1155/2019/7247238] [Citation(s) in RCA: 606] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.
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Alvarenga V, Silva PTD, Bonfá ND, Pêgo B, Nanini H, Bernardazzi C, Madi K, Baetas da Cruz W, Castelo-Branco MT, de Souza HSP, Schanaider A. Protective effect of adipose tissue-derived mesenchymal stromal cells in an experimental model of high-risk colonic anastomosis. Surgery 2019; 166:914-925. [PMID: 31519305 DOI: 10.1016/j.surg.2019.07.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/20/2019] [Accepted: 07/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dehiscence of intestinal anastomosis results in high morbidity and mortality. The aim of this study was to investigate the effects of locally administered adipose tissue-derived mesenchymal stromal cells in a model of high-risk colonic anastomosis in rats. METHODS Seven days after induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, Wistar rats were submitted to a transection of the descending colon followed by end-to-end anastomosis and were then treated with 2×106 adipose tissue-derived mesenchymal stromal cells (from the preperitoneal fat) or an acellular culture solution instilled onto the surface of the anastomosis. At day 14, after macroscopic survey of the abdominal cavity, the anastomotic area was submitted to histologic and immunohistochemical analysis, evaluation of myeloperoxidase activity, fibrosis, epithelial integrity, NF-κ B activation, expression of inflammatory cytokines, and extracellular matrix-related genes. RESULTS Anastomotic leakage and mortality associated with high-risk anastomosis decreased with treatment with adipose tissue-derived mesenchymal stromal cells (P < .03). Application of adipose tissue-derived mesenchymal stromal cells resulted in lower histologic scores (P = .011), decreased deposition of collagen fibers (P = .003), preservation of goblet cells (P = .033), decreased myeloperoxidase activity (P = .012), decreased accumulation of CD4+ T-cells (P = .014) and macrophages (P = .011) in the lamina propria, a decrease in the number of apoptotic cells (P = .008), and the activation of NF-κ B (P = .036). Overexpression of IL-17, TNF-α , IFN-γ, and metalloproteinases in the acellular culture solution-treated, high-risk anastomosis group decreased (P < .05) to near normal values with adipose tissue-derived mesenchymal stromal cells treatment. CONCLUSION Improvements in outcomes of a high-risk colonic anastomosis with adipose tissue-derived mesenchymal stromal cells therapy reflect the immunomodulatory activity and healing effect of these cells, even after just topical administration and reinforces their use in future translational research.
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Affiliation(s)
- Valter Alvarenga
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Beatriz Pêgo
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil
| | - Hayandra Nanini
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil
| | - Cláudio Bernardazzi
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil
| | - Kalil Madi
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Wagner Baetas da Cruz
- Laboratório Translacional em Fisiologia Molecular (LabTrans) do Centro de Cirurgia Experimental, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Morgana Teixeira Castelo-Branco
- Laboratório de Imunologia Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Alberto Schanaider
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Remission in Crohn's disease is accompanied by alterations in the gut microbiota and mucins production. Sci Rep 2019; 9:13263. [PMID: 31520001 PMCID: PMC6744406 DOI: 10.1038/s41598-019-49893-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/16/2019] [Indexed: 12/13/2022] Open
Abstract
Previous studies have demonstrated that patients with Crohn’s disease (CD) in remission do not exhibit an improvement in gut microbiota composition, which might trigger relapses. The present study investigated the dysbiosis and mucins production in CD patients during remission. We performed an analytical cross-sectional single center study, which recruited 18 CD patients and 18 healthy controls (CG) residing in the same home, meaning that all of the participants experienced the same environmental factors, with similar hygiene status, diet, pollution and other common lifestyle characteristics that may influence the composition of the gut microbiota. When compared to healthy controls, the CD patients exhibited lower microbial α-diversity (p = 0.047), a greater abundance of the Proteobacteria phylum (p = 0.037) and a reduction in the Deltaproteobacteria class (p = 0.0006). There was also a reduction in the Akkermansia (p = 0.002) and Oscillospira (p = 0.024) genera and in the proportion of the yeast Saccharomyces cerevisiae (p = 0.01). Additionally, CD patients in remission presented increased neutral (p = 0.001) and acid mucin (p = 0.002) concentrations. The reductions in the proportions of Oscollospira and Akkermansia genera, sulfate-reducing bacteria and Saccharomyces cerevisiae, observed in the CD group, may account for the increased mucins production observed in these patients.
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A high-sugar diet rapidly enhances susceptibility to colitis via depletion of luminal short-chain fatty acids in mice. Sci Rep 2019; 9:12294. [PMID: 31444382 PMCID: PMC6707253 DOI: 10.1038/s41598-019-48749-2] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Western-style diets have been implicated in triggering inflammatory bowel disease activity. The aim of this study was to identify the effect of a short-term diet high in sugar on susceptibility to colitis. Adult wild-type mice were placed on chow or a high sugar diet (50% sucrose) ± acetate. After two days of diet, mice were treated with dextran sodium sulfate (DSS) to induce colitis. Disease severity was assessed daily. Colonic tissues were analyzed for cytokine expression using the MesoScale discovery platform. Intestinal dextran permeability and serum lipopolysaccharide levels (LPS) were measured. Gut microbiota were analyzed by 16s rRNA sequencing and short chain fatty acid (SCFA) concentrations by gas chromatography. Bone marrow-derived macrophages (BMDM) were incubated with LPS and cytokine secretion measured. Mice on a high sugar diet had increased gut permeability, decreased microbial diversity and reduced SCFA. BMDM derived from high sugar fed mice were highly responsive to LPS. High sugar fed mice had increased susceptibility to colitis and pro-inflammatory cytokine concentrations. Oral acetate significantly attenuated colitis in mice by restoring permeability. In conclusion, short term exposure to a high sugar diet increases susceptibility to colitis by reducing short-chain fatty acids and increasing gut permeability.
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Bourke CD, Jones KDJ, Prendergast AJ. Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition. Front Immunol 2019; 10:1728. [PMID: 31417545 PMCID: PMC6681674 DOI: 10.3389/fimmu.2019.01728] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/09/2019] [Indexed: 12/13/2022] Open
Abstract
Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.
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Affiliation(s)
- Claire D Bourke
- Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom.,Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Kelsey D J Jones
- Kennedy Institute for Rheumatology, University of Oxford, Oxford, United Kingdom.,Department of Paediatric Gastroenterology & Nutrition, University of Oxford NHS Foundation Trust, Oxford, United Kingdom
| | - Andrew J Prendergast
- Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom.,Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
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Abdool Karim SS, Baxter C, Passmore JS, McKinnon LR, Williams BL. The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women. J Int AIDS Soc 2019; 22:e25300. [PMID: 31144462 PMCID: PMC6541743 DOI: 10.1002/jia2.25300] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 05/09/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Young women in sub-Saharan Africa are disproportionately affected by HIV, accounting for 25% of all new infections in 2017. Several behavioural and biological factors are known to impact a young woman's vulnerability for acquiring HIV. One key, but lesser understood, biological factor impacting vulnerability is the vaginal microbiome. This review describes the vaginal microbiome and examines its alterations, its influence on HIV acquisition as well as the efficacy of HIV prevention technologies, the role of the rectal microbiome in HIV acquisition, advances in technologies to study the microbiome and some future research directions. DISCUSSION Although the composition of each woman's vaginal microbiome is unique, a microbiome dominated by Lactobacillus species is generally associated with a "healthy" vagina. Disturbances in the vaginal microbiota, characterized by a shift from a low-diversity, Lactobacillus-dominant state to a high-diversity non-Lactobacillus-dominant state, have been shown to be associated with a range of adverse reproductive health outcomes, including increasing the risk of genital inflammation and HIV acquisition. Gardnerella vaginalis and Prevotella bivia have been shown to contribute to both HIV risk and genital inflammation. In addition to impacting HIV risk, the composition of the vaginal microbiome affects the vaginal concentrations of some antiretroviral drugs, particularly those administered intravaginally, and thereby their efficacy as pre-exposure prophylaxis (PrEP) for HIV prevention. Although the role of rectal microbiota in HIV acquisition in women is less well understood, the composition of this compartment's microbiome, particularly the presence of species of bacteria from the Prevotellaceae family likely contribute to HIV acquisition. Advances in technologies have facilitated the study of the genital microbiome's structure and function. While next-generation sequencing advanced knowledge of the diversity and complexity of the vaginal microbiome, the emerging field of metaproteomics, which provides important information on vaginal bacterial community structure, diversity and function, is further shedding light on functionality of the vaginal microbiome and its relationship with bacterial vaginosis (BV), as well as antiretroviral PrEP efficacy. CONCLUSIONS A better understanding of the composition, structure and function of the microbiome is needed to identify opportunities to alter the vaginal microbiome and prevent BV and reduce the risk of HIV acquisition.
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Affiliation(s)
- Salim S Abdool Karim
- Centre for the AIDS Programme of Research in South Africa (CAPRISA)University of KwaZulu‐NatalDurbanSouth Africa
- Department of EpidemiologyColumbia UniversityNew YorkNYUSA
| | - Cheryl Baxter
- Centre for the AIDS Programme of Research in South Africa (CAPRISA)University of KwaZulu‐NatalDurbanSouth Africa
| | - Jo‐Ann S Passmore
- Centre for the AIDS Programme of Research in South Africa (CAPRISA)University of KwaZulu‐NatalDurbanSouth Africa
- National Health Laboratory ServiceCape TownSouth Africa
- Institute of Infectious Diseases and Molecular Medicine (IDM)University of Cape TownCape TownSouth Africa
| | - Lyle R McKinnon
- Centre for the AIDS Programme of Research in South Africa (CAPRISA)University of KwaZulu‐NatalDurbanSouth Africa
- Department of Medical Microbiology and Infectious DiseasesUniversity of ManitobaWinnipegManitobaCanada
- Department of Medical MicrobiologyUniversity of NairobiNairobiKenya
| | - Brent L Williams
- Department of EpidemiologyColumbia UniversityNew YorkNYUSA
- Department of Pathology and Cell BiologyColumbia UniversityNew YorkNYUSA
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Pêgo B, Martinusso CA, Bernardazzi C, Ribeiro BE, de Araujo Cunha AF, de Souza Mesquita J, Nanini HF, Machado MP, Castelo-Branco MTL, Cavalcanti MG, de Souza HSP. Schistosoma mansoni Coinfection Attenuates Murine Toxoplasma gondii-Induced Crohn's-Like Ileitis by Preserving the Epithelial Barrier and Downregulating the Inflammatory Response. Front Immunol 2019; 10:442. [PMID: 30936867 PMCID: PMC6432985 DOI: 10.3389/fimmu.2019.00442] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/19/2019] [Indexed: 12/11/2022] Open
Abstract
Background and aims: Mice orally infected with T. gondii develop Crohn's disease (CD)-like enteritis associated with severe mucosal damage and a systemic inflammatory response, resulting in high morbidity and mortality. Previously, helminthic infections have shown therapeutic potential in experimental colitis. However, the role of S. mansoni in T. gondii-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying T. gondii-induced ileitis and the potential therapeutic effect of S. mansoni coinfection. Methods: C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of S. mansoni, and 7-9 weeks later, they were orally infected with cysts of the ME49 strain of T. gondii. After euthanasia, the ileum was removed for histopathological analysis; staining for goblet cells; immunohistochemistry characterizing mononuclear cells, lysozyme expression, apoptotic cells, and intracellular pathway activation; and measuring gene expression levels by real-time PCR. Cytokine concentrations were measured in the serial serum samples and culture supernatants of the ileal explants, in addition to myeloperoxidase (MPO) activity. Results:T. gondii-monoinfected mice presented dense inflammatory cell infiltrates and ulcerations in the terminal ileum, with abundant cell extrusion, apoptotic bodies, and necrosis; these effects were absent in S. mansoni-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in T. gondii-infected mice. Densities of CD4- and CD11b-positive cells were increased in T. gondii- compared to S. mansoni-infected mice and controls. MPO was significantly increased among T. gondii-mice, while attenuated in coinfected animals. In T. gondii-infected mice, the culture supernatants of the explants showed increased concentrations of TNF-alpha, IFN-gamma, and IL-17, and the ileal tissue revealed increased expression of the mRNA transcripts for IL-1 beta, NOS2, HMOX1, MMP3, and MMP9 and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by S. mansoni coinfection. Conclusion:S. mansoni coinfection attenuates T. gondii-induced ileitis by preserving mucosal integrity and downregulating the local inflammatory response based on the activation of NF-kappa B and MAPK. The protective function of prior S. mansoni infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.
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Affiliation(s)
- Beatriz Pêgo
- Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Claudio Bernardazzi
- Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | | | - Hayandra F. Nanini
- Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Marta Guimarães Cavalcanti
- Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Infectious Diseases Clinic, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Heitor S. P. de Souza
- Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
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Schoultz I, Keita ÅV. Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function. Cells 2019; 8:193. [PMID: 30813280 PMCID: PMC6407030 DOI: 10.3390/cells8020193] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 02/18/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023] Open
Abstract
The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.
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Affiliation(s)
- Ida Schoultz
- School of Medical Sciences, Örebro University, 703 62 Örebro, Sweden.
| | - Åsa V Keita
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Medical Faculty, Linköping University, 581 85 Linköping, Sweden.
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Sharp RC, Naser ES, Alcedo KP, Qasem A, Abdelli LS, Naser SA. Development of multiplex PCR and multi-color fluorescent in situ hybridization ( m-FISH) coupled protocol for detection and imaging of multi-pathogens involved in inflammatory bowel disease. Gut Pathog 2018; 10:51. [PMID: 30534203 PMCID: PMC6280354 DOI: 10.1186/s13099-018-0278-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/29/2018] [Indexed: 12/28/2022] Open
Abstract
Background Several pathogens have been debated to play a role in inflammatory bowel disease (IBD) including Crohn's disease (CD). None of these pathogens have been investigated together in same clinical samples. We developed a multiplex PCR and multi-color fluorescent in situ hybridization (m-FISH) protocols for simultaneous detection of CD-associated pathogens including Mycobacterium avium subspecies paratuberculosis (MAP), Klebsiella pneumoniae, and adherent-invasive Escherichia coli strain LF82. Methods The multiplex PCR is based on 1-h DNAzol® extraction protocol modified for rapid extraction of bacterial DNA from culture, blood, and intestinal biopsies. Oligonucleotide primers sequences unique to these pathogens were evaluated individually and in combinations using bioinformatics and experimental approaches. m-FISH was based on fluorescent-tagged oligonucleotides and confocal scanning laser microscopy (CSLM). Results Following several attempts, the concentration of the oligonucleotide primers and DNA templates and the PCR annealing temperatures were optimized. Multiplex PCR analyses revealed excellent amplification signal in trials where a single primer set and combinations of two and three primers sets were tested against a mixture of DNA from three different bacteria or a mixture of three bacterial cultures mixed in one tube before DNA extraction. Slides with individual and mixtures of bacterial cultures and intestinal tissue sections from IBD patients were tested by m-FISH and the CSLM images verified multiplex PCR results detected on 3% agarose gel. Conclusion We developed a 4-h multiplex PCR protocol, which was validated by m-FISH images, capable of detecting up to four genes from major pathogens associated with CD. The new protocol should serve as an excellent tool to support efforts to study multi-pathogens involved in CD and other autoimmune disease.
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Affiliation(s)
- Robert C Sharp
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Ebraheem S Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Karel P Alcedo
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Ahmad Qasem
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Latifa S Abdelli
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Saleh A Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
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Henson MA, Phalak P. Suboptimal community growth mediated through metabolite crossfeeding promotes species diversity in the gut microbiota. PLoS Comput Biol 2018; 14:e1006558. [PMID: 30376571 PMCID: PMC6226200 DOI: 10.1371/journal.pcbi.1006558] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 11/09/2018] [Accepted: 10/09/2018] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota represent a highly complex ecosystem comprised of approximately 1000 species that forms a mutualistic relationship with the human host. A critical attribute of the microbiota is high species diversity, which provides system robustness through overlapping and redundant metabolic capabilities. The gradual loss of bacterial diversity has been associated with a broad array of gut pathologies and diseases including malnutrition, obesity, diabetes and inflammatory bowel disease. We formulated an in silico community model of the gut microbiota by combining genome-scale metabolic reconstructions of 28 representative species to explore the relationship between species diversity and community growth. While the individual species offered a broad range of metabolic capabilities, communities optimized for maximal growth on simulated Western and high-fiber diets had low diversities and imbalances in short-chain fatty acid (SCFA) synthesis characterized by acetate overproduction. Community flux variability analysis performed with the 28-species model and a reduced 20-species model suggested that enhanced species diversity and more balanced SCFA production were achievable at suboptimal growth rates. We developed a simple method for constraining species abundances to sample the growth-diversity tradeoff and used the 20-species model to show that tradeoff curves for Western and high-fiber diets resembled Pareto-optimal surfaces. Compared to maximal growth solutions, suboptimal growth solutions were characterized by higher species diversity, more balanced SCFA synthesis and lower exchange rates of crossfed metabolites between more species. We hypothesized that modulation of crossfeeding relationships through host-microbiota interactions could be an important means for maintaining species diversity and suggest that community metabolic modeling approaches that allow multiobjective optimization of growth and diversity are needed for more realistic simulation of complex communities.
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Affiliation(s)
- Michael A. Henson
- Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA
- Institute for Applied Life Sciences, University of Massachusetts, Amherst, Massachusetts, USA
- * E-mail:
| | - Poonam Phalak
- Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA
- Institute for Applied Life Sciences, University of Massachusetts, Amherst, Massachusetts, USA
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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: 143] [Impact Index Per Article: 20.4] [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.
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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.
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Roy U, Gálvez EJC, Iljazovic A, Lesker TR, Błażejewski AJ, Pils MC, Heise U, Huber S, Flavell RA, Strowig T. Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells. Cell Rep 2018; 21:994-1008. [PMID: 29069606 PMCID: PMC5668567 DOI: 10.1016/j.celrep.2017.09.097] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/15/2017] [Accepted: 09/28/2017] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4+ T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures.
Gut microbiota composition modulates colitis severity in immunocompetent hosts Colitogenic microbiota drive colitis via innate or adaptive immunity Distinct microbiota members induce pathogenic CD4+ T cells to drive colitis
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Affiliation(s)
- Urmi Roy
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Eric J C Gálvez
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Aida Iljazovic
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Till Robin Lesker
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Adrian J Błażejewski
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Marina C Pils
- Mouse Pathology Platform, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Ulrike Heise
- Mouse Pathology Platform, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Samuel Huber
- I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA
| | - Till Strowig
- Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
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Schäffler H, Rohde M, Rohde S, Huth A, Gittel N, Hollborn H, Koczan D, Glass Ä, Lamprecht G, Jaster R. NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients. World J Gastroenterol 2018; 24:1196-1205. [PMID: 29568200 PMCID: PMC5859222 DOI: 10.3748/wjg.v24.i11.1196] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 01/29/2018] [Accepted: 02/01/2018] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate disease-specific gene expression profiles of peripheral blood mononuclear cells (PBMCs) from Crohn’s disease (CD) patients in clinical remission.
METHODS Patients with CD in clinical remission or with very low disease activity according to the Crohn’s disease activity index were genotyped regarding nucleotide-binding oligomerization domain 2 (NOD2), and PBMCs from wild-type (WT)-NOD2 patients, patients with homozygous or heterozygous NOD2 mutations and healthy donors were isolated for further analysis. The cells were cultured with vitamin D, peptidoglycan (PGN) and lipopolysaccharide (LPS) for defined periods of time before RNA was isolated and subjected to microarray analysis using Clariom S assays and quantitative real-time PCR. NOD2- and disease-specific gene expression profiles were evaluated with repeated measure ANOVA by a general linear model.
RESULTS Employing microarray assays, a total of 267 genes were identified that were significantly up- or downregulated in PBMCs of WT-NOD2 patients, compared to healthy donors after challenge with vitamin D and/or a combination of LPS and PGN (P < 0.05; threshold: ≥ 2-fold change). For further analysis by real-time PCR, genes with known impact on inflammation and immunity were selected that fulfilled predefined expression criteria. In a larger cohort of patients and controls, a disease-associated expression pattern, with higher transcript levels in vitamin D-treated PBMCs from patients, was observed for three of these genes, CLEC5A (P < 0.030), lysozyme (LYZ; P < 0.047) and TREM1 (P < 0.023). Six genes were found to be expressed in a NOD2-dependent manner (CD101, P < 0.002; CLEC5A, P < 0.020; CXCL5, P < 0.009; IL-24, P < 0.044; ITGB2, P < 0.041; LYZ, P < 0.042). Interestingly, the highest transcript levels were observed in patients with heterozygous NOD2 mutations.
CONCLUSION Our data identify CLEC5A and LYZ as CD- and NOD2-associated genes of PBMCs and encourage further studies on their pathomechanistic roles.
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Affiliation(s)
- Holger Schäffler
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Maria Rohde
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Sarah Rohde
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Astrid Huth
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Nicole Gittel
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Hannes Hollborn
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Dirk Koczan
- Institute of Immunology, Rostock University Medical Center, Rostock 18057, Germany
| | - Änne Glass
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock 18057, Germany
| | - Georg Lamprecht
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
| | - Robert Jaster
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
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Accumulation of HLA-DR4 in Colonic Epithelial Cells Causes Severe Colitis in Homozygous HLA-DR4 Transgenic Mice. Inflamm Bowel Dis 2017; 23:2121-2133. [PMID: 29084077 DOI: 10.1097/mib.0000000000001282] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Homozygous HLA-DR4/I-E transgenic mice (tgm) spontaneously developed colitis similar to human ulcerative colitis. We explored whether endoplasmic reticulum stress in colonic epithelial cells due to overexpression of HLA-DR4/I-E was involved in the pathogenesis of colitis. METHODS Major histocompatibility complex class II transactivator-knockout (CIITAKO) background tgm were established to test the involvement of HLA-DR4/I-E expression in the pathogenesis of colitis. Histological and cellular analyses were performed and the effect of oral administration of the molecular chaperone tauroursodeoxycholic acid (TUDCA) and antibiotics were investigated. IgA content of feces and serum and presence of IgA-coated fecal bacteria were also investigated. RESULTS Aberrantly accumulated HLA-DR4/I-E molecules in colonic epithelial cells were observed only in the colitic homozygous tgm, which was accompanied by upregulation of the endoplasmic reticulum stress marker Binding immunoglobulin protein (BiP) and reduced mucus. Homozygous tgm with CIITAKO, and thus absent of HLA-DR4/I-E expression, did not develop colitis. Oral administration of TUDCA to homozygotes reduced HLA-DR4/I-E and BiP expression in colonic epithelial cells and restored the barrier function of the intestinal tract. The IgA content of feces and serum, and numbers of IgA-coated fecal bacteria were higher in the colitic tgm, and antibiotic administration suppressed the expression of HLA-DR4/I-E and colitis. CONCLUSIONS The pathogenesis of the colitis observed in the homozygous tgm was likely due to endoplasmic reticulum stress, resulting in goblet cell damage and compromised mucus production in the colonic epithelial cells in which HLA-DR4/I-E molecules were heavily accumulated. Commensal bacteria seemed to be involved in the accumulation of HLA-DR4/I-E, leading to development of the colitis.
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Glymenaki M, Barnes A, O'Hagan S, Warhurst G, McBain AJ, Wilson ID, Kell DB, Else KJ, Cruickshank SM. Stability in metabolic phenotypes and inferred metagenome profiles before the onset of colitis-induced inflammation. Sci Rep 2017; 7:8836. [PMID: 28821731 PMCID: PMC5562868 DOI: 10.1038/s41598-017-08732-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is associated with altered microbiota composition and metabolism, but it is unclear whether these changes precede inflammation or are the result of it since current studies have mainly focused on changes after the onset of disease. We previously showed differences in mucus gut microbiota composition preceded colitis-induced inflammation and stool microbial differences only became apparent at colitis onset. In the present study, we aimed to investigate whether microbial dysbiosis was associated with differences in both predicted microbial gene content and endogenous metabolite profiles. We examined the functional potential of mucus and stool microbial communities in the mdr1a -/- mouse model of colitis and littermate controls using PICRUSt on 16S rRNA sequencing data. Our findings indicate that despite changes in microbial composition, microbial functional pathways were stable before and during the development of mucosal inflammation. LC-MS-based metabolic phenotyping (metabotyping) in urine samples confirmed that metabolite profiles in mdr1a -/- mice were remarkably unaffected by development of intestinal inflammation and there were no differences in previously published metabolic markers of IBD. Metabolic profiles did, however, discriminate the colitis-prone mdr1a -/- genotype from controls. Our results indicate resilience of the metabolic network irrespective of inflammation. Importantly as metabolites differentiated genotype, genotype-differentiating metabolites could potentially predict IBD risk.
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Affiliation(s)
- M Glymenaki
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - A Barnes
- Shimadzu Corporation, Manchester, UK
| | - S O'Hagan
- School of Chemistry, University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
| | - G Warhurst
- Infection, Injury and Inflammation Research Group, Division of Medicine and Neurosciences, University of Manchester and Salford Royal Hospitals NHS Trust, Salford, UK
| | - A J McBain
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - I D Wilson
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College, London, UK
| | - D B Kell
- School of Chemistry, University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
| | - K J Else
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - S M Cruickshank
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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El-Salhy M, Solomon T, Hausken T, Gilja OH, Hatlebakk JG. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J Gastroenterol 2017; 23:5068-5085. [PMID: 28811704 PMCID: PMC5537176 DOI: 10.3748/wjg.v23.i28.5068] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/15/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.
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Abstract
Inflammatory bowel diseases (IBDs) result in diarrhea and abdominal pain with further potential complications such as tissue fibrosis and stenosis. Animal models help in understanding the immunopathogenesis of IBDs and in the design of novel therapeutic concepts. Here we present an updated version of a protocol we published in 2007 for key models of acute and chronic forms of colitis induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS), oxazolone and dextran sulfate sodium (DSS). This protocol update describes an adaptation of the existing protocol that modifies the technique. This protocol has been used to generate improved mouse models that better reflect the nature of IBDs in humans. In TNBS and oxazolone colitis models, topical administration of hapten reagents results in T-cell-mediated immunity against haptenized proteins and luminal antigens. By contrast, to generate DSS colitis models, mice orally receive DSS, causing death of epithelial cells, compromising barrier function and causing subsequent inflammation. The analysis of the acute colitis models can be performed within 1-2 weeks, whereas that of the chronic models may take 2-4 months. The strengths of the acute models are that they are based on the analysis of short-lasting barrier alterations, innate immune effects and flares. The advantages of the chronic models are that they may offer better insight into adaptive immunity and complications such as neoplasia and tissue fibrosis. The protocol requires basic skills in laboratory animal research.
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Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway. Cell Death Dis 2017; 8:e2723. [PMID: 28358365 PMCID: PMC5386545 DOI: 10.1038/cddis.2017.150] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Revised: 02/20/2017] [Accepted: 02/20/2017] [Indexed: 02/07/2023]
Abstract
The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.
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Suwandi A, Bargen I, Pils MC, Krey M, Zur Lage S, Singh AK, Basler T, Falk CS, Seidler U, Hornef MW, Goethe R, Weiss S. CD4 T Cell Dependent Colitis Exacerbation Following Re-Exposure of Mycobacterium avium ssp. paratuberculosis. Front Cell Infect Microbiol 2017; 7:75. [PMID: 28361039 PMCID: PMC5352692 DOI: 10.3389/fcimb.2017.00075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/27/2017] [Indexed: 11/21/2022] Open
Abstract
Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic inflammatory bowel disease of cattle characterized by intermittent to chronic diarrhea. In addition, MAP has been isolated from Crohn's disease (CD) patients. The impact of MAP on severity of clinical symptoms in JD as well as its role in CD are yet unknown. We have previously shown that MAP is able to colonize inflamed enteric tissue and to exacerbate the inflammatory tissue response (Suwandi et al., 2014). In the present study, we analyzed how repeated MAP administration influences the course of dextran sulfate sodium (DSS)-induced colitis. In comparison to mice exposed to DSS or MAP only, repeated exposure of DSS-treated mice to MAP (DSS/MAP) revealed a significantly enhanced clinical score, reduction of colon length as well as severe CD4+ T cell infiltration into the colonic lamina propria. Functional analysis identified a critical role of CD4+ T cells in the MAP-induced disease exacerbation. Additionally, altered immune responses were observed when closely related mycobacteria species such as M. avium ssp. avium and M. avium ssp. hominissuis were administered. These data reveal the specific ability of MAP to aggravate intestinal inflammation and clinical symptoms. Overall, this phenotype is compatible with similar disease promoting capabilites of MAP in JD and CD.
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Affiliation(s)
- Abdulhadi Suwandi
- Molecular Immunology, Helmholtz Centre for Infection ResearchBraunschweig, Germany; German Centre for Infection Research, Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical SchoolHannover, Germany
| | - Imke Bargen
- Molecular Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Marina C Pils
- Mouse Pathology, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Martina Krey
- Molecular Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Susanne Zur Lage
- Molecular Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Anurag K Singh
- Department of Gastroenterology, Hepatology, Endocrinology, Hannover Medical School Hannover, Germany
| | - Tina Basler
- Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany
| | - Christine S Falk
- Integrated Research and Treatment Center Transplantation, Institute of Transplant Immunology, Hannover Medical School Hannover, Germany
| | - Ursula Seidler
- Department of Gastroenterology, Hepatology, Endocrinology, Hannover Medical School Hannover, Germany
| | - Mathias W Hornef
- Institute of Medical Microbiology, RWTH University Hospital Aachen Aachen, Germany
| | - Ralph Goethe
- Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany
| | - Siegfried Weiss
- Molecular Immunology, Helmholtz Centre for Infection ResearchBraunschweig, Germany; Institute of Immunology, Hannover Medical SchoolHannover, Germany
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Földes A, Kádár K, Kerémi B, Zsembery Á, Gyires K, S Zádori Z, Varga G. Mesenchymal Stem Cells of Dental Origin-Their Potential for Antiinflammatory and Regenerative Actions in Brain and Gut Damage. Curr Neuropharmacol 2017; 14:914-934. [PMID: 26791480 PMCID: PMC5333580 DOI: 10.2174/1570159x14666160121115210] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 12/14/2015] [Accepted: 01/20/2016] [Indexed: 02/07/2023] Open
Abstract
Alzheimer’s disease, Parkinson’s disease, traumatic brain and spinal cord injury and neuroinflammatory multiple sclerosis are diverse disorders of the central nervous system. However, they are all characterized by various levels of inappropriate inflammatory/immune response along with tissue destruction. In the gastrointestinal system, inflammatory bowel disease (IBD) is also a consequence of tissue destruction resulting from an uncontrolled inflammation. Interestingly, there are many similarities in the immunopathomechanisms of these CNS disorders and the various forms of IBD. Since it is very hard or impossible to cure them by conventional manner, novel therapeutic approaches such as the use of mesenchymal stem cells, are needed. Mesenchymal stem cells have already been isolated from various tissues including the dental pulp and periodontal ligament. Such cells possess transdifferentiating capabilities for different tissue specific cells to serve as new building blocks for regeneration. But more importantly, they are also potent immunomodulators inhibiting proinflammatory processes and stimulating anti-inflammatory mechanisms. The present review was prepared to compare the immunopathomechanisms of the above mentioned neurodegenerative, neurotraumatic and neuroinflammatory diseases with IBD. Additionally, we considered the potential use of mesenchymal stem cells, especially those from dental origin to treat such disorders. We conceive that such efforts will yield considerable advance in treatment options for central and peripheral disorders related to inflammatory degeneration.
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Affiliation(s)
| | | | | | | | | | | | - Gábor Varga
- Departments of Oral Biology, Semmelweis University, Budapest, Hungary
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