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Zhang F, Kamm MA, Wu X, Kao D, Borody TJ, Chen LA, He X, Fischer M, Wong SH, Ng SC, Cui B, Chan FKL, Nie Y, Sood A, Li J, Sun Y, Dai I, Chen Q, Lv M, Zhang Z, Ianiro G, Yang Y, Kelly CR. Preferred Reporting Items for Microbiotherapy (PRIM) Guidelines Across Medical Disciplines: An International Delphi Consensus. J Gastroenterol Hepatol 2025. [PMID: 40143713 DOI: 10.1111/jgh.16947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 02/06/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025]
Abstract
Microbiotherapy has opened new avenues for managing dysbiosis-related diseases. However, many studies did not cover all the necessary reporting items for microbiotherapy making the interpretation of results, safety assessment, technology extension, and even the transparency of legitimacy difficult. This project consisted of 2 phases. First, we proposed an initial preferred reporting items for microbiotherapy (PRIM) checklist and applied it to oncology studies from 2011 to 2023 according to Meta-Analyses guideline. Only 39.3% (n = 64) of these studies (n = 163) met all PRIM checklist items. The culture-based microbiotherapy (CMT) studies had higher score than non-culture-based (NMT) ones (p = 0.018). In the second phase, the expert panel consisting of 22 specialists from eight countries across Asia, Australia, Europe, and North America refined and finalized the PRIM guidelines (named as PRIM 2024) through Delphi consensus. The PRIM 2024 guidelines conclude 10 statements and 18 points on diagnosis, delivery route, source, classification, preparation, dosage, state, concomitant treatment, efficacy, and safety. The panel defined less than 80% of all PRIM points (14 points) as low-quality reports. These guidelines are recommended for reporting on microbiotherapy in clinical studies and reports on compassionate use, including but not limited to fecal microbiota transplantation, phage therapy, probiotics, and synbiotics. These consistent and transparent reporting items can help researchers and practitioners better evaluate, compare, implement research findings in microbiotherapy.
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Affiliation(s)
- Faming Zhang
- Department of Microbiota Medicine and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Michael A Kamm
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Xia Wu
- Department of Microbiota Medicine and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Thomas J Borody
- Center for Digestive Diseases, Sydney, New South Wales, Australia
| | - Lea Ann Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers, New Brunswick, USA
| | - Xingxiang He
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Monika Fischer
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sunny H Wong
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, National Healthcare Group, Singapore
| | - Siew C Ng
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Bota Cui
- Department of Microbiota Medicine and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Francis K-L Chan
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Yongzhan Nie
- National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Yang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ishikawa Dai
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Qiyi Chen
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Shanghai, China
| | - Muhan Lv
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zulun Zhang
- Department of Microbiota Medicine and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gianluca Ianiro
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Yunsheng Yang
- National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Colleen R Kelly
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Williams EG, Alissa M, Alsugoor MH, Albakri GS, Altamimi AA, Alabdullateef AA, Almansour NM, Aldakheel FM, Alessa S, Marber M. Integrative approaches to atrial fibrillation prevention and management: Leveraging gut health for improved cardiovascular outcomes in the aging population. Curr Probl Cardiol 2025; 50:102952. [PMID: 39626858 DOI: 10.1016/j.cpcardiol.2024.102952] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 11/30/2024] [Indexed: 12/14/2024]
Abstract
Atrial fibrillation (AF) is a prevalent clinical arrhythmia associated with a high incidence and severe complications such as cerebral embolism and heart failure. While the etiology and pathogenesis of AF involve numerous factors, recent research emphasizes the significant role of intestinal microbiota imbalance in the emergence and progression of AF, particularly among older adults. This review investigates the mechanisms by which intestinal flora and their metabolites contribute to the onset of AF in the elderly, highlighting novel interactions between gut health and cardiac function. Current literature often overlooks these critical connections, indicating a substantial research gap in understanding how dysbiosis may exacerbate AF and hinder recovery. Furthermore, exploring the bidirectional relationship between the gut microbiome and systemic inflammation in the context of AF provides a unique perspective that has yet to be thoroughly investigated. Future research should focus on longitudinal studies assessing gut microbiota composition and function in AF patients and consider probiotics or prebiotics as potential adjunctive therapies for mitigating AF. This comprehensive approach may pave the way for innovative treatments integrating cardiology with gastroenterology, enhancing patient outcomes through a holistic understanding of health.
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Affiliation(s)
- Emma Grace Williams
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112; 2 Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Mahdi H Alsugoor
- Department of Emergency Medical Services, Faculty of Health Sciences, AlQunfudah, Umm Al-Qura University, Makkah 21912, Saudi Arabia
| | - Ghadah Shukri Albakri
- Department of Teaching and Learning, College of Education and Human Development, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Ali A Altamimi
- Department of Medical Laboratory, Prince Sultan Air Base Hospital, Al-Kharj, Saudi Arabia
| | | | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia
| | - Fahad M Aldakheel
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
| | - Salem Alessa
- Department of Medical Laboratory, Al Kharj Military Industries Corporation Hospital, Al-kharj, Saudi Arabia
| | - Michael Marber
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
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Lin DJ, Hu DX, Wu QT, Huang LG, Lin ZH, Xu JT, He XX, Wu L. Analysis of influencing factors of washed microbiota transplantation in treating patients with metabolic syndrome. Front Nutr 2025; 12:1508381. [PMID: 39963663 PMCID: PMC11830617 DOI: 10.3389/fnut.2025.1508381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Background and aims Metabolic Syndrome (MS) is a cluster of metabolic abnormalities closely associated with hypertension, diabetes, hyperlipidemia, obesity, etc. Our previous research indicated that fecal microbiota transplantation (FMT) could improve MS, but the factors influencing the efficacy of washed microbiota transplantation (WMT) in treating MS patients remain unclear. The objective of this study is to analyze the influencing factors of WMT in treating MS patients. Methods The clinical data and influencing factors related to MS patients were collected retrospectively. Not only the changes in body mass index [BMI = weight (kg)/height (m)2], blood glucose, blood lipids, and blood pressure were analyzed, but also the influencing factors of WMT in treating MS patients were carried out based on Logistic Regression. The 16S rRNA gene amplicon sequencing was performed on fecal samples before and after WMT treatment. Results A total of 210 patients were included, including 68 patients in the WMT group and 142 patients in the drug treatment (DT) group. WMT had a significant improvement and ASCVD downregulation effect on MS patients, and 42.65% of MS patients removed the label of MS after WMT treatment. Independent influencing factors for treating MS patients through WMT include age < 60 years old, high smoking index, infection, single donor selection, single-course WMT treatment, and having hypertension, diabetes, or obesity. WMT treated MS patients by maintaining the balance of gut microbiota. Conclusions WMT has a significant effect in improving MS and downregulating ASCVD risk stratification. The therapeutic effect of WMT on MS patients is closely related to their age, smoking index, infection, chronic disease status, donor type, and WMT courses. Therefore, we can improve the efficacy of WMT by reducing independent influencing factors that affect gut microbiota homeostasis.
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Affiliation(s)
- De-Jiang Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Dong-Xia Hu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing-Ting Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lin-Gui Huang
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zi-Han Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jia-Ting Xu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xing-Xiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lei Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- School of Biological Sciences and Engineering, South China University of Technology, Guangzhou, China
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Khanna S. Microbiota restoration for recurrent Clostridioides difficile infection. Panminerva Med 2024; 66:417-426. [PMID: 39382853 DOI: 10.23736/s0031-0808.24.05111-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
Since the publication of the recent North American and European guidelines on management of Clostridioides difficile infection (CDI), new evidence describing the epidemiology, testing and treatment of CDI has emerged. Despite all advances in infection control and antibiotic stewardship, the incidence and burden of CDI in the hospitals and the community remains at a stable high. Coupled with the incidence of primary CDI, there is a stable high incidence of recurrent CDI. Testing for primary and recurrent CDI remains a clinical challenge owing to high sensitivity of the PCR (leading to false positives) and somewhat limited sensitivity of EIA for toxin. The pathophysiology of recurrent CDI involves an ongoing disruption of the microbiota owing to the infection and the treatment of CDI employed. Broad spectrum antibiotics such as vancomycin leads to further disruption of microbiota compared to fidaxomicin which has a lower disruption of the microbiota and leads to fewer recurrences. Owing to these data fidaxomicin is considered as the first line antibiotic for recurrent CDI. Intravenous bezlotoxumab is a monoclonal antibody that reduces the risk of recurrence in high-risk patients but does not restore the microbiota. Experimental fecal microbiota transplantation (FMT) has been available for more than a decade. Owing to the success of FMT, two new non-invasive donor dependent Food and Drug Administration (FDA) approved therapies have been available since late 2022. This review summarizes all these conundrums regarding CDI and provides clinical pearls to use in day-to-day practice.
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Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA -
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Lin D, Hu D, Song Y, He X, Wu L. Long-term efficacy of washed microbiota transplantation in overweight patients. Eur J Clin Invest 2024; 54:e14260. [PMID: 38858775 DOI: 10.1111/eci.14260] [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: 04/01/2024] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Faecal microbiota transplantation holds promise in mitigating fat accumulation and improving obesity. This study aimed to evaluate the long-term efficacy of washed microbiota transplantation (WMT) among overweight patients. METHODS The clinical data pertaining to the treatment of patients with WMT were collected retrospectively. Compared alterations in body mass index (BMI), blood glucose, blood lipids and blood pressure prior to and following WMT treatment. Comprehensive efficacy evaluation and atherosclerosis cardiovascular disease (ASCVD) grading evaluation were carried out, with an analysis of gut microbiota composition before and after WMT. RESULTS A total of 186 patients were included (80 overweight, 106 normal weight). WMT not only had the effect of improving overweight patients to the normal weight patients (p < .001), but also could significantly reduce BMI in the long term by restoring gut microbiota homeostasis (p < .001). In addition, the BMI improvement value of multi course was more significant than that of single course or double course. WMT had a significant ASCVD downgrade effect on the high-risk and medium-risk groups outside 1 year, while it did not increase the risk of upgrading ASCVD for low-risk group. CONCLUSIONS WMT could significantly reduce the BMI of overweight patients and still had an improvement effect in the long term.
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Affiliation(s)
- Dejiang Lin
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Dongxia Hu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Youlin Song
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xingxiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lei Wu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Boyle BL, Khanna S. Fecal microbiota live - jslm (Rebyota™/RBL) for management of recurrent Clostridioides difficile infection. Future Microbiol 2024; 19:1243-1251. [PMID: 38989699 PMCID: PMC11633411 DOI: 10.1080/17460913.2024.2364583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 06/03/2024] [Indexed: 07/12/2024] Open
Abstract
There is an unmet need for effective treatments of Clostridioides difficile infection, an emerging health crisis in the United States. The management of C. difficile infection should include treatment of active infection and a strategy to prevent recurrence. Current gold standard therapy includes oral antibiotics which predispose patients to gut dysbiosis and increase the risk of recurrent infection. Addressing dysbiosis via fecal microbiota transplantation is an active and promising area of research, but studies have lacked standardization which makes outcome and safety data difficult to interpret. Rebyota™, formerly known as RBX2660, is a live biotherapeutic product designed using a standardized protocol and manufacturing process that has been shown to be effective for preventing recurrent C. difficile infection.
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Affiliation(s)
| | - Sahil Khanna
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN55905, USA
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He H, Li M, Qiu Y, Wu Z, Wu L. Washed microbiota transplantation improves sleep quality in patients with sleep disorder by the gut-brain axis. Front Neurosci 2024; 18:1415167. [PMID: 38979127 PMCID: PMC11228149 DOI: 10.3389/fnins.2024.1415167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 06/07/2024] [Indexed: 07/10/2024] Open
Abstract
Background The clinical impact of washed microbiota transplantation (WMT) from healthy donors in sleep disorder (SD) patients is unclear. This study aimed to investigate the effect of WMT in SD patients. Methods The clinical data were collected from patients with different indications receiving 1-3 courses of WMT, divided into two groups by 7 points of PSQI scale. The score of PQSI and SF-36 scale was used to assess the improvement in sleep quality and life quality among patients with sleep disorders following WMT. Finally, 16S rRNA gene amplicon sequencing was performed on fecal samples of patients with sleep disorders before and after WMT. Results WMT significantly improved sleep quality in patients with sleep disorder in the short and medium term. WMT significantly improved sleep latency, sleep time and total score in the short term. WMT significantly improved sleep quality and total score in the medium term. In terms of sleep quality and sleep latency, the improvement value also increased with the increase of treatment course, and the improvement effect of multiple treatment course was better than that of single and double treatment course. In the total score, the improvement effect of double and multiple treatment was better than that of single treatment. WMT also improved quality of life in the sleep disorder group. WMT significantly improved general health, vitality, social function and mental health in the short term. WMT significantly improved role-physical, general health, vitality, and mental health in the medium term. WMT regulated the disturbed gut microbiota in patients with sleep disorders. In the normal sleep group, WMT had no effect on the decline of sleep quality in the short, medium and long term, and had an improving effect on the quality of life. Conclusion WMT could significantly improve sleep quality and life quality in patients with sleep disorders with no adverse events. The improvement in sleep quality resulting from WMT could lead to an overall enhancement in life quality. WMT could be a potentially effective treatment for patients with sleep disorders by regulating the gut microbiota.
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Affiliation(s)
- Hongxin He
- Sun Yat-sen University School of Medicine, Guangzhou, China
| | - Manqing Li
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangzhou Xinhai Hospital, Guangzhou, China
| | - Yifan Qiu
- Sun Yat-sen University School of Medicine, Guangzhou, China
| | - Zhiqing Wu
- Sun Yat-sen University School of Medicine, Guangzhou, China
| | - Lei Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- School of Biological Sciences and Engineering, South China University of Technology, Guangzhou, China
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Larsen C, Offersen SM, Brunse A, Pirolo M, Kar SK, Guadabassi L, Thymann T. Effects of early postnatal gastric and colonic microbiota transplantation on piglet gut health. J Anim Sci Biotechnol 2023; 14:158. [PMID: 38143275 PMCID: PMC10749501 DOI: 10.1186/s40104-023-00954-w] [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: 07/08/2023] [Accepted: 10/22/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Diarrhea is a major cause of reduced growth and mortality in piglets during the suckling and weaning periods and poses a major threat to the global pig industry. Diarrhea and gut dysbiosis may in part be prevented via improved early postnatal microbial colonization of the gut. To secure better postnatal gut colonization, we hypothesized that transplantation of colonic or gastric content from healthy donors to newborn recipients would prevent diarrhea in the recipients in the post-weaning period. Our objective was to examine the impact of transplanting colonic or gastric content on health and growth parameters and paraclinical parameters in recipient single-housed piglets exposed to a weaning transition and challenged with enterotoxigenic Escherichia coli (ETEC). METHODS Seventy-two 1-day-old piglets were randomized to four groups: colonic microbiota transplantation (CMT, n = 18), colonic content filtrate transplantation (CcFT, n = 18), gastric microbiota transplantation (GMT, n = 18), or saline (CON, n = 18). Inoculations were given on d 2 and 3 of life, and all piglets were milk-fed until weaning (d 20) and shortly after challenged with ETEC (d 24). We assessed growth, diarrhea prevalence, ETEC concentration, organ weight, blood parameters, small intestinal morphology and histology, gut mucosal function, and microbiota composition and diversity. RESULTS Episodes of diarrhea were seen in all groups during both the milk- and the solid-feeding phase, possibly due to stress associated with single housing. However, CcFT showed lower diarrhea prevalence on d 27, 28, and 29 compared to CON (all P < 0.05). CcFT also showed a lower ETEC prevalence on d 27 (P < 0.05). CMT showed a higher alpha diversity and a difference in beta diversity compared to CON (P < 0.05). Growth and other paraclinical endpoints were similar across groups. CONCLUSION In conclusion, only CcFT reduced ETEC-related post-weaning diarrhea. However, the protective effect was marginal, suggesting that higher doses, more effective modalities of administration, longer treatment periods, and better donor quality should be explored by future research to optimize the protective effects of transplantation.
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Affiliation(s)
- Christina Larsen
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark
| | - Simone Margaard Offersen
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark
| | - Anders Brunse
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark
| | - Mattia Pirolo
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark
| | - Soumya Kanti Kar
- Animal Nutrition, Wageningen Livestock Research, Wageningen University & Research, 1 De Elst, 6708, Wageningen, The Netherlands
| | - Luca Guadabassi
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark
| | - Thomas Thymann
- Department of Veterinary and Animal Science, University of Copenhagen, Dyrlægevej 68, 1870, Frederiksberg C, Denmark.
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Xu J, Zhang Y, Fang XH, Liu Y, Huang YB, Ke ZL, Wang Y, Zhang YF, Zhang Y, Zhou JH, Su HT, Chen N, Liu YL. The oral bacterial microbiota facilitates the stratification for ulcerative colitis patients with oral ulcers. Ann Clin Microbiol Antimicrob 2023; 22:99. [PMID: 37946238 PMCID: PMC10633958 DOI: 10.1186/s12941-023-00646-3] [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: 07/13/2023] [Accepted: 10/24/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Clinically, a large part of inflammatory bowel disease (IBD) patients is complicated by oral lesions. Although previous studies proved oral microbial dysbiosis in IBD patients, the bacterial community in the gastrointestinal (GI) tract of those IBD patients combined with oral ulcers has not been profiled yet. METHODS In this study, we enrolled four groups of subjects, including healthy controls (CON), oral ulcer patients (OU), and ulcerative colitis patients with (UC_OU) and without (UC) oral ulcers. Bio-samples from three GI niches containing salivary, buccal, and fecal samples, were collected for 16S rRNA V3-V4 region sequencing. Bacterial abundance and related bio-functions were compared, and data showed that the fecal microbiota was more potent than salivary and buccal microbes in shaping the host immune system. ~ 22 UC and 10 UC_OU 5-aminosalicylate (5-ASA) routine treated patients were followed-up for six months; according to their treatment response (a decrease in the endoscopic Mayo score), they were further sub-grouped as responding and non-responding patients. RESULTS We found those UC patients complicated with oral ulcers presented weaker treatment response, and three oral bacterial genera, i.e., Fusobacterium, Oribacterium, and Campylobacter, might be connected with treatment responding. Additionally, the salivary microbiome could be an indicator of treatment responding in 5-ASA routine treatment rather than buccal or fecal ones. CONCLUSIONS The fecal microbiota had a strong effect on the host's immune indices, while the oral bacterial microbiota could help stratification for ulcerative colitis patients with oral ulcers. Additionally, the oral microbiota had the potential role in reflecting the treatment response of UC patients. Three oral bacteria genera (Fusobacterium, Oribacterium, and Campylobacter) might be involved in UC patients with oral ulcers lacking treatment responses, and monitoring oral microbiota may be meaningful in assessing the therapeutic response in UC patients.
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Affiliation(s)
- Jun Xu
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yu Zhang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiao-Hui Fang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yun Liu
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yi-Bo Huang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Zi-Liang Ke
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yi-Fan Zhang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yang Zhang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Jian-Hua Zhou
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Hui-Ting Su
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Ning Chen
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yu-Lan Liu
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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10
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Wu L, Lin ZH, Lu XJ, Hu X, Zhong HJ, Lin DJ, Liu T, Xu JT, Lin WY, Wu QP, He XX. Washed Microbiota Transplantation Improves Patients with Overweight by the Gut Microbiota and Sphingolipid Metabolism. Biomedicines 2023; 11:2415. [PMID: 37760856 PMCID: PMC10525780 DOI: 10.3390/biomedicines11092415] [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: 07/03/2023] [Revised: 07/25/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Overweight (OW) and obesity have become increasingly serious public health problems worldwide. The clinical impact of washed microbiota transplantation (WMT) from healthy donors in OW patients is unclear. This study aimed to investigate the effect of WMT in OW patients. METHODS The changes in body mass index (BMI = weight (kg)/height (m)2), blood glucose, blood lipids and other indicators before and after WMT were compared. At the same time, 16S rRNA gene amplicon sequencing was performed on fecal samples of OW patients before and after transplantation. Finally, serum samples were tested for sphingolipids targeted by lipid metabolomics. RESULTS A total of 166 patients were included, including 52 in the OW group and 114 in the normal weight (NOW) group. For OW patients, WMT significantly improved the comprehensive efficacy of OW. In the short term (about 1 month) and medium term (about 2 months), a significant reduction in BMI was seen. At the same time, in the short term (about 1 month), liver fat attenuation (LFA), triglyceride (TG) and fasting blood glucose (FBG) were significantly reduced. In the long term (about 5 months), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein (non-HDL-c), etc. were significantly reduced. WMT improved the gut microbiota of OW patients, and also had an improvement effect on OW patients by regulating sphingolipid metabolism. CONCLUSION WMT had a significant improvement effect on OW patients. WMT could restore gut microbiota homeostasis and improve OW patients by regulating sphingolipid metabolism.
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Affiliation(s)
- Lei Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Zi-Han Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Xin-Jian Lu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Xuan Hu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Hao-Jie Zhong
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - De-Jiang Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Tao Liu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Jia-Ting Xu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Wen-Ying Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
| | - Qing-Ping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Xing-Xiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (L.W.); (Z.-H.L.); (X.-J.L.); (X.H.); (H.-J.Z.); (W.-Y.L.)
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11
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Feuerstadt P, Allegretti JR, Khanna S. Practical Use of RBX2660 for the Prevention of Recurrent Clostridioides difficile Infection. Am J Gastroenterol 2023; 118:1303-1306. [PMID: 36695753 DOI: 10.14309/ajg.0000000000002195] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/19/2023] [Indexed: 01/26/2023]
Affiliation(s)
- Paul Feuerstadt
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- PACT-Gastroenterology Center, Hamden, Connecticut, USA
| | - Jessica R Allegretti
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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12
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Feuerstadt P, Harvey A, Yoho DS, Garcia-Diaz JB, Knapple WL, Bancke L. Retrospective Analysis of the Safety and Efficacy of Fecal Microbiota, Live-jslm (REBYOTA TM) Administered Under Enforcement Discretion to Patients With Clostridioides difficile Infection. Open Forum Infect Dis 2023; 10:ofad171. [PMID: 37256213 PMCID: PMC10225279 DOI: 10.1093/ofid/ofad171] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/24/2023] [Indexed: 12/10/2023] Open
Abstract
Background Fecal microbiota, live-jslm (RBL; REBYOTA™), the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent Clostridioides difficile infection (rCDI) in adults, has been evaluated in 5 prospective clinical trials. A retrospective analysis considered the safety and efficacy of RBL administered under US Food and Drug Administration enforcement discretion to patients with rCDI and broad eligibility criteria mimicking real-world practice. Methods We retrospectively identified adults with rCDI treated with RBL under enforcement discretion between November 1, 2015, and September 30, 2019, across 5 study sites. CDI diagnosis was based on site-specific practice. The primary safety set (PSS) included all patients who were naïve to previous RBL treatment and had continuously comprehensive medical records for 6 months following treatment. Results The primary treatment cohort had 94 patients; the PSS included 64 patients with common comorbidities receiving diverse chronic therapeutics. Most treatment-emergent adverse events were mild to moderate in severity and comparable between comorbidity subgroups and the overall population. There were no serious adverse events related to RBL or the administration procedure. In the PSS, 82.8% of RBL-treated patients responded at 8 weeks, of whom 88.7% had sustained response through 6 months. The number of RBL doses administered had no marked effect on outcome. Conclusions Together with prospective clinical trial outcomes, these findings support the efficacy and safety of RBL to prevent rCDI, with diagnostics and comorbidities representative of real-world clinical practice.
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Affiliation(s)
- Paul Feuerstadt
- Yale University School of Medicine; PACT Gastroenterology Center, Hamden, Connecticut, USA
| | - Adam Harvey
- Rebiotix (a Ferring Company), Roseville, Minnesota, USA
| | - David S Yoho
- Department of Gastroenterology, Mid-Atlantic Permanente Medical Group, Springfield, Virginia, USA
| | - Julia B Garcia-Diaz
- Department of Clinical Infectious Diseases Research and Medical Subspecialties, Ochsner Medical Center, New Orleans, Louisiana, USA
| | - Whitfield L Knapple
- Department of Gastroenterology, Arkansas Gastroenterology, North Little Rock, Arkansas, USA
| | - Lindy Bancke
- Rebiotix (a Ferring Company), Roseville, Minnesota, USA
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13
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Larsen C, Andersen AB, Sato H, Brunse A, Thymann T. Transplantation of fecal filtrate to neonatal pigs reduces post-weaning diarrhea: A pilot study. Front Vet Sci 2023; 10:1110128. [PMID: 37008345 PMCID: PMC10060900 DOI: 10.3389/fvets.2023.1110128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
Post-weaning diarrhea (PWD) remains a major source of mortality and morbidity in swine production. Transplantation of bacteria-free filtrate of feces (fecal filtrate transplant, FFT) has shown gut protective effects in neonatal pigs, and early postnatal establishment of the gut microbiome is suggested to determine later stability and robustness of the gut. We, therefore, hypothesized that early postnatal transplantation of bacteria-free feces would have a protective effect against PWD. Using fecal filtrates derived from healthy lactating sows, we compared oral administration of fecal filtrate transplantation (FFT, n = 20) and saline (CON, n = 18) in newborn piglets. We assessed growth, diarrhea prevalence, blood parameters, organ measurements, morphology, and gut brush border enzymes and analyzed luminal bacterial composition using 16S rRNA gene amplicon sequencing. The two groups showed similar average daily gain (ADG) during the suckling period, whereas in the post-weaning period, a negative ADG was observed in both groups. While diarrhea was largely absent in both groups before weaning, there was a lower diarrhea prevalence on days 27 (p = 2.07*10−9), 28 (p = 0.04), and 35 (p = 0.04) in the FFT group relative to CON. At weaning on day 27, the FFT group had higher numbers of red blood cells, monocytes, and lymphocytes, while on day 35, i.e., 1 week after weaning, the two groups were similar regarding hematology. The biochemical profile was largely similar between FFT and CON on days 27 and 35, except for a higher level of alanine aminotransferase and a lower level of Mg in the FFT group. Likewise, organ weights relative to body weight were largely similar on day 35, albeit with a lower stomach weight and more colon content in FFT relative to CON. Gut mucosal percentage and mucosal enzyme activity were similar between the two groups on days 27 and 35. Gut bacterial composition was slightly different on day 35 but not on day 27. In conclusion, early postnatal administration of FFT, showed positive clinical effects in post-weaning pigs, albeit with subtle effects on the gut mucosa and microbiome. Prophylactic treatment with FFT may offer a means to reduce morbidity, yet larger studies are required to document effect size.
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14
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Raue KD, David BT, Fessler RG. Spinal Cord-Gut-Immune Axis and its Implications Regarding Therapeutic Development for Spinal Cord Injury. J Neurotrauma 2023; 40:793-806. [PMID: 36509451 DOI: 10.1089/neu.2022.0264] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) affects ∼1,300,000 people living in the United States. Most research efforts have been focused on reversing paralysis, as this is arguably the most defining feature of SCI. The damage caused by SCI, however, extends past paralysis and includes other debilitating outcomes including immune dysfunction and gut dysbiosis. Recent efforts are now investigating the pathophysiology of and developing therapies for these more distal manifestations of SCI. One exciting avenue is the spinal cord-gut-immune axis, which proposes that gut dysbiosis amplifies lesion inflammation and impairs SCI recovery. This review will highlight the most recent findings regarding gut and immune dysfunction following SCI, and discuss how the central nervous system (CNS), gut, and immune system all coalesce to form a bidirectional axis that can impact SCI recovery. Finally, important considerations regarding how the spinal cord-gut-immune axis fits within the larger framework of therapeutic development (i.e., probiotics, fecal transplants, dietary modifications) will be discussed, emphasizing the lack of interdepartmental investigation and the missed opportunity to maximize therapeutic benefit in SCI.
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Affiliation(s)
- Kristen D Raue
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Brian T David
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Richard G Fessler
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
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15
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Abstract
Fecal microbiota transplantation (FMT) is the process of transplanting stool from a healthy donor into the gut of a patient for therapeutic purposes. Current guidelines recommend FMT for the prevention of multiply recurrent Clostridioides difficile infection (CDI) after two recurrences, with cure rates approaching 90%. Emerging evidence also supports the use of FMT in the management of severe and fulminant CDI, resulting in decreased mortality and colectomy rates compared with standard of care approach. FMT shows promise as salvage therapy for critically-ill, refractory CDI patients who are poor surgical candidates. FMT should be considered early in the clinical course of severe CDI, preferably within 48 hours of failing to respond to antibiotic therapy and volume resuscitation. Besides CDI, ulcerative colitis was more recently identified as a potential treatment target for FMT. Several live biotherapeutics for microbiome restoration are on the horizon.
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Affiliation(s)
- Yao-Wen Cheng
- Department of Gastroenterology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California
| | - Monika Fischer
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
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16
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Chopra T, Hecht G, Tillotson G. Gut microbiota and microbiota-based therapies for Clostridioides difficile infection. Front Med (Lausanne) 2023; 9:1093329. [PMID: 36698844 PMCID: PMC9868170 DOI: 10.3389/fmed.2022.1093329] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/15/2022] [Indexed: 01/10/2023] Open
Abstract
Clostridioides difficile infection poses significant clinical challenges due to its recurrent nature. Current antibiotic management does not address the underlying issue, that of a disturbed gastrointestinal microbiome, called dysbiosis. This provides a supportive environment for the germination of C. difficile spores which lead to infection and toxin production as well as an array of other health conditions. The use of microbiome restoration therapies such as live biotherapeutics can reverse dysbiosis and lead to good clinical outcomes. Several such therapies are under clinical investigation.
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Affiliation(s)
- Teena Chopra
- Division of Infectious Diseases, Wayne State University, Detroit, MI, United States,*Correspondence: Teena Chopra,
| | - Gail Hecht
- Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
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17
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Green JE, McGuinness AJ, Berk M, Castle D, Athan E, Hair C, Strandwitz P, Loughman A, Nierenberg AA, Cryan JF, Mohebbi M, Jacka F. Safety and feasibility of faecal microbiota transplant for major depressive disorder: study protocol for a pilot randomised controlled trial. Pilot Feasibility Stud 2023; 9:5. [PMID: 36624505 PMCID: PMC9827014 DOI: 10.1186/s40814-023-01235-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 01/02/2023] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Mental disorders, including major depressive disorder (MDD), are a leading cause of non-fatal burden of disease globally. Current conventional treatments for depression have significant limitations, and there have been few new treatments in decades. The microbiota-gut-brain-axis is now recognised as playing a role in mental and brain health, and promising preclinical and clinical data suggest Faecal Microbiota Transplants (FMT) may be efficacious for treating a range of mental illnesses. However, there are no existing published studies in humans evaluating the efficacy of FMT for MDD. METHODS AND DESIGN This protocol describes an 8-week, triple-blind, 2:1 parallel group, randomised controlled pilot trial (n = 15), of enema-delivered FMT treatment (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. There will be a further 26-week follow-up to monitor longer-term safety. Participants will receive four FMT or placebo enemas over four consecutive days. The primary aims of the study are to evaluate feasibility and safety of FMT as an adjunctive treatment for MDD in adults. Changes in gut microbiota will be assessed as a secondary outcome. Other data will be collected, including changes in depression and anxiety symptoms, and safety parameters. DISCUSSION Modification of the microbiota-gut-brain axis via FMT is a promising potential treatment for MDD, but there are no published rigorous clinical trials evaluating its use. If this study finds that our FMT strategy is safe and feasible, a larger fully powered RCT is planned. Further high-quality research in this field is urgently needed to address unmet need. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry: ACTRN12621000932864.
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Affiliation(s)
- Jessica E. Green
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.1002.30000 0004 1936 7857Monash Alfred Psychiatry Research Centre (MAPrc), Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia ,grid.466993.70000 0004 0436 2893Department of Psychiatry, Peninsula Health, Frankston, Australia
| | - Amelia J. McGuinness
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Michael Berk
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.1008.90000 0001 2179 088XDepartment of Psychiatry, University of Melbourne, Parkville, Australia ,grid.488596.e0000 0004 0408 1792Orygen Youth Health Research Centre and the Centre of Youth Mental Health, Melbourne, Australia ,grid.418025.a0000 0004 0606 5526The Florey Institute for Neuroscience and Mental Health, Parkville, Australia ,grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia
| | - David Castle
- grid.17063.330000 0001 2157 2938Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Eugene Athan
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia ,grid.1021.20000 0001 0526 7079School of Medicine, Deakin University, Geelong, Australia
| | - Christopher Hair
- grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia
| | | | - Amy Loughman
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Andrew A. Nierenberg
- grid.32224.350000 0004 0386 9924Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XHarvard Medical School, Boston, MA USA
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork and APC Microbiome, Cork, Ireland
| | - Mohammadreza Mohebbi
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Felice Jacka
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.416107.50000 0004 0614 0346Centre for Adolescent Health, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Australia ,grid.418393.40000 0001 0640 7766Black Dog Institute, Melbourne, Australia ,grid.1011.10000 0004 0474 1797James Cook University, Townsville, Australia
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18
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Zhang J, Zhu G, Wan L, Liang Y, Liu X, Yan H, Zhang B, Yang G. Effect of fecal microbiota transplantation in children with autism spectrum disorder: A systematic review. Front Psychiatry 2023; 14:1123658. [PMID: 36937721 PMCID: PMC10017995 DOI: 10.3389/fpsyt.2023.1123658] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
Background Fecal microbiota transplantation (FMT) may be helpful in the treatment of autism spectrum disorder (ASD) as rebalancing the gut microbiome has been shown to potentially improve behavioral symptoms in children with ASD. Methods This systematic review was conducted to assess the effect of FMT for children with ASD. The Embase, PubMed, Web of Science, and Cochrane Library databases were searched for articles published from inception to October 6, 2022. Two reviewers independently screened the identified records and undertook data extraction. Results The search identified a total of five studies: two prospective open-label studies, two retrospective observational studies, and a case report; however, no randomized controlled trial was identified. All five studies reported a significant post-FMT-treatment improvement in neuropsychological assessment of ASD. The two prospective open-label studies suggested that the Autism Behavior Checklist (ABC) score, and the Social Responsiveness Scale (SRS) score at the posttreatment assessment decreased from the baseline (Wilcoxon signed-rank test; all p < 0.01]). The two retrospective observational studies suggested that FMT helped to improve the ASD symptoms. One observational study reported that the Childhood Autism Rating Scale (CARS) score and ABC score of the constipation group decreased from the baseline after the second course assessment (CARS [baseline: mean 35.25 ± standard deviation 4.36, second course: 32.5 ± 3.1, p = 0.015]; ABC [baseline: 56.21 ± 16.08, second course: 46.54 ± 16.54, p = 0.046]). Another observational study found that both ABC and CARS scores decreased as the number of FMT courses increased, and significant differences were found at the end of each course as compared with the baseline. Conclusion Compared with the baseline, FMT significantly improved symptoms of autism in children with ASD in observational studies. However, rigorously designed randomized controlled clinical trials are needed to establish the safety and efficacy of FMT as a treatment for ASD.
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Affiliation(s)
- Jing Zhang
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Gang Zhu
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Lin Wan
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Yan Liang
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xinting Liu
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Huimin Yan
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Bo Zhang
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- Bo Zhang
| | - Guang Yang
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Pediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Guang Yang
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19
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Orenstein R. The Role of Microbiome-Based Therapeutics in Clostridioides difficile Infection: Durable, Long-Term Results of RBX2660. Infect Dis Ther 2023; 12:1-7. [PMID: 36342653 PMCID: PMC9868035 DOI: 10.1007/s40121-022-00714-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 10/05/2022] [Indexed: 11/09/2022] Open
Abstract
A recently published manuscript described findings from a phase 2 open label study of the microbiota-based live biotherapeutic product RBX2660 in patients with two or more previous recurrent Clostridioides difficile infection (rCDI) episodes, and described long-term safety and sustained treatment success through 24 months. As previous studies have typically focused on short-term clinical outcomes, these new data provide insight into the tolerability, safety, and efficacy of RBX2660 over the long term. When microbiota-based products were first evaluated, the long-term efficacy and safety were principal concerns of the United States Food and Drug Administration. Microbiota-based live biotherapeutic products (LBPs) represent an emerging approach to the management of CDI and perhaps other gastrointestinal and medical conditions whose pathogenesis is defined by microbial dysbiosis. RBX2660 is a human-derived, broad consortium microbiota-based LBP that consists of a population of microbes obtained from healthy stool donors and may reflect the symbiotic nature of a healthy colonic microbiome. RBX2660 is rectally administered and does not require sedation or special preparation of the recipient. Potential advantages of the rectal administration of RBX2660 include the ease of administration and lack of need for any bowel preparation, which may benefit those who are frail, have swallowing issues, or cannot take bowel laxative preparations. In this multicenter prospective trial of rCDI, patients who achieved treatment success 8 weeks after receiving RBX2660 continued to have a sustained clinical response over the course of long-term follow-up, with more than 90% of treatment responders remaining CDI-free at 6, 12, and 24 months. Following receipt of RBX2660, the gut microbiota of those with treatment success were restored from a dysbiotic state to become more diverse and similar to RBX2660 composition. The restoration of the microbiota occurred as early as 7 days after RBX2660 administration and remained stable through the 24-month analysis. No new adverse outcomes were observed during the prospective assessment, and the safety profile of RBX2660 was consistent with previous studies. Based on the clinical studies, RBX2660 will most likely benefit those with ≥ 1 rCDI episode or those who are at a high risk of subsequent rCDI, such as patients who have comorbid conditions including renal disease, heart disease, or inflammatory bowel disease, or who are immunosuppressed. The role of microbiome-based therapeutics in 47 Clostridioides difficile infection: Durable, long-term results of RBX2660 (MP4 511833 KB).
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Affiliation(s)
- Robert Orenstein
- grid.417468.80000 0000 8875 6339Division of Infectious Diseases, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ 85054 USA
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Saifi S, Swaminathan A, Devi P, Chattopadhyay P, Gupta S, Garg A, Saxena S, Parveen S, Pandey R. A Tour-d’Horizon of microbiota therapeutics for metabolic disorders. MICROBIOME THERAPEUTICS 2023:231-253. [DOI: 10.1016/b978-0-323-99336-4.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Seekatz AM, Safdar N, Khanna S. The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol 2022; 15:17562848221134396. [PMID: 36425405 PMCID: PMC9679343 DOI: 10.1177/17562848221134396] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 10/04/2022] [Indexed: 11/21/2022] Open
Abstract
UNLABELLED The species composition of the human gut microbiota is related to overall health, and a healthy gut microbiome is crucial in maintaining colonization resistance against pathogens. Disruption of gut microbiome composition and functionality reduces colonization resistance and has been associated with several gastrointestinal and non-gastrointestinal diseases. One prime example is Clostridioides difficile infection (CDI) and subsequent recurrent infections that occur after the development of systemic antibiotic-related dysbiosis. Standard-of-care antibiotics used for both acute and recurrent infections do not address dysbiosis and often worsen the condition. Moreover, monoclonal antibodies, recommended in conjunction with standard-of-care antibiotics for the prevention of recurrent CDI in patients at high risk of recurrence, reduce recurrences but do not address the underlying dysbiosis. Fecal microbiota transplantation (FMT) is an evolving therapeutic strategy in which microbes are harvested from healthy donor stool and transplanted into the gut of a recipient to restore the gut microbiome. Although effective in the prevention of recurrent CDI, some existing challenges include screening and the standardization of stool acquisition and processing. Recent safety alerts by the US Food and Drug Administration raised concern about the possibility of transmission of multidrug-resistant organisms or severe acute respiratory syndrome coronavirus 2 via FMT. Increased knowledge that microbes are beneficial in restoring the gut microbiome has led to the clinical development of several newer biotherapeutic formulations that are more regulated than FMT, which may allow for improved restoration of the gut microbiome and prevention of CDI recurrence. This review focuses on mechanisms by which gut microbiome restoration could influence colonization resistance against the pathogen C. difficile. PLAIN LANGUAGE SUMMARY The Role of the Gut Microbiome in Clostridioides difficile Infection Introduction: A rich and diverse gut microbiome is key to immune system regulation and colonization resistance against pathogens.A disruption in the gut microbiome composition can make the gut more vulnerable to diseases such as Clostridioides difficile infection (CDI), caused by the bacterium C. difficile.CDI management presents a therapeutic dilemma, as it is usually treated with antibiotics that can treat the infection but also can damage the microbiome.Treatment of CDI using antibiotics can further reduce microbial diversity and deplete beneficial bacteria from the gut leading to a condition called dysbiosis.Antibiotic treatment can be followed by therapies that restore the gut microbiota, boost colonization resistance, and prevent the development of antimicrobial resistance.It is important to evaluate treatment options to determine their safety and effectiveness. Methods: The researchers provided an overview of the mechanisms that the gut microbiome uses to prevent colonization of the gut by pathogens.They subsequently reviewed the efficacy and shortcomings of the following treatments for CDI: - Antibiotics- Monoclonal antibodies- Fecal microbiota transplantation (FMT) Results: Commensal intestinal bacteria prevent colonization of the gut by pathogens using mechanisms such as: - Competition for key nutrients- Production of inhibitory bile acids- Short-chain fatty acid production- Lowering the luminal pH- Production of bacteriocinsAntibiotic therapy is recommended as a standard treatment for CDI. However, patients are vulnerable to recurrent CDI after discontinuation of the therapy.Monoclonal antibodies that inactivate C. difficile toxins may be recommended along with antibiotics to prevent recurrent CDI. However, this approach does not restore the microbiome.FMT is one method of microbial restoration, where stool is harvested from a healthy donor and transplanted into a patient's colon.Although FMT has shown some efficacy in the treatment of recurrent CDI, the procedure is not standardized.Safety concerns have been raised about the possibility of transmission of multidrug-resistant pathogens via FMT. Conclusion: Treatment methods that can efficiently restore the diversity of the gut microbiome are crucial in preventing recurrence of CDI.
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Affiliation(s)
| | - Nasia Safdar
- University of Wisconsin, Madison, WI, USA
- William S. Middleton Memorial VA Hospital, Madison, WI, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Wu L, Lu XJ, Lin DJ, Chen WJ, Xue XY, Liu T, Xu JT, Xie YT, Li MQ, Lin WY, Zhang Q, Wu QP, He XX. Washed microbiota transplantation improves patients with metabolic syndrome in South China. Front Cell Infect Microbiol 2022; 12:1044957. [PMID: 36457852 PMCID: PMC9705737 DOI: 10.3389/fcimb.2022.1044957] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background Metabolic syndrome (MS) is a growing public health problem worldwide. The clinical impact of fecal microbiota transplantation (FMT) from healthy donors in MS patients is unclear, especially in southern Chinese populations. This study aimed to investigate the effect of washed microbiota transplantation (WMT) in MS patients in southern China. Methods The clinical data of patients with different indications receiving 1-3 courses of WMT were retrospectively collected. The changes of BMI, blood glucose, blood lipids, blood pressure and other indicators before and after WMT were compared, such as fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c)), high-density lipoprotein cholesterol (HDL-c), non-high-density lipoprotein (non-HDL-c), systolic blood pressure (SBP), diastolic blood pressure (DBP), etc. At the same time, comprehensive efficacy evaluation and atherosclerotic cardiovascular disease (ASCVD) grade assessment were performed on MS patients. Finally, 16S rRNA gene amplicon sequencing was performed on fecal samples of MS patients before and after transplantation. Results A total of 237 patients were included, including 42 in the MS group and 195 in the non-MS group. For MS patients, WMT significantly improved the comprehensive efficacy of MS in short term 40.48% (p<0.001), medium term 36.00% (p=0.003), and long term 46.15% (p=0.020). Short-term significantly reduced FBG (p=0.023), TG (p=0.030), SBP (p=0.026) and BMI (p=0.031), and increased HDL-c (p=0.036). The medium term had a significant reduction in FBG (p=0.048), TC (p=0.022), LDL-c (p=0.043), non-HDL-c (p=0.024) and BMI (p=0.048). WMT had a significant short term (p=0.029) and medium term (p=0.011) ASCVD downgrading effect in the high-risk group of MS patients. WMT improved gut microbiota in MS patients. Conclusion WMT had a significant improvement effect on MS patients and a significant downgrade effect on ASCVD risk in the high-risk group of patients with MS. WMT could restore gut microbiota homeostasis in MS patients. Therefore, the regulation of gut microbiota by WMT may provide a new clinical approach for the treatment of MS.
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Affiliation(s)
- Lei Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Xin-Jian Lu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - De-Jiang Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wen-Jia Chen
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xing-Ying Xue
- Xiamen Treatgut Biotechnology Co., Ltd., Xiamen, China
| | - Tao Liu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jia-Ting Xu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Ya-Ting Xie
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Man-Qing Li
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wen-Ying Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing Zhang
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing-Ping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xing-Xiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Khanna S, Assi M, Lee C, Yoho D, Louie T, Knapple W, Aguilar H, Garcia-Diaz J, Wang GP, Berry SM, Marion J, Su X, Braun T, Bancke L, Feuerstadt P. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs 2022; 82:1527-1538. [PMID: 36287379 PMCID: PMC9607700 DOI: 10.1007/s40265-022-01797-x] [Citation(s) in RCA: 156] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection. METHODS A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment. RESULTS Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events. CONCLUSIONS RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months. CLINICAL TRIAL REGISTRATION NCT03244644; 9 August, 2017.
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Affiliation(s)
- Sahil Khanna
- Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.
| | - Maha Assi
- University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | | | - David Yoho
- Kaiser Permanente Springfield Medical Center, Springfield, VA, USA
| | | | | | | | | | | | | | | | - Xin Su
- Formerly of Rebiotix, Inc, Roseville, MN, USA
| | | | | | - Paul Feuerstadt
- Yale School of Medicine, New Haven, CT, USA
- PACT Gastroenterology Center, Hamden, CT, USA
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Wu L, Li MQ, Xie YT, Zhang Q, Lu XJ, Liu T, Lin WY, Xu JT, Wu QP, He XX. Washed microbiota transplantation improves patients with high blood glucose in South China. Front Endocrinol (Lausanne) 2022; 13:985636. [PMID: 36213281 PMCID: PMC9539914 DOI: 10.3389/fendo.2022.985636] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/08/2022] [Indexed: 12/08/2022] Open
Abstract
Background and Aims Although fecal microbiota transplantation (FMT) from healthy donors has been shown to have hypoglycemic effects in animal models of diabetes, its clinical impact in patients with abnormal blood glucose metabolism is unclear, especially in southern Chinese populations. The aim of this study was to investigate the feasibility and efficacy of washed microbiota transplantation (WMT) in the treatment of abnormal blood glucose metabolism in a population in southern China. Methods The clinical data of patients with different indications who received 1-3 treatments of WMT were retrospectively collected. The changes of blood glucose, blood lipids, blood pressure, liver function and blood routine before and after WMT were compared, such as fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), systolic blood pressure (SBP), white blood cells (WBC), lymphocytes (LY) and platelets (PLT), etc. Results A total of 195 patients were included in the First Affiliated Hospital of Guangdong Pharmaceutical University, including 20 patients with high blood glucose and 175 patients with normal blood glucose. WMT has a significant effect in reducing short term blood glucose level (FBG) in patients with high blood glucose (p < 0.05). The fasting blood glucose (FBG) of 72.22% of patients with high blood glucose decreased to normal in a short term (about 1 month) (p < 0.001); In the medium term (about 2 months), there was a significant hypolipidemic (TG) (p = 0.043) effect, long term (about 6 months) significant blood pressure lowering (SBP, p = 0.048) effect. Overall, WMT significantly reduced the risk of high risk classes of Atherosclerotic Cardiovascular Disease (ASCVD) in the short term (p = 0.029) and medium term (p = 0.050). Conclusion WMT can significantly improve blood glucose in patients with high blood glucose, and there is no long-term elevated risk of blood glucose and ASCVD. FBG levels were significantly reduced in both the short and medium term in patients with high blood glucose treated with WMT. Therefore, the regulation of gut microbiota by WMT may provide a new clinical approach for the treatment of abnormal blood glucose metabolism.
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Affiliation(s)
- Lei Wu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Man-Qing Li
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Ya-Ting Xie
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing Zhang
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin-Jian Lu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Tao Liu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wen-Ying Lin
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jia-Ting Xu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing-Ping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xing-Xiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Pasokh A, Farzipour M, Mahmoudi J, Sadigh-Eteghad S. The effect of fecal microbiota transplantation on stroke outcomes: A systematic review. J Stroke Cerebrovasc Dis 2022; 31:106727. [PMID: 36162378 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106727] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 08/14/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND AND PURPOSE Fecal microbiota transplantation (FMT) is a novel microbiota-based therapeutic method that transfers stool from donor into a recipient and its application is under investigating for neurological disorders such as stroke. In this systematic review, we assessed the effect of FMT in progression and treatment of stroke and recovery of post-stroke complications. METHODS Preliminary studies were searched in MEDLINE via PubMed, Scopus, COCHRANE library and Google Scholar, databases up to February 2022. The search strategy was restricted to articles about FMT in stroke. The initial search yielded 4570 articles, of which 19 publications were included in our systematic review. RESULTS Based on outcomes transferring microbiome from healthy or ischemic donor to other ischemic recipient can affect brain infarct volume and survival rate, neurological and behavioral outcomes, and inflammatory pathways. CONCLUSIONS Our systematic review on preclinical studies showed that manipulating gut microbiota via FMT can be a possible therapeutic approach for treatment of stroke and recovery of post-stroke complications.
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Affiliation(s)
- Amir Pasokh
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Farzipour
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Khanna S, Sims M, Louie TJ, Fischer M, LaPlante K, Allegretti J, Hasson BR, Fonte AT, McChalicher C, Ege DS, Bryant JA, Straub TJ, Ford CB, Henn MR, Wang EEL, von Moltke L, Wilcox MH. SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI). Antibiotics (Basel) 2022; 11:1234. [PMID: 36140013 PMCID: PMC9495252 DOI: 10.3390/antibiotics11091234] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20−25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.
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Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Matthew Sims
- Section of Infectious Diseases and International Medicine, Department of Internal Medicine, Beaumont, Royal Oak, MI 48073, USA
- Department of Internal Medicine and Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Thomas J. Louie
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Monika Fischer
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN 46202, USA
| | - Kerry LaPlante
- Department of Pharmacy Practice, University of Rhode Island, Kingston, RI 02881, USA
- Division of Infectious Diseases, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Jessica Allegretti
- Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | | | | | | | | | | | | | | | | | | | | | - Mark H. Wilcox
- University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK
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Targeting Gut Microbiota as a Novel Strategy for Prevention and Treatment of Hypertension, Atrial Fibrillation and Heart Failure: Current Knowledge and Future Perspectives. Biomedicines 2022; 10:biomedicines10082019. [PMID: 36009566 PMCID: PMC9406184 DOI: 10.3390/biomedicines10082019] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 12/19/2022] Open
Abstract
Cardiovascular diseases (CVDs) remain the major public health concern worldwide. Over the last two decades, a considerable amount of literature has been published on gut microbiota (GMB) composition and its metabolites, involved in the pathophysiology of CVDs, including arterial hypertension, atrial fibrillation, and congestive heart failure. Although many types of medicines are available to treat CVD, new therapeutic tools are needed to improve clinical outcomes. A challenge that often arises in the researchers’ community is how to manipulate the GMB to manage cardiovascular risk factors. Therapeutic strategies designed to manipulate GMB composition and/or its metabolites include dietary approaches, prebiotics/probiotics supplementation, and fecal microbiota transplantation (FMT). In this review, we have focused on three main cardiovascular pathologies (arterial hypertension, atrial fibrillation and heart failure) due to their shared common pathophysiological pathways and structural changes in myocardium, such as inflammation, hypertrophy, fibrosis, and myocardial remodeling. The main aims of the review are: (1) to summarize current knowledge on the key pathophysiologic links between GMB and CVDs, and (2) discuss the results of the studies on GMB modulation for the prevention and treatment of selected CVDs.
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Feuerstadt P, Aroniadis OC, Svedlund FL, Garcia M, Stong L, Boules M, Khanna S. Heterogeneity of Randomized Controlled Trials of Fecal Microbiota Transplantation in Recurrent Clostridioides difficile Infection. Dig Dis Sci 2022; 67:2763-2770. [PMID: 34275058 PMCID: PMC9236970 DOI: 10.1007/s10620-021-07141-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Clinical trials have demonstrated the efficacy of FMT for reduction in CDI recurrences (rCDI), but this treatment and its reporting in the literature has significant heterogeneity. Recent publications (e.g., Ramai et al. in Dig Dis Sci 2020. https://doi.org/10.1007/s10620-020-06185-7 ) present the clinical outcomes for different FMT methodologies. However, to understand, compare, and contextualize outcomes, this heterogeneity in methods and reporting must be understood. METHODS We performed a literature review of randomized controlled trials (RCTs) of FMT for rCDI to evaluate heterogeneity among trials. A methodical search between January 2010 and May 2019 of Medline, Embase, and Cochrane was conducted for studies investigating FMT in adults with rCDI. RCTs were evaluated for a variety of methodological and reporting criteria. RESULTS Eight RCTs were identified, wherein 14 different FMT preparations were considered (each with distinct protocols for processing, storage, administration, and dosing). Sample sizes were generally small, with only two studies performing FMT in more than 100 patients. Three studies used non-FMT controls (vancomycin), while the remaining compared FMT with differing routes of administration or formulations. Across the identified studies, there was no standardized manner for reporting the timing of the FMT procedure. All studies tracked adverse events; however, follow-up periods were limited. CONCLUSIONS Considerable variability exists among RCTs, with marked differences in study design, control groups, and outcome assessment. Lack of a standard-of-care control in many trials may impact reproducibility of FMT trial outcomes in patients with rCDI. Widespread use of FMT for rCDI is still investigational; therefore, these foundational studies provide opportunities to optimize future trials.
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Affiliation(s)
- Paul Feuerstadt
- PACT-Gastroenterology Center, Hamden, CT, USA.
- Yale University School of Medicine, New Haven, CT, USA.
| | - Olga C Aroniadis
- Division of Gastroenterology, Renaissance School of Medicine At Stony, Brook University, Stony Brook, NY, USA
| | | | | | - Laura Stong
- Ferring Pharmaceuticals, Inc, Parsippany, NJ, USA
| | - Mena Boules
- Ferring Pharmaceuticals, Inc, Parsippany, NJ, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Orenstein R, Dubberke ER, Khanna S, Lee CH, Yoho D, Johnson S, Hecht G, DuPont HL, Gerding DN, Blount KF, Mische S, Harvey A. Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial. BMC Infect Dis 2022; 22:245. [PMID: 35279084 PMCID: PMC8917640 DOI: 10.1186/s12879-022-07256-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660-a standardized microbiota-based investigational live biotherapeutic-and a closely-matched historical control cohort. METHODS This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment. RESULTS In this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p < 0.0001; Chi-square test). Post-hoc analysis indicated that 91% (88/97) of evaluable RBX2660 responders remained CDI occurrence-free to 24 months after treatment demonstrating durability. RBX2660 was well-tolerated with mostly mild to moderate adverse events. The composition and diversity of RBX2660 responders' fecal microbiome significantly changed from before to after treatment to become more similar to RBX2660, and these changes were durable to 24 months after treatment. CONCLUSIONS In this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence. Clinical Trials Registration NCT02589847 (10/28/2015).
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Affiliation(s)
- Robert Orenstein
- Division of Infectious Diseases, Mayo Clinic in Arizona, 5777 e Mayo Blvd, Phoenix, AZ, 85054, USA.
| | - Erik R Dubberke
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Christine H Lee
- Hamilton Regional Laboratory Medicine Program, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Vancouver Island Health Authority, Victoria, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - David Yoho
- Infectious Diseases, Mid-Atlantic Permanente Medical Group, Springfield, VA, USA
| | - Stuart Johnson
- Infectious Disease, Loyola University Medical Center, Chicago, IL, USA
- Edward Hines Jr. VA Hospital, Hines, IL, USA
| | - Gail Hecht
- Division of Gastroenterology, Hepatology and Nutrition, Loyola University Medical Center, Maywood, IL, USA
| | - Herbert L DuPont
- University of Texas Health Science Center and Kelsey Research Foundation, Houston, TX, USA
| | | | - Ken F Blount
- Rebiotix Inc., a Ferring Company, Roseville, MN, USA
| | - Sarah Mische
- Rebiotix Inc., a Ferring Company, Roseville, MN, USA
| | - Adam Harvey
- Rebiotix Inc., a Ferring Company, Roseville, MN, USA
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Mehta N, Wang T, Friedman-Moraco RJ, Carpentieri C, Mehta AK, Rouphael N, Dhere T, Larsen CP, Kraft CS, Woodworth MH. Fecal Microbiota Transplantation Donor Screening Updates and Research Gaps for Solid Organ Transplant Recipients. J Clin Microbiol 2022; 60:e0016121. [PMID: 34133889 PMCID: PMC8849208 DOI: 10.1128/jcm.00161-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
In this review, we discuss stool donor screening considerations to mitigate potential risks of pathogen transmission through fecal microbiota transplant (FMT) in solid organ transplant (SOT) recipients. SOT recipients have a higher risk for Clostridioides difficile infection (CDI) and are more likely to have severe CDI. FMT has been shown to be a valuable tool in the treatment of recurrent CDI (RCDI); however, guidelines for screening for opportunistic infections transmitted through FMT are underdeveloped. We review reported adverse effects of FMT as they pertain to an immunocompromised population and discuss the current understanding and recommendations for screening found in the literature while noting gaps in research. We conclude that while FMT is being performed in the SOT population, typically with positive results, there remain many unanswered questions which may have major safety implications and warrant further study.
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Affiliation(s)
- Nirja Mehta
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Tiffany Wang
- Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Rachel J. Friedman-Moraco
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Cynthia Carpentieri
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Aneesh K. Mehta
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
- Department of Surgery, Division of Transplantation, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Nadine Rouphael
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Tanvi Dhere
- Department of Medicine, Division of Digestive Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Department of Surgery, Division of Transplantation, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Colleen S. Kraft
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
| | - Michael H. Woodworth
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA
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Detection of Newly Secreted Antibodies Predicts Non-recurrence in Primary Clostridioides difficile Infection. J Clin Microbiol 2022; 60:e0220121. [PMID: 35107301 DOI: 10.1128/jcm.02201-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: Within eight weeks of primary Clostridioides difficile infection (CDI), as many as 30% of patients develop recurrent disease with the associated risks of multiple relapses, morbidity, and economic burden. There are no clear clinical correlates or validated biomarkers that can predict recurrence during primary infection. This study demonstrates the potential of a simple test for identifying hospitalized CDI patients at low risk for disease recurrence. Methods: Forty-six hospitalized CDI patients were enrolled at Emory University Hospitals. Serum and a novel matrix from circulating plasmablasts called "Medium Enriched for Newly Synthesized Antibodies" (MENSA) samples were collected during weeks 1, 2, and 4. Antibodies specific for ten C. difficile antigens were measured in each sample Results: Among the 46 C. difficile-infected patients, nine (19.5%) experienced recurrence within eight weeks of primary infection. Among the 37 non-recurrent patients, 23 (62%; 23/37) had anti-C. difficile MENSA antibodies specific for any of the three toxin antigens: TcdB-CROP, TcdBvir-CROP, and/or CDTb. Positive MENSA responses occurred early (within the first 12 days post-symptom onset), including six patients who never seroconverted. A similar trend was observed in serum responses, but they peaked later and identified fewer patients (51%; 19/37). In contrast, none (0%; 0/9) of the patients who subsequently recurred after hospitalization produced antibodies specific for any of the three C. difficile toxin antigens. Thus, patients with a negative early MENSA response against all three C. difficile toxin antigens had a 19-fold greater relative risk of recurrence. Discussion: MENSA and serum levels of IgA and/or IgG antibodies for three C. difficile toxins have prognostic potential. These immunoassays measure nascent immune responses that reduce the likelihood of recurrence thereby providing a biomarker of protection from recurrent CDI. Patients who are positive by this immunoassay are unlikely to suffer recurrence. Early identification of patients at-risk for recurrence by negative MENSA creates opportunities for targeted prophylactic strategies that can reduce the incidence, cost and morbidity due to recurrent CDI.
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Tsigalou C, Konstantinidis T, Aloizou AM, Bezirtzoglou E, Tsakris A. Future Therapeutic Prospects in Dealing with Autoimmune Diseases: Treatment Based on the Microbiome Model. ROLE OF MICROORGANISMS IN PATHOGENESIS AND MANAGEMENT OF AUTOIMMUNE DISEASES 2022:489-520. [DOI: 10.1007/978-981-19-4800-8_25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Pan ZY, Zhong HJ, Huang DN, Wu LH, He XX. Beneficial Effects of Repeated Washed Microbiota Transplantation in Children With Autism. Front Pediatr 2022; 10:928785. [PMID: 35783298 PMCID: PMC9249087 DOI: 10.3389/fped.2022.928785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE While fecal microbiota transplantation is demonstrated to improve symptoms of autism spectrum disorder (ASD), it remains unclear whether additional treatment courses yield better results. This study sought to evaluate the efficacy of repeated washed microbiota transplantation (WMT) in children with ASD. METHODS Retrospective data from children who were serially treated with WMT, including ASD symptoms, sleep disorders, gastrointestinal (GI) symptoms, and white blood cell (WBC) and globulin levels were obtained. The effect of WMT on children with ASD and whether additional WMT courses led to a further improvement in symptoms were assessed. RESULTS Aberrant Behavior Checklist (ABC), Childhood Autism Rating Scale, and Sleep Disturbance Scale for Children (SDSC) scores, the proportion of children with constipation and abnormal fecal forms, and WBC and globulin levels were all significantly lower in ASD children after WMT. More WMT treatment courses led to significantly lower scores on the ABC and SDSC. CONCLUSION WMT significantly improved ASD and GI symptoms and sleep disorders in children with ASD, and reduced systemic inflammation. Additional WMT courses led to more obvious improvements in ASD symptoms within three treatment courses.
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Affiliation(s)
- Zhao-Yu Pan
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Hao-Jie Zhong
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- *Correspondence: Hao-Jie Zhong,
| | - Dong-Ni Huang
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Li-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Xing-Xiang He
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
- Xing-Xiang He,
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Sandhu A, Chopra T. Fecal microbiota transplantation for recurrent Clostridioides difficile, safety, and pitfalls. Therap Adv Gastroenterol 2021; 14:17562848211053105. [PMID: 34992678 PMCID: PMC8725027 DOI: 10.1177/17562848211053105] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/20/2021] [Indexed: 02/04/2023] Open
Abstract
Clostridioides difficile infection (CDI) is one of the leading causes of hospital-acquired infection attributing to substantial morbidity, mortality, and healthcare cost. Recurrent CDI (rCDI) is common and occurs after effective treatment of first episode. Treatment of rCDI is based on accurate diagnoses, due to difficulty in distinguishing between colonization of C. difficile spores or CDI; coronavirus disease 2019 (COVID-19) added to the complexity of diagnoses as both entities can co-occur. It is difficult to eradicate rCDI, and there remains a critical gap regarding treatment of rCDI. The treatment goal of rCDI is to reestablish normal microbiota. Fecal microbiota transplantation (FMT) is suggested as a treatment for second episode of rCDI. Based on the collective evidence of all randomized controlled trials, FMT was reported more efficacious compared with vancomycin or fidaxomicin; however, these trials had limited number of patients and all patients were pre-treated with vancomycin prior to FMT. Furthermore, when comparing various routes of instillation and types of preparation of fecal microbiota, no difference was observed in cure rate. Despite the success rate of FMT, there remains a concern for transmission of infectious agents, such as Gram negative bacteremia or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adverse events (diarrhea and abdominal pain), and reports of new diagnoses (inflammatory bowel disease, weight gain and irritable bowel syndrome). To lessen the risk of transmissible infections, donor screening should be performed, which includes screening for medical comorbidities and infectious pathogens in blood and feces. Scheduling complexities and reimbursement places an additional roadblock for using FMT. Microbiome-based therapies are being developed to eliminate the logistical challenges related to FMT. Large prospective and placebo-controlled studies are needed to evaluate the efficacy and long-term safety of FMT, so its use can be justified in clinical practice.
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Affiliation(s)
- Avnish Sandhu
- Department of Internal Medicine, Division of Infectious Disease, Wayne State Universit School of Medicine, Detroit Medical Center Detroit, MI, USA
| | - Teena Chopra
- Department of Internal Medicine, Division of Infectious Disease, Wayne State Universit School of Medicine, Detroit Medical Center Detroit, Harper University Hospital, 3990 John R street, Detroit, MI, 48201, USA
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Dose-Dependent Relationship between Protection of Thioacetamide-Induced Acute Liver Injury and Hyperammonemia and Concentration of Lactobacillus salivarius Li01 in Mice. Microbiol Spectr 2021; 9:e0184721. [PMID: 34937168 PMCID: PMC8694139 DOI: 10.1128/spectrum.01847-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Recently, probiotics have been widely used as an adjuvant therapy to cure, prevent, or improve certain diseases. However, no research has been carried out into the dose of probiotics, especially the maximum dose. Therefore, the effective and safe dosage of probiotics needs to be studied. Recently, L. Yang, X. Bian, W. Wu, L. Lv, et al. (Microb Biotechnol 13:1860–1876, 2020, https://doi.org/10.1111/1751-7915.13629) discovered that Lactobacillus salivarius Li01 had a protective effect on thioacetamide-induced acute liver injury and hyperammonemia, and a fixed concentration (3 × 109 CFU/mL) of L. salivarius Li01 was applied in their study. However, the most effective treatment concentration of L. salivarius Li01 remains unknown. Therefore, four concentration gradients of L. salivarius Li01 suspension were prepared for groups of mice to have different levels of bacterial colonization by gavage. Then, acute liver injury and hyperammonemia were induced via thioacetamide administration. By observation and detection, an inverted U-shaped protective effect from L. salivarius Li01 existed in thioacetamide-induced acute liver injury and hyperammonemia. Of note, significant deterioration was confirmed within the group that was orally administered with an excessive concentration of L. salivarius Li01 suspension, and this was attributed to endotoxemia that resulted from compromised immunity, a damaged intestinal barrier, and bacterial translocation. IMPORTANCE This research investigated the relationship between the concentration of Lactobacillus salivarius Li01 and its impact on mice that had a thioacetamide-induced acute liver injury and hyperammonemia. These findings could provide new insights into the effective, proper, and safe use of probiotics.
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Payne E, Harrington K, Richard P, Brackin R, Davis R, Couture S, Liff J, Asmus F, Mutina E, Fisher A, Giuvelis D, Sannajust S, Rostama B, King T, Mattei LM, Lee JJ, Friedman ES, Bittinger K, May M, Stevenson GW. Effects of Vancomycin on Persistent Pain-Stimulated and Pain-Depressed Behaviors in Female Fischer Rats With or Without Voluntary Access to Running Wheels. THE JOURNAL OF PAIN 2021; 22:1530-1544. [PMID: 34029686 PMCID: PMC8578155 DOI: 10.1016/j.jpain.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 05/02/2021] [Accepted: 05/15/2021] [Indexed: 10/21/2022]
Abstract
The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. PERSPECTIVE: The narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.
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Affiliation(s)
- Emily Payne
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Kylee Harrington
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Philomena Richard
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Rebecca Brackin
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Ravin Davis
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Sarah Couture
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Jacob Liff
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Francesca Asmus
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Elizabeth Mutina
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Anyssa Fisher
- Department of Psychology, University of New England, Biddeford, ME, 04005
| | - Denise Giuvelis
- Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005
| | - Sebastien Sannajust
- Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005
| | - Bahman Rostama
- Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, 04005
| | - Tamara King
- Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, 04005
| | - Lisa M Mattei
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104
| | - Jung-Jin Lee
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104
| | - Elliot S Friedman
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104
| | - Kyle Bittinger
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104
| | - Meghan May
- Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, 04005
| | - Glenn W Stevenson
- Department of Psychology, University of New England, Biddeford, ME, 04005; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, 04005.
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Khanna S, Pardi DS, Jones C, Shannon WD, Gonzalez C, Blount K. RBX7455, a Non-frozen, Orally Administered Investigational Live Biotherapeutic, Is Safe, Effective, and Shifts Patients' Microbiomes in a Phase 1 Study for Recurrent Clostridioides difficile Infections. Clin Infect Dis 2021; 73:e1613-e1620. [PMID: 32966574 PMCID: PMC8492147 DOI: 10.1093/cid/ciaa1430] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recurrent Clostridioides difficile infections (rCDI) are a global public health threat. To reduce rCDI, microbiota-restoring therapies are needed, particularly standardized, easy-to-administer formulations. METHODS This phase I open-label trial assessed the safety, efficacy in preventing rCDI recurrence, and intestinal microbiome effects of RBX7455, a room temperature-stable, orally administered investigational live biotherapeutic. Adult participants with 1 or more prior episodes of rCDI received: 4 RBX7455 capsules twice daily for 4 days (group 1); 4 RBX7455 capsules twice daily for 2 days (group 2); or 2 RBX7455 capsules twice daily for 2 days (group 3). For all groups, the first dose was administered in clinic, with remaining doses self-administered at home. Adverse events were monitored during and for 6 months after treatment. Treatment success was defined as rCDI prevention through 8 weeks after treatment. Participants' microbiome composition was assessed prior to and for 6 months after treatment. RESULTS Nine of 10 group 1 patients (90%), 8 of 10 group 2 patients (80%), and 10 of 10 group 3 patients (100%) were recurrence-free at the 8-week endpoint with durability to 6 months. Seventy-five treatment-emergent adverse events were observed in 27 participants with no serious investigational product-related events. Prior to treatment, participants' microbiomes were dissimilar from the RBX7455 composition with decreased Bacteroidia- and Clostridia-class bacteria, whereas after treatment, responders' microbiomes showed increased Bacteroidia and Clostridia. CONCLUSIONS Three dosing regimens of RBX7455 were safe and effective at preventing rCDI. Responders' microbiomes converged toward the composition of RBX7455. These results support its continued clinical evaluation. CLINICAL TRIALS REGISTRATION NCT02981316.
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Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Courtney Jones
- Rebiotix Inc, a Ferring Company, Roseville, Minnesota, USA
| | | | | | - Ken Blount
- Rebiotix Inc, a Ferring Company, Roseville, Minnesota, USA
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Khanna S. Advances in Clostridioides difficile therapeutics. Expert Rev Anti Infect Ther 2021; 19:1067-1070. [PMID: 33427531 DOI: 10.1080/14787210.2021.1874919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Khanna S. Microbiota restoration for recurrent Clostridioides difficile: Getting one step closer every day! J Intern Med 2021; 290:294-309. [PMID: 33856727 DOI: 10.1111/joim.13290] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
Clostridioides difficile infection (CDI) is an urgent health threat being the most common healthcare-associated infection, and its management is a clinical conundrum. Over 450 000 infections are seen in the United States with similar incidence seen in the rest of the developed world. The majority of infections seen are mild-moderate with fulminant disease and mortality being rare complications seen in the elderly and in those with comorbidities. The most common complication of CDI is recurrent infection with rates as high as 60% after three or more infections. A dilemma in the management of primary and recurrent CDI is testing due to the high sensitivity of the nucleic acid amplification tests such as the polymerase chain reaction, which leads to clinical false positives if patients are not chosen carefully (with symptoms) before testing. A newer testing regimen involving a 2-step strategy is emerging using glutamate dehydrogenase as a screening strategy followed by enzyme immunoassay for the C. difficile toxin. Microbiota restoration therapies are the cornerstone of management of recurrent CDI to prevent future recurrences. The most common modality of microbiota restoration is faecal microbiota transplantation, which has been tainted with heterogeneity and adverse events such as serious infectious transmission. The success rates for recurrence prevention from microbiota restoration therapies are over 90% compared with less than 50% of recurrence prevention with courses of antibiotics. This has led to development and emergence of standardized microbiota restoration therapies in capsule and enema forms. Capsule-based therapies include CP101 (positive phase II results), RBX7455 (positive phase I results), SER-109 (positive phase III results) and VE303 (ongoing phase II trial). Enema-based therapy includes RBX2660 (positive phase III data). This review summarizes the principles of management and diagnosis of CDI and focuses on emerging and existing data on faecal microbiota transplantation and standardized microbiota restoration therapies.
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Affiliation(s)
- S Khanna
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Khanna S. My Treatment Approach to Clostridioides difficile Infection. Mayo Clin Proc 2021; 96:2192-2204. [PMID: 34175104 DOI: 10.1016/j.mayocp.2021.03.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 03/16/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Clostridioides difficile infection is the most common cause of infectious diarrhea in hospitals with an increasing incidence in the community. Clinical presentation of C difficile infection ranges from diarrhea manageable in the outpatient setting to fulminant infection requiring intensive care admission. There have been significant advances in the management of primary and recurrent C difficile infection including diagnostics, newer antibiotics, antibody treatments, and microbiome restoration therapies. Because of the risk of clinical false-positive results with the polymerase chain reaction test, a two-step assay combining an enzyme immune assay for glutamate dehydrogenase and the C difficile toxin is being used. Cost permitting, I treat a first episode of C difficile infection preferably with fidaxomicin over vancomycin but not metronidazole. The most common complication after C difficile infection is recurrence. I manage a first recurrence with a vancomycin taper and pulse or fidaxomicin and recommend a single dose of intravenous bezlotoxumab (a monoclonal antibody against the toxin B) to reduce recurrence rates for those patients at high risk. Patients with multiply recurrent C difficile infection are managed with a course of antibiotics such as vancomycin or fidaxomicin followed by microbiota restoration. The success of fecal microbiota transplantation is greater than 85%, compared with the 40% to 50% success rate of antibiotics in this situation. Fecal microbiota transplantation is heterogeneous and has rare but serious risks such as transmission of infections. Standardized microbiota restoration therapies are in clinical development and have completed phase III clinical trials. This review answers common clinical questions in the management of C difficile infection.
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Affiliation(s)
- Sahil Khanna
- C difficile Clinic and Microbiome Restoration Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
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Zhao J, Bai M, Yang X, Wang Y, Li R, Sun S. Alleviation of refractory IgA nephropathy by intensive fecal microbiota transplantation: the first case reports. Ren Fail 2021; 43:928-933. [PMID: 34134605 PMCID: PMC8901287 DOI: 10.1080/0886022x.2021.1936038] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Gut dysbiosis may be implicated in the pathogenesis of IgA nephropathy (IgAN) through immune and/or metabolite pathways. Fecal microbiota transplantation (FMT) could reestablish the micro-ecological balance in IgAN, although this has never been attempted before. We explored whether FMT could be efficacious in treating IgAN in two patients with refractory IgAN. Case presentation Two Chinese female patients with IgAN failed to achieve clinical remission after receiving several rounds of immunosuppressive therapy and suffered from unbearable adverse effects due to immunosuppressants. Both patients received intensive fresh FMT conducted through transendoscopic enteral tubing (TET) regularly for 6–7 months, and were followed up for a further 6 months. Partial clinical remission was achieved in both patients, evidenced by a decrease in the 24-h urinary protein (24-hUP) to less than half of baseline during FMT treatment or follow-up, along with increased serum albumin (sAlb) and stable kidney function. The gut microbiota of both patients was distorted with lower biodiversity and altered composition, which was reversed following FMT. Phylum Proteobacteria decreased while genus Prevotella increased during and after FMT. The intensive fresh FMT was well-tolerated, and no severe adverse events occurred. Conclusions Preliminary evidence of the safety and efficacy of FMT for treating refractory IgAN may provide a new direction by which to decipher the pathogenesis of IgAN.
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Affiliation(s)
- Jin Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
| | - Ming Bai
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
| | - Xiaoxia Yang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
| | - Yan Wang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
| | - Rong Li
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xìan, P. R. China
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McGovern BH, Ford CB, Henn MR, Pardi DS, Khanna S, Hohmann EL, O’Brien EJ, Desjardins CA, Bernardo P, Wortman JR, Lombardo MJ, Litcofsky KD, Winkler JA, McChalicher CWJ, Li SS, Tomlinson AD, Nandakumar M, Cook DN, Pomerantz RJ, Auninš JG, Trucksis M. SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial. Clin Infect Dis 2021; 72:2132-2140. [PMID: 32255488 PMCID: PMC8204772 DOI: 10.1093/cid/ciaa387] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/05/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. METHODS In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. RESULTS 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11-2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. CONCLUSIONS Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. CLINICAL TRIALS REGISTRATION NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
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Affiliation(s)
| | | | | | - Darrell S Pardi
- Mayo Clinic, Gastroenterology Division, Rochester, Minnesota, USA
| | - Sahil Khanna
- Mayo Clinic, Gastroenterology Division, Rochester, Minnesota, USA
| | - Elizabeth L Hohmann
- Massachusetts General Hospital, Infectious Diseases Division, Boston, Massachusetts, USA
| | | | | | | | | | | | | | | | | | - Sunny S Li
- Seres Therapeutics, Cambridge, Massachusetts, USA
| | | | | | - David N Cook
- Seres Therapeutics, Cambridge, Massachusetts, USA
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Poylin V, Hawkins AT, Bhama AR, Boutros M, Lightner AL, Khanna S, Paquette IM, Feingold DL. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Clostridioides difficile Infection. Dis Colon Rectum 2021; 64:650-668. [PMID: 33769319 DOI: 10.1097/dcr.0000000000002047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Vitaliy Poylin
- Division of Gastrointestinal Surgery, Northwestern Medicine, Chicago, Illinois
| | - Alexander T Hawkins
- Department of Surgery, Section of Colon & Rectal Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anuradha R Bhama
- Department of Surgery, Division of Colon & Rectal Surgery, Rush University Medical Center, Chicago, Illinois
| | - Marylise Boutros
- Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Sahil Khanna
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ian M Paquette
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Daniel L Feingold
- Section of Colorectal Surgery, Rutgers University, New Brunswick, New Jersey
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Khanna S, Kraft CS. Fecal Microbiota Transplantation: Tales of Caution. Clin Infect Dis 2021; 72:e881-e882. [PMID: 32991697 DOI: 10.1093/cid/ciaa1492] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Indexed: 12/29/2022] Open
Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Colleen S Kraft
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
- Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA
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Khanna S, Tande A, Rubin DT, Khoruts A, Kahn SA, Pardi DS. Fecal Microbiota Transplantation for Recurrent C difficile Infection During the COVID-19 Pandemic: Experience and Recommendations. Mayo Clin Proc 2021; 96:1418-1425. [PMID: 34088413 PMCID: PMC8169126 DOI: 10.1016/j.mayocp.2021.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/23/2021] [Accepted: 04/12/2021] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To report experience with fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (rCDI) and provide recommendations for management of rCDI and donor testing during the COVID-19 pandemic. METHODS A retrospective study of patients with rCDI who underwent FMT from May 26, 2020, to September 30, 2020, with stool from well-screened donors with health and infectious screening and a newly implemented strategy for COVID-19 screening with every 2-week bookend testing with stool quarantine. Patients were followed up for development of rCDI and COVID-19. RESULTS Of the 57 patients who underwent FMT for rCDI, 29 were tested for COVID-19 via nasopharyngeal polymerase chain reaction (PCR) and 22 via serology. All results were negative, except for 1 positive serology. Donor testing every 2 weeks for COVID-19 via serology and nasopharyngeal swab PCR was negative, except for 2 donors at 1 center who were excluded. Three patients had rCDI after FMT, and 1 underwent repeat FMT. One patient developed respiratory symptoms suggestive of COVID-19 and tested negative via nasopharyngeal PCR. Eleven patients who underwent COVID-19 testing for elective procedures or hospitalizations tested negative. No SARS-CoV-2 transmission was noted. CONCLUSIONS With appropriate donor screening, FMT can be performed safely for rCDI during the COVID-19 pandemic. Development of a validated stool assay for SARS-CoV-2 will simplify this process further.
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Affiliation(s)
- Sahil Khanna
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
| | - Aaron Tande
- Infectious Diseases, Mayo Clinic, Rochester, MN
| | - David T Rubin
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, IL
| | - Alexander Khoruts
- Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN
| | - Stacy A Kahn
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
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Yadav D, Khanna S. Safety of fecal microbiota transplantation for Clostridioides difficile infection focusing on pathobionts and SARS-CoV-2. Therap Adv Gastroenterol 2021; 14:17562848211009694. [PMID: 33959193 PMCID: PMC8064662 DOI: 10.1177/17562848211009694] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/23/2021] [Indexed: 02/04/2023] Open
Abstract
Clostridioides difficile infection (CDI) is a consequence of flagrant use of antibiotics, an aging population with increasing comorbidities, and increased hospitalizations. The treatment of choice for CDI is antibiotics (vancomycin or fidaxomicin), with a possibility of recurrent CDI despite lack of additional risk factors for CDI. For the last 10 years, fecal microbiota transplantation (FMT) has emerged as a promising therapy for recurrent CDI, with success rates of over 85% compared with less than 50% with antibiotics for multiple recurrent CDI. Along with the success of FMT, several adverse and serious adverse events with FMT have been reported. These range from self-limiting abdominal pain to death due to severe sepsis. This review focuses on the safety of FMT, emphasizing the reports of transmission of pathobionts like extended-spectrum beta lactamase Escherichia coli and Shiga toxin-producing E. coli. The severe acute respiratory syndrome coronavirus-2 is a potential pathogen that could be transmitted via FMT during the COVID-19 pandemic. The challenges faced by clinicians for donor screening, clinical trials, and other aspects of FMT during the pandemic are discussed.
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Affiliation(s)
- Devvrat Yadav
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
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Mehta SR, Yen EF. Microbiota-based Therapies Clostridioides difficile infection that is refractory to antibiotic therapy. Transl Res 2021; 230:197-207. [PMID: 33278650 DOI: 10.1016/j.trsl.2020.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/05/2020] [Accepted: 11/29/2020] [Indexed: 11/27/2022]
Abstract
Clostridioides difficile infection (CDI) has had a devastating impact worldwide with significant rates of mortality, especially among the elderly. Despite effective antibiotics, the incidence of recurrent CDI (rCDI) is increasing and more difficult to treat with antibiotics alone. Fecal Microbiota Transplantation (FMT) has emerged as a consistently effective treatment for rCDI. Mechanisms for FMT are not entirely understood, but remain an area of active investigation. There have been recent safety reports with the use of FMT regarding transmission of pathogens in a few patients that have led to serious illness. With appropriate screening, FMT can be safely administered and continue to have a significant impact on eradication of rCDI and improve the lives of patients suffering from this disease. In this review, we summarize current treatments for CDI with a focus on microbiota-based therapies used for antibiotic refractory disease.
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Affiliation(s)
- Shama R Mehta
- NorthShore University HealthSystem, Division of Gastroenterology, 2650 Ridge Avenue, Suite G221, Evanston, IL 60201
| | - Eugene F Yen
- NorthShore University HealthSystem, Division of Gastroenterology, 2650 Ridge Avenue, Suite G221, Evanston, IL 60201.
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Schmidt EKA, Raposo PJF, Madsen KL, Fenrich KK, Kabarchuk G, Fouad K. What Makes a Successful Donor? Fecal Transplant from Anxious-Like Rats Does Not Prevent Spinal Cord Injury-Induced Dysbiosis. BIOLOGY 2021; 10:254. [PMID: 33804928 PMCID: PMC8063845 DOI: 10.3390/biology10040254] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/16/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022]
Abstract
Spinal cord injury (SCI) causes gut dysbiosis and an increased prevalence of depression and anxiety. Previous research showed a link between these two consequences of SCI by using a fecal transplant from healthy rats which prevented both SCI-induced microbiota changes and the subsequent development of anxiety-like behaviour. However, whether the physical and mental state of the donor are important factors in the efficacy of FMT therapy after SCI remains unknown. In the present study, rats received a fecal transplant following SCI from uninjured donors with increased baseline levels of anxiety-like behaviour and reduced proportion of Lactobacillus in their stool. This fecal transplant increased intestinal permeability, induced anxiety-like behaviour, and resulted in minor but long-term alterations in the inflammatory state of the recipients compared to vehicle controls. There was no significant effect of the fecal transplant on motor recovery in rehabilitative training, suggesting that anxiety-like behaviour did not affect the motivation to participate in rehabilitative therapy. The results of this study emphasize the importance of considering both the microbiota composition and the mental state of the donor for fecal transplants following spinal cord injury.
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Affiliation(s)
- Emma K. A. Schmidt
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; (E.K.A.S.); (K.K.F.); (G.K.)
| | - Pamela J. F. Raposo
- Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada;
- Department of Physical Therapy, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Karen L. Madsen
- Division of Gastroenterology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| | - Keith K. Fenrich
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; (E.K.A.S.); (K.K.F.); (G.K.)
- Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| | - Gillian Kabarchuk
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; (E.K.A.S.); (K.K.F.); (G.K.)
| | - Karim Fouad
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; (E.K.A.S.); (K.K.F.); (G.K.)
- Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada;
- Department of Physical Therapy, University of Alberta, Edmonton, AB T6G 2R3, Canada
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Olesen SW, Gerardin Y. Re-Evaluating the Evidence for Faecal Microbiota Transplantation 'Super-Donors' in Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:453-461. [PMID: 32808030 DOI: 10.1093/ecco-jcc/jjaa170] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Faecal microbiota transplantation [FMT] is a recommended treatment for recurrent Clostridioides difficile infection, and there is promise that FMT may be effective for conditions such as inflammatory bowel disease [IBD]. Previous FMT clinical trials have considered the possibility of a 'donor effect', that is, that FMT material from different donors has different clinical efficacies. METHODS Here we re-evaluate evidence for donor effects in published FMT clinical trials for IBD. RESULTS In ten of 12 published studies, no statistically significant donor effect was detected when rigorously re-evaluating the original analyses. One study showed statistically significant separation of microbiota composition of pools of donor stool when stratified by patient outcome. One study reported a significant effect but did not have underlying data available for re-evaluation. When quantifying the uncertainty on the magnitude of the donor effect, confidence intervals were large, including both zero donor effects and very substantial donor effects. CONCLUSION Although we found very little evidence for donor effects, the existing data cannot rule out the possibility that donor effects are clinically important. Large clinical trials prospectively designed to detect donor effects are probably needed to determine if donor effects are clinically relevant for IBD.
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Affiliation(s)
- Scott W Olesen
- OpenBiome, Cambridge, MA, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
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MacLellan AD, Finlay BB, Appel-Cresswell S. Age-Matching in Pediatric Fecal Matter Transplants. Front Pediatr 2021; 9:603423. [PMID: 34336729 PMCID: PMC8322514 DOI: 10.3389/fped.2021.603423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 06/17/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Abigale D MacLellan
- Department of Integrated Sciences, University of British Columbia, Vancouver, BC, Canada
| | - B Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Silke Appel-Cresswell
- Pacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
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