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Yan JH, Liang CX, Ma RR, Li BJ, Chen QW, Li W, Zeng X, Zhang XZ. Sulfasalazine-Loaded Copper-Tannic Acid Coordination Nanozyme Enables ROS Scavenging and Immunomodulation for Inflammatory Bowel Disease Therapy. Adv Healthc Mater 2024:e2403738. [PMID: 39648654 DOI: 10.1002/adhm.202403738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/20/2024] [Indexed: 12/10/2024]
Abstract
Inflammatory bowel disease (IBD) is associated with elevated levels of reactive oxygen species (ROS) and an increased expression of proinflammatory cytokines. Anti-inflammatory drugs, monoclonal antibodies, and immunomodulators are commonly employed to control the inflammatory response in the management of IBD. Here, a copper and tannic acid (TA) coordination nanozyme (CuTA) loaded with sulfasalazine (SSZ-CuTA) is synthesized for the treatment of IBD by simultaneous scavenging ROS and immunosuppression. The CuTA exhibits both dismutase-like activity and catalase-like activity, making it efficient at scavenging ROS. These nanozymes can efficiently traverse gastric acid and subsequently exert their effects within the intestinal tract. It is verified that SSZ-CuTA can restore intestinal mucosal and goblet cells to a healthy state by effectively eliminating ROS and reducing the pro-inflammatory factors in a mouse IBD model. Overall, the SSZ-CuTA will offer a promising alternative treatment for patients suffering from IBD where excessive ROS and high inflammation coexist.
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Affiliation(s)
- Jian-Hua Yan
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Chun-Xiao Liang
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Ran-Ran Ma
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Bo-Jia Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Qi-Wen Chen
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Wen Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Xuan Zeng
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, & Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
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Yu Z, Zhang X, Zhao Q, Yan X, Wu C, Qing L, He Z, Chen Q, Huang M, Zhao J, Cao M. Urolithin B alleviates Helicobacter pylori-induced inflammation and oxidative stress in mice. Helicobacter 2023; 28:e13016. [PMID: 37623311 DOI: 10.1111/hel.13016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Helicobacter pylori is one of the most common chronic bacterial infections. Active eradication of H. pylori infection is rare due to the fact that most infected patients are asymptomatic and the use of large amounts of antibiotics in eradication therapy leads to severe side effects. Urolithin B (UB) is an additional major intestinal metabolite of ellagic acid (EA), which has been shown to possess anti-inflammatory, antioxidant, and antiapoptotic biological activities. Preventing the incidence of H. pylori-related gastric disease and reducing the damage to the host by H. pylori is a current approach to control H. pylori infection. In this study, we explored the effect of UB on H. pylori infection. MATERIALS AND METHODS The effects of UB on inflammation and oxidative stress induced by H. pylori in vivo and in vitro were investigated by qPCR, ELISA, HE staining, IHC staining, etc. RESULTS: UB reduced the adhesion and colonization of H. pylori and improved H. pylori-induced inflammation and oxidative stress in vivo and in vitro. Moreover, UB had better anti-inflammatory and antioxidant effects than clarithromycin (CLR) and metronidazole (MET). In addition to inhibiting the secretion of CagA, UB reduced tissue damage by H. pylori infection. CONCLUSIONS UB was effective in improving damage caused by H. pylori.
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Affiliation(s)
- Zhihao Yu
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
- Department of Microbiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China
| | - Xiangyue Zhang
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Qiao Zhao
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Xin Yan
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Chengmeng Wu
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Liting Qing
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zongyu He
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Qian Chen
- Irradiation Preservation Technology Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu, China
| | - Min Huang
- Irradiation Preservation Technology Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu, China
| | - Jian Zhao
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Mei Cao
- Core Laboratory, School of Medicine, Sichuan Provincial People's Hospital Affiliated to University of Electronic Science and Technology of China, Chengdu, China
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3
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Bitencourt KCQM, Schapochnik A, de Souza V, Rodrigues VMM, da Cruz MP, Damazo AS, Ferreira CM, Cecatto RB, Rodrigues MFSD, Lino-Dos-Santos-Franco A. Effects of photobiomodulation in the experimental acetic acid-induced colitis: comparison between male and female. Lasers Med Sci 2023; 38:271. [PMID: 37989885 DOI: 10.1007/s10103-023-03932-w] [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: 04/19/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023]
Abstract
Ulcerative colitis (UC) is an important chronic and multifactorial disease, which alters the colon mucosal with a significant impact on life quality affecting both men and women. The difference between genders causes changes in the inflammatory processes, modulating the development of several diseases. The available drugs to treat UC exhibit limited outcomes and side effects; thus, new therapies are needed. Photobiomodulation (PBM) emerges as potential treatment by modulating the inflammatory process without side effects and low costs. The aim of this study was to evaluate the effects of PBM in acetic acid-induced UC comparing the responses between male and females. For this purpose, male and female Wistar rats (36) were submitted to induction of UC by rectal administration of 10% acetic acid (colitis group) and treated or not with PBM (colitis-PBM group) (LED, 660 nm, 100 mW, 150 s) in three points: right side and left of the ventral surface and in the external anal region. Non-manipulated rats were used as control (basal group). We investigated the disease activity index (DAI score), myeloperoxidase enzyme activity (MPO) and release of cytokines in the intestine homogenates, and histological analysis. PBM reduces DAI score, MPO activity, and mast cell degranulation while increased mucous production in both females and males. Moreover, PBM reduced histopathological score as well as the levels of IL-6 and IL-4 in the bowel only in males. We also showed reduced levels of IL-1beta and TNF-alpha after PBM in both males and females, while the levels of IL-10 and IFN-gamma were increased. In conclusion, despite our study has shown some differences between males and females, PBM attenuated the biomarkers of UC in both genders constituting a potential combined treatment that is non-invasive and low cost.
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Affiliation(s)
| | - Adriana Schapochnik
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil
| | - Vanessa de Souza
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil
| | - Virgínia Mendes Matias Rodrigues
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil
| | - Marlon Palma da Cruz
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil
| | - Amílcar Sabino Damazo
- Department of Basic Science in Health, Faculty of Medical Sciences, Federal University of Cuiabá, Cuiabá, Brazil
| | | | - Rebeca Boltes Cecatto
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil
| | | | - Adriana Lino-Dos-Santos-Franco
- Post Graduate Program in Biophotonic Medicine, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP CEP, 01504-000, Brazil.
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Yu Z, Cao M, Peng J, Wu D, Li S, Wu C, Qing L, Zhang A, Wang W, Huang M, Zhao J. Lacticaseibacillus casei T1 attenuates Helicobacter pylori-induced inflammation and gut microbiota disorders in mice. BMC Microbiol 2023; 23:39. [PMID: 36765272 PMCID: PMC9921057 DOI: 10.1186/s12866-023-02782-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 01/23/2023] [Indexed: 02/12/2023] Open
Abstract
Probiotics are defined as live microbial food elements that are beneficial to human health. Lacticaseibacillus casei T1 was considered to have potential as a bioactive ingredient in functional foods, which was isolated from kurut. Previous research by our group proved that L. casei T1 could prevent inflammatory responses caused by Helicobacter pylori. This study aimed to investigate whether treatment with L. casei T1 resulted in a suppressive effect on H. pylori-induced oxidative stress and inflammatory responses. The results showed that treatment with L. casei T1 could relieve H. pylori-induced overexpression of inflammatory cytokines in GES-1 cells. Experiments in animals suggested that taking long-term L. casei T1 could reduce oxidative stress and inflammatory cytokines and improve H. pylori-induced gastric mucosal damage. Furthermore, taking L. casei T1 could increase the relative abundance of beneficial intestinal bacterium (Lachnospiraceae and Odoribacter) of H. pylori-infected mice and help in maintaining the balance of intestinal microflora.Collectively, L. casei T1 had certain degrees of therapeutic effect against H. pylori. In the future, it combined with antibiotics for H. pylori eradication deserves further study.
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Affiliation(s)
- Zhihao Yu
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Mei Cao
- grid.54549.390000 0004 0369 4060Core Laboratory, School of Medicine, Sichuan Provincial People’s Hospital Affiliated to University of Electronic Science and Technology of China, Chengdu, 610072 People’s Republic of China
| | - Jingshan Peng
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Daoyan Wu
- grid.413458.f0000 0000 9330 9891Department of Microbiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025 People’s Republic of China
| | - Shu Li
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Chengmeng Wu
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Liting Qing
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Andong Zhang
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Wenjie Wang
- grid.13291.380000 0001 0807 1581Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064 People’s Republic of China
| | - Min Huang
- Irradiation Preservation Technology Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu, 610101 People’s Republic of China
| | - Jian Zhao
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu, 610064, People's Republic of China.
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Yu ZH, Cao M, Wang YX, Yan SY, Qing LT, Wu CM, Li S, Li TY, Chen Q, Zhao J. Urolithin A Attenuates Helicobacter pylori-Induced Damage In Vivo. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:11981-11993. [PMID: 36106620 DOI: 10.1021/acs.jafc.2c03711] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Urolithin A (UA) is a metabolite produced in the gut following the consumption of ellagic acid (EA) rich foods. EA has shown anti-inflammatory, antioxidant, and anticancer properties. Because EA is poorly absorbed in the gastrointestinal tract, urolithins are considered to play a major role in bioactivity. Helicobacter pylori (H. pylori) infection is the most common chronic bacterial infection all over the world. It is potentially hazardous to humans because of its relationship to various gastrointestinal diseases. In this study, we investigated the effect of UA on inflammation by H. pylori. The results indicated that UA attenuated H. pylori-induced inflammation in vitro and in vivo. UA also reduced the secretion of H. pylori virulence factors and tissue injuries in mice. Furthermore, UA decreased the relative abundance of Helicobacteraceae in feces of H. pylori-infected mice. In summary, taking UA effectively inhibited the injury caused by H. pylori.
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Affiliation(s)
- Zhi-Hao Yu
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Mei Cao
- Core Laboratory, School of Medicine, Sichuan Provincial People's Hospital Affiliated to University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Yuan-Xiao Wang
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Shi-Ying Yan
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Li-Ting Qing
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Cheng-Meng Wu
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Shu Li
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Tian-Yi Li
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Qian Chen
- Irradiation Preservation Technology Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610101, China
| | - Jian Zhao
- Key Laboratory of Biological Resource and Ecological Environment of Chinese Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610065, China
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Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease. Can J Gastroenterol Hepatol 2022; 2022:8416578. [PMID: 35360442 PMCID: PMC8964223 DOI: 10.1155/2022/8416578] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/05/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies. AIMS This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options. METHODS We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease. RESULTS Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease. CONCLUSIONS Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.
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7
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El-Sayed A, Aleya L, Kamel M. Microbiota and epigenetics: promising therapeutic approaches? ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:49343-49361. [PMID: 34319520 PMCID: PMC8316543 DOI: 10.1007/s11356-021-15623-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/20/2021] [Indexed: 04/15/2023]
Abstract
The direct/indirect responsibility of the gut microbiome in disease induction in and outside the digestive tract is well studied. These results are usually from the overpopulation of certain species on the cost of others, interaction with beneficial microflora, interference with normal epigenetic control mechanisms, or suppression of the immune system. Consequently, it is theoretically possible to cure such disorders by rebalancing the microbiome inside our bodies. This can be achieved by changing the lifestyle pattern and diet or by supplementation with beneficial bacteria or their metabolites. Various approaches have been explored to manipulate the normal microbial inhabitants, including nutraceutical, supplementations with prebiotics, probiotics, postbiotics, synbiotics, and antibiotics, or through microbiome transplantation (fecal, skin, or vaginal microbiome transplantation). In the present review, the interaction between the microbiome and epigenetics and their role in disease induction is discussed. Possible future therapeutic approaches via the reestablishment of equilibrium in our internal micro-ecosystem are also highlighted.
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Affiliation(s)
- Amr El-Sayed
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, F-25030, Besançon Cedex, France
| | - Mohamed Kamel
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
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8
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Oerlemans MM, Akkerman R, Ferrari M, Walvoort MT, de Vos P. Benefits of bacteria-derived exopolysaccharides on gastrointestinal microbiota, immunity and health. J Funct Foods 2021. [DOI: 10.1016/j.jff.2020.104289] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Verdecchia P, Angeli F, Cavallini C, Reboldi G. Use of Antibiotics and Mortality in Women: Does Duration of Exposure Matter? Circ Res 2020; 126:374-376. [PMID: 31999533 DOI: 10.1161/circresaha.119.316406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Paolo Verdecchia
- From the Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy (P.V., C.C.)
| | - Fabio Angeli
- Department of Medicine and Surgery, University of Insubria, Varese and Maugeri Care and Research Institute, IRCCS Tradate, Italy (F.A.)
| | - Claudio Cavallini
- From the Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy (P.V., C.C.)
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Abstract
Despite the revolution in inflammatory bowel disease (IBD) treatment over the past two decades with the advent of biological therapies, there remains a substantial proportion of patients with inadequate or unsustained response to existent therapies. The overwhelming focus of IBD therapeutics has been targeting mucosal immunity, however with the developing evidence base pointing to the role of gut microbes in the inflammatory process, renewed focus should be placed on the impact of manipulating the microbiome in IBD management. This review provides an overview of the evidence implicating bacteria in the pathogenesis of gut inflammation in IBD and provides an overview of the evidence of antibiotics in IBD treatment. We also suggest a potential role of antibiotics in clinical practice based on available evidence and clinical experience.
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Affiliation(s)
- Oren Ledder
- Shaare Zedek Medical Center, Jerusalem, Israel.,The Hebrew University of Jerusalem, Jerusalem, Israel
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11
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Ledder O, Turner D. Antibiotics in IBD: Still a Role in the Biological Era? Inflamm Bowel Dis 2018; 24:1676-1688. [PMID: 29722812 DOI: 10.1093/ibd/izy067] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Indexed: 02/06/2023]
Abstract
Despite compelling evidence pointing to a critical role of gut microflora in inflammatory bowel disease (IBD) pathogenesis, the role of antibiotics in clinical practice remains limited, largely due to heterogeneous trials with often conflicting evidence. In this review, we revisit previous randomized controlled trials and high-quality uncontrolled studies in an effort to better elucidate the role of antibiotics in contemporary treatment algorithms. The most established role of antibiotics is in perianal Crohn's disease (CD), utilizing ciprofloxacin with or without metronidazole often as an adjunct to biological therapy. Evidence also points to a likely modest role of various antibiotic classes in mild to moderate luminal CD, including ciprofloxacin, metronidazole, azithromycin, and rifaximin. The benefit of metronidazole in preventing postoperative recurrence in CD is well reported; however, the long-term benefit of this intervention remains uncertain. The use of antibiotics in ulcerative colitis (UC) is even more controversial, but studies using broad-spectrum oral antibiotic cocktails have reported a possible role in acute severe colitis and chronic persistent UC. Similarly, the role of oral vancomycin and gentamicin in very early-onset IBD has interesting preliminary results. Adverse events of antibiotics, the resulting alterations in the microbiome with its associated unknown long-term sequela, and the emergence of antibiotic-resistant strains must be carefully balanced. Therefore, although antibiotics may be underused in the treatment of IBD, their integration into clinical practice must be approached judiciously and individually.
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Affiliation(s)
- Oren Ledder
- Shaare Zedek Medical Center, Jerusalem, Israel.,The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Dan Turner
- Shaare Zedek Medical Center, Jerusalem, Israel.,The Hebrew University of Jerusalem, Jerusalem, Israel
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Cao Y, Wu K, Mehta R, Drew DA, Song M, Lochhead P, Nguyen LH, Izard J, Fuchs CS, Garrett WS, Huttenhower C, Ogino S, Giovannucci EL, Chan AT. Long-term use of antibiotics and risk of colorectal adenoma. Gut 2018; 67:672-678. [PMID: 28377387 PMCID: PMC5628103 DOI: 10.1136/gutjnl-2016-313413] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 02/07/2017] [Accepted: 02/09/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Recent evidence suggests that antibiotic use, which alters the gut microbiome, is associated with an increased risk of colorectal cancer. However, the association between antibiotic use and risk of colorectal adenoma, the precursor for the majority of colorectal cancers, has not been investigated. DESIGN We prospectively evaluated the association between antibiotic use at age 20-39 and 40-59 (assessed in 2004) and recent antibiotic use (assessed in 2008) with risk of subsequent colorectal adenoma among 16 642 women aged ≥60 enrolled in the Nurses' Health Study who underwent at least one colonoscopy through 2010. We used multivariate logistic regression to calculate ORs and 95% CIs. RESULTS We documented 1195 cases of adenoma. Increasing duration of antibiotic use at age 20-39 (ptrend=0.002) and 40-59 (ptrend=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared with non-users, women who used antibiotics for ≥2 months between age 20 and 39 had a multivariable OR of 1.36 (95% CI 1.03 to 1.79). Women who used ≥2 months of antibiotics between age 40 and 59 had a multivariable OR of 1.69 (95% CI 1.24 to 2.31). The associations were similar for low-risk versus high-risk adenomas (size ≥1 cm, or with tubulovillous/villous histology, or ≥3 detected lesions), but appeared modestly stronger for proximal compared with distal adenomas. In contrast, recent antibiotic use within the past four years was not associated with risk of adenoma (ptrend=0.44). CONCLUSIONS Long-term antibiotic use in early-to-middle adulthood was associated with increased risk of colorectal adenoma.
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Affiliation(s)
- Yin Cao
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Raaj Mehta
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - David A. Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Paul Lochhead
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Long H. Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Jacques Izard
- Food Science and Technology Department, University of Nebraska, Lincoln, NE
| | - Charles S. Fuchs
- Yale Cancer Center, New Haven, CT
- Department of Medicine, Yale School of Medicine, New Haven, CT
- Smilow Cancer Hospital, New Haven, CT
| | - Wendy S. Garrett
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
- Broad Institute of MIT and Harvard, Cambridge, MA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
- Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Edward L. Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Broad Institute of MIT and Harvard, Cambridge, MA
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13
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Barko P, McMichael M, Swanson K, Williams D. The Gastrointestinal Microbiome: A Review. J Vet Intern Med 2018; 32:9-25. [PMID: 29171095 PMCID: PMC5787212 DOI: 10.1111/jvim.14875] [Citation(s) in RCA: 406] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 08/30/2017] [Accepted: 10/12/2017] [Indexed: 12/14/2022] Open
Abstract
The gastrointestinal microbiome is a diverse consortium of bacteria, archaea, fungi, protozoa, and viruses that inhabit the gut of all mammals. Studies in humans and other mammals have implicated the microbiome in a range of physiologic processes that are vital to host health including energy homeostasis, metabolism, gut epithelial health, immunologic activity, and neurobehavioral development. The microbial genome confers metabolic capabilities exceeding those of the host organism alone, making the gut microbiome an active participant in host physiology. Recent advances in DNA sequencing technology and computational biology have revolutionized the field of microbiomics, permitting mechanistic evaluation of the relationships between an animal and its microbial symbionts. Changes in the gastrointestinal microbiome are associated with diseases in humans and animals including inflammatory bowel disease, asthma, obesity, metabolic syndrome, cardiovascular disease, immune-mediated conditions, and neurodevelopmental conditions such as autism spectrum disorder. While there remains a paucity of data regarding the intestinal microbiome in small animals, recent studies have helped to characterize its role in host animal health and associated disease states. This review is intended to familiarize small animal veterinarians with recent advances in the field of microbiomics and to prime them for a future in which diagnostic tests and therapies will incorporate these developments into clinical practice.
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Affiliation(s)
- P.C. Barko
- Veterinary Clinical MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL
| | - M.A. McMichael
- Veterinary Clinical MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL
| | - K.S. Swanson
- Veterinary Clinical MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL
- Department of Animal SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIL
| | - D.A. Williams
- Veterinary Clinical MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL
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14
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Knoop KA, Gustafsson JK, McDonald KG, Kulkarni DH, Kassel R, Newberry RD. Antibiotics promote the sampling of luminal antigens and bacteria via colonic goblet cell associated antigen passages. Gut Microbes 2017; 8:400-411. [PMID: 28267403 PMCID: PMC5570560 DOI: 10.1080/19490976.2017.1299846] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 01/11/2017] [Accepted: 02/21/2017] [Indexed: 02/03/2023] Open
Abstract
Bacterial translocation is defined as the passage of live bacteria from the gut lumen to distant sites. Gut commensal bacteria translocation has been attributed to 'leakiness', or 'barrier breach' of the intestinal epithelium, allowing live bacteria to cross an inappropriately permeable barrier and disseminate to distant sites. Alternatively, studies suggest dendritic cells directly capture luminal commensal bacteria and transport them to distant sites in the steady-state by extending dendrites between epithelial cells into the lumen. Recently we identified translocation of commensal gut bacteria following antibiotics was associated with the formation of goblet cell associated antigen passages (GAPs) in the colon and dependent upon goblet cells (GCs). The translocation of native gut commensal bacteria resulted in low-level inflammatory responses and potentiated mucosal damage in response to concurrent epithelial injury. Here we extend these observations and demonstrate properties of colonic GAPs and observations supporting their priority in the translocation of colonic commensal bacteria.
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Affiliation(s)
- Kathryn A. Knoop
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jenny K. Gustafsson
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Keely G. McDonald
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Devesha H. Kulkarni
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Rachel Kassel
- Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rodney D. Newberry
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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15
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Cao Y, Wu K, Mehta R, Drew DA, Song M, Lochhead P, Nguyen LH, Izard J, Fuchs CS, Garrett WS, Huttenhower C, Ogino S, Giovannucci EL, Chan AT. Long-term use of antibiotics and risk of colorectal adenoma. Gut 2017. [PMID: 28377387 DOI: 10.1136/gutjnl.2016.313413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023]
Abstract
OBJECTIVE Recent evidence suggests that antibiotic use, which alters the gut microbiome, is associated with an increased risk of colorectal cancer. However, the association between antibiotic use and risk of colorectal adenoma, the precursor for the majority of colorectal cancers, has not been investigated. DESIGN We prospectively evaluated the association between antibiotic use at age 20-39 and 40-59 (assessed in 2004) and recent antibiotic use (assessed in 2008) with risk of subsequent colorectal adenoma among 16 642 women aged ≥60 enrolled in the Nurses' Health Study who underwent at least one colonoscopy through 2010. We used multivariate logistic regression to calculate ORs and 95% CIs. RESULTS We documented 1195 cases of adenoma. Increasing duration of antibiotic use at age 20-39 (ptrend=0.002) and 40-59 (ptrend=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared with non-users, women who used antibiotics for ≥2 months between age 20 and 39 had a multivariable OR of 1.36 (95% CI 1.03 to 1.79). Women who used ≥2 months of antibiotics between age 40 and 59 had a multivariable OR of 1.69 (95% CI 1.24 to 2.31). The associations were similar for low-risk versus high-risk adenomas (size ≥1 cm, or with tubulovillous/villous histology, or ≥3 detected lesions), but appeared modestly stronger for proximal compared with distal adenomas. In contrast, recent antibiotic use within the past four years was not associated with risk of adenoma (ptrend=0.44). CONCLUSIONS Long-term antibiotic use in early-to-middle adulthood was associated with increased risk of colorectal adenoma.
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Affiliation(s)
- Yin Cao
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Raaj Mehta
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Paul Lochhead
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Long H Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jacques Izard
- Food Science and Technology Department, University of Nebraska, Lincoln, Nebraska, USA
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, Connecticut, USA.,Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Smilow Cancer Hospital, New Haven, Connecticut, USA
| | - Wendy S Garrett
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.,Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.,Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.,Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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16
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Fecal microbiota transplant in patients with Clostridium difficile infection. J Trauma Acute Care Surg 2016; 81:756-64. [DOI: 10.1097/ta.0000000000001195] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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17
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Knoop KA, McDonald KG, Kulkarni DH, Newberry RD. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut 2016; 65:1100-9. [PMID: 26045138 PMCID: PMC4670297 DOI: 10.1136/gutjnl-2014-309059] [Citation(s) in RCA: 182] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/17/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Antibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria. DESIGN Oral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques. RESULTS Oral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3CR1(+) dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation. CONCLUSIONS These findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders.
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Affiliation(s)
- Kathryn A Knoop
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA, 63110
| | - Keely G McDonald
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA, 63110
| | - Devesha H Kulkarni
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA, 63110
| | - Rodney D Newberry
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA, 63110,Corresponding author: Rodney Newberry MD, Washington University School of Medicine, 660 S. Euclid Ave. Campus Box 8124, St. Louis, MO 63110, Ph: 314 362-2671 Fax: 314 362-2609,
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18
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Abstract
The intestinal microbiota has important metabolic and host-protective functions. Conversely to these beneficial functions, the intestinal microbiota is thought to play a central role in the etiopathogenesis of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), a chronic inflammation of the gut mucosa. Genetic screens and studies in experimental mouse models have clearly demonstrated that IBD can develop due to excessive translocation of bacteria into the bowel wall or dysregulated handling of bacteria in genetically susceptible hosts. In healthy individuals, the microbiota is efficiently separated from the mucosal immune system of the gut by the gut barrier, a single layer of highly specialized epithelial cells, some of which are equipped with innate immune functions to prevent or control access of bacterial antigens to the mucosal immune cells. It is currently unclear whether the composition of the microbial flora or individual bacterial strains or pathogens induces or supports the pathogenesis of IBD. Further research will be necessary to carefully dissect the contribution of individual bacterial species to this disease and to ascertain whether specific modulation of the intestinal microbiome may represent a valuable further option for future therapeutic strategies.
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Affiliation(s)
- Christoph Becker
- Christoph Becker, PhD, is associated professor, Markus F. Neurath, MD, is director, and Stefan Wirtz, PhD, is senior scientist at the Department of Medicine 1 at the Friedrich-Alexander University Erlangen-Nuremberg in Erlangen, Germany
| | - Markus F Neurath
- Christoph Becker, PhD, is associated professor, Markus F. Neurath, MD, is director, and Stefan Wirtz, PhD, is senior scientist at the Department of Medicine 1 at the Friedrich-Alexander University Erlangen-Nuremberg in Erlangen, Germany
| | - Stefan Wirtz
- Christoph Becker, PhD, is associated professor, Markus F. Neurath, MD, is director, and Stefan Wirtz, PhD, is senior scientist at the Department of Medicine 1 at the Friedrich-Alexander University Erlangen-Nuremberg in Erlangen, Germany
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19
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Schaubeck M, Clavel T, Calasan J, Lagkouvardos I, Haange SB, Jehmlich N, Basic M, Dupont A, Hornef M, von Bergen M, Bleich A, Haller D. Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence. Gut 2016; 65:225-37. [PMID: 25887379 PMCID: PMC4752651 DOI: 10.1136/gutjnl-2015-309333] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 03/21/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. DESIGN Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. RESULTS GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis. CONCLUSIONS We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.
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Affiliation(s)
- Monika Schaubeck
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Thomas Clavel
- ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
| | - Jelena Calasan
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Ilias Lagkouvardos
- ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
| | - Sven Bastiaan Haange
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany
| | - Nico Jehmlich
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany
| | - Marijana Basic
- Institut for Medical Microbiology, RWTH University, Aachen, Germany
| | - Aline Dupont
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany,Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Mathias Hornef
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany,Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Martin von Bergen
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany,UFZ, Department of Metabolomics, Helmholtz-Centre for Environmental Research, Leipzig, Germany,Department of Biotechnology, Chemistry and Environmental Engineering, University of Aalborg, Aalborg, Denmark
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany,ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
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20
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Beneficial Effects of Probiotics, Prebiotics, Synbiotics, and Psychobiotics in Inflammatory Bowel Disease. Inflamm Bowel Dis 2015; 21:1674-82. [PMID: 25822014 DOI: 10.1097/mib.0000000000000364] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of diseases characterized by inflammation of the small and large intestine and primarily includes ulcerative colitis and Crohn's disease. Although the etiology of IBD is not fully understood, it is believed to result from the interaction of genetic, immunological, and environmental factors, including gut microbiota. Recent studies have shown a correlation between changes in the composition of the intestinal microbiota and IBD. Moreover, it has been suggested that probiotics and prebiotics influence the balance of beneficial and detrimental bacterial species, and thereby determine homeostasis versus inflammatory conditions. In this review, we focus on recent advances in the understanding of the role of prebiotics, probiotics, and synbiotics in functions of the gastrointestinal tract and the induction and maintenance of IBD remission. We also discuss the role of psychobiotics, which constitute a novel class of psychotropic agents that affect the central nervous system by influencing gut microbiota.
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21
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Hansen JJ, Sartor RB. Therapeutic Manipulation of the Microbiome in IBD: Current Results and Future Approaches. ACTA ACUST UNITED AC 2015; 13:105-20. [PMID: 25595930 DOI: 10.1007/s11938-014-0042-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OPINION STATEMENT Despite recent major strides in our understanding of the genetic and microbial influences that contribute to the development of the inflammatory bowel diseases (IBDs), their etiology continues to be enigmatic. Results from experiments in animal models of IBDs overwhelmingly support a causal role of the microbiota in these diseases, though whether such a cause-effect relationship exists in human IBDs is still uncertain. Therefore, virtually all currently approved and most often prescribed treatments for IBDs are directed toward the over-active immune response in these diseases rather than the intestinal bacteria. Nevertheless, there is an important need for non-immunosuppressive therapies that may present a more favorable risk-benefit profile such as those that selectively target the disruptions in gut microbiota that accompany IBDs. This need has led to clinical trials of various microbial-directed therapies including fecal microbial transplant, antibiotics, probiotics, and prebiotics. Unfortunately, these published studies, many of which are small, have generally failed to demonstrate a consistent benefit of these agents in IBDs, thus leading to slow acceptance of microbe-focused treatments for these conditions. In this article, we review and summarize the microbial basis for IBDs and the results of the most recent trials of fecal microbial transplant, antibiotics, probiotics, and prebiotics in IBDs. We also comment on possible safety concerns with these agents, speculate on why they have failed to show efficacy in certain clinical settings, and propose strategies to improve their usefulness.
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Affiliation(s)
- Jonathan J Hansen
- Department of Medicine, University of North Carolina at Chapel Hill, CB 7032, Chapel Hill, NC, 27599, USA,
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22
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Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: State of the art and future perspectives. World J Gastroenterol 2015; 21:21-46. [PMID: 25574078 PMCID: PMC4284336 DOI: 10.3748/wjg.v21.i1.21] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/31/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Distinction between Crohn’s disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
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23
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Sang Y, Blecha F. Alternatives to antibiotics in animal agriculture: an ecoimmunological view. Pathogens 2014; 4:1-19. [PMID: 25551290 PMCID: PMC4384068 DOI: 10.3390/pathogens4010001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 12/24/2014] [Indexed: 12/13/2022] Open
Abstract
Ecological immunology (or ecoimmunology) is a new discipline in animal health and immunology that extends immunologists’ views into a natural context where animals and humans have co-evolved. Antibiotic resistance and tolerance (ART) in bacteria are manifested in antibiosis-surviving subsets of resisters and persisters. ART has emerged though natural evolutionary consequences enriched by human nosocomial and agricultural practices, in particular, wide use of antibiotics that overwhelms other ecological and immunological interactions. Most previous reviews of antibiotic resistance focus on resisters but overlook persisters, although both are fundamental to bacteria survival through antibiosis. Here, we discuss resisters and persisters together to contrast the distinct ecological responses of persisters during antibiotic stress and propose different regimens to eradicate persisters. Our intention is not only to provide an ecoimmunological interpretation, but also to use an ecoimmunological system to categorize available alternatives and promote the discovery of prospective approaches to relieve ART problems within the general scope of improving animal health. Thus, we will categorize available alternatives to antibiotics and envision applications of ecoimmunological tenets to promote related studies in animal production.
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Affiliation(s)
- Yongming Sang
- Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
| | - Frank Blecha
- Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
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