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Mougiou D, Gioula G, Skoura L, Anastassopoulou C, Kachrimanidou M. Insights into the Interaction Between Clostridioides difficile and the Gut Microbiome. J Pers Med 2025; 15:94. [PMID: 40137411 PMCID: PMC11943401 DOI: 10.3390/jpm15030094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/19/2025] [Accepted: 02/27/2025] [Indexed: 03/27/2025] Open
Abstract
Clostridioides difficile (C. difficile) is a significant healthcare-associated pathogen that is predominantly caused by antibiotic-induced microbiota disturbance. Antibiotics decrease microbial diversity, resulting in C. difficile colonization and infection. Clostridium difficile infection (CDI) manifests through toxins A and B, causing diarrhea and colitis. Antibiotic usage, old age, and hospitalization are significant risk factors. A healthy gut microbiota, which is dominated by Firmicutes and Bacteroidetes, provides colonization resistance to C. difficile due to competition for nutrients, creating inhibitory substances and stimulating the immune response. Antibiotic-induced dysbiosis decreases resistance, allowing C. difficile spores to transform into vegetative forms. Patients with CDI have decreased gut microbiota diversity, with a decrease in beneficial bacteria, including Bacteroidetes, Prevotella, and Bifidobacterium, and a rise in harmful bacteria like Clostridioides and Lactobacillus. This disparity worsens the infection's symptoms and complicates therapy. Fecal Microbiota Transplantation (FMT) has emerged as a potential therapy for recurrent CDI by restoring gut microbiota diversity and function. Comprehending the connection between gut microbiota and CDI pathogenesis is critical for establishing effective preventive and treatment plans. Maintaining a healthy gut microbiota through careful antibiotic use and therapeutic options such as FMT can help in the management and prevention of CDI.
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Affiliation(s)
- Dimitra Mougiou
- Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.M.); (G.G.)
| | - Georgia Gioula
- Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.M.); (G.G.)
| | - Lemonia Skoura
- Department of Microbiology, AHEPA University Hospital, 54124 Thessaloniki, Greece;
| | - Cleo Anastassopoulou
- Department of Microbiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Melania Kachrimanidou
- Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.M.); (G.G.)
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Menon R, Bhattarai SK, Crossette E, Prince AL, Olle B, Silber JL, Bucci V, Faith J, Norman JM. Multi-omic profiling a defined bacterial consortium for treatment of recurrent Clostridioides difficile infection. Nat Med 2025; 31:223-234. [PMID: 39747680 DOI: 10.1038/s41591-024-03337-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 10/02/2024] [Indexed: 01/04/2025]
Abstract
Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo. VE303 organisms robustly colonized the gut in the high-dose group and were among the top taxa associated with non-recurrence. Multi-omic modeling identified antibiotic history, baseline stool metabolites and serum cytokines as predictors of both on-study CDI recurrence and VE303 colonization. VE303 potentiated early recovery of the host microbiome and metabolites with increases in short-chain fatty acids, secondary bile acids and bile salt hydrolase genes after antibiotic treatment for CDI, which is considered important to prevent CDI recurrences. These results support the idea that VE303 promotes efficacy in rCDI through multiple mechanisms.
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Affiliation(s)
| | - Shakti K Bhattarai
- Program in Microbiome Dynamics, Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | | | | | - Bernat Olle
- Vedanta Biosciences, Inc., Cambridge, MA, USA
| | | | - Vanni Bucci
- Program in Microbiome Dynamics, Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jeremiah Faith
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Marsiglia R, Pane S, Del Chierico F, Russo A, Vernocchi P, Romani L, Cardile S, Diamanti A, Galli L, Tamborino A, Terlizzi V, De Angelis P, Angelino G, Putignani L. Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infections in a Cystic Fibrosis Child Previously Screen Positive, Inconclusive Diagnosis (CFSPID): A Case Report. Microorganisms 2024; 12:2059. [PMID: 39458368 PMCID: PMC11509880 DOI: 10.3390/microorganisms12102059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Clostridioides difficile infection (CDI) is generally treated with vancomycin, metronidazole or fidaxomicin, although fecal microbiota transplantation (FMT) represents a promising therapeutic option for antibiotic-resistant recurrent C. difficile infections (rCDIs) in adults. In pediatric cystic fibrosis (CF) patients, CDIs are generally asymptomatic and respond to treatment. Here, we present the case of an 8-year-old female, initially diagnosed as "CFTR-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis" (CMRS/CFSPID), who then progressed to CF at 12 months. In the absence of CF-related symptoms, she presented multiple and disabling episodes of bloody diarrhoea with positive tests for C. difficile antigen and A/B toxin. After conventional treatments failed and several CDI relapses, FMT was proposed. Donor screening and GM donor-receiver matching identified her mother as a donor. Metataxonomy and targeted metabolomics provided, through a pre- and post-FMT time course, gut microbiota (GM) profiling to assess GM engraftment. At first, the GM map revealed severe dysbiosis, with a prevalence of Bacteroidetes and Proteobacteria (i.e., Klebsiella spp., Escherichia coli), a reduction in Firmicutes, a GM nearly entirely composed of Enterococcaceae (i.e., Enterococcus) and an almost complete depletion of Verrucomicrobia and Actinobacteria, mostly represented by Veillonella dispar. Post FMT, an increment in Bifidobacterium spp. and Collinsella spp. with a decrease in V. dispar restored intestinal eubiosis. Consistently, four weeks after FMT treatment, the child's gut symptoms cleared, without CDI recurrence.
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Affiliation(s)
- Riccardo Marsiglia
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Research Microbiome, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (R.M.); (F.D.C.); (P.V.)
| | - Stefania Pane
- Unit of Microbiomics, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.P.); (A.R.)
| | - Federica Del Chierico
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Research Microbiome, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (R.M.); (F.D.C.); (P.V.)
| | - Alessandra Russo
- Unit of Microbiomics, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.P.); (A.R.)
| | - Pamela Vernocchi
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Research Microbiome, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (R.M.); (F.D.C.); (P.V.)
| | - Lorenza Romani
- Infectious Diseases Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy;
| | - Sabrina Cardile
- Unit of Gastroenterology and Nutrition, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.C.); (A.D.); (P.D.A.); (G.A.)
| | - Antonella Diamanti
- Unit of Gastroenterology and Nutrition, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.C.); (A.D.); (P.D.A.); (G.A.)
| | - Luisa Galli
- Department of Health Sciences, University of Florence, 50121 Florence, Italy;
- Infectious Disease Unit, Meyer Children’s Hospital IRCCS, 50121 Florence, Italy;
| | - Agnese Tamborino
- Infectious Disease Unit, Meyer Children’s Hospital IRCCS, 50121 Florence, Italy;
| | - Vito Terlizzi
- Department of Pediatric Medicine, Meyer Children’s Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Viale Gaetano Pieraccini 24, 50139 Florence, Italy;
| | - Paola De Angelis
- Unit of Gastroenterology and Nutrition, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.C.); (A.D.); (P.D.A.); (G.A.)
| | - Giulia Angelino
- Unit of Gastroenterology and Nutrition, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.C.); (A.D.); (P.D.A.); (G.A.)
| | - Lorenza Putignani
- Unit of Microbiomics and Unit of Research of Microbiome, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
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Lin X, Xu G, Li Y, Yu Y. Chemical fertilizers promote dissemination of ARGs in maize rhizosphere: An overlooked risk revealed after 37-year traditional agriculture practice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 941:173737. [PMID: 38844214 DOI: 10.1016/j.scitotenv.2024.173737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/01/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
Bacterial communities in soil and rhizosphere maintain a large collection of antibiotic resistance genes (ARGs). However, few of these ARGs and antibiotic resistant bacteria (ARB) are well-characterized under traditional farming practices. Here we compared the ARG profiles of maize rhizosphere and their bulk soils using metagenomic analysis to identify the ARG dissemination and explored the potential impact of chemical fertilization on ARB. Results showed a relatively lower abundance but higher diversity of ARGs under fertilization than straw-return. Moreover, the abundance and diversity of MGEs were significantly promoted by chemical fertilizer inputs in the rhizosphere compared to bulk soil. Machine learning and bipartite networks identified three bacterial genera (Pseudomonas, Bacillus and Streptomyces) as biomarkers for ARG accumulation. Thus we cultured 509 isolates belonging to these three genera from the rhizosphere and tested their antimicrobial susceptibility, and found that multi-resistance was frequently observed among Pseudomonas isolates. Assembly-based tracking explained that ARGs and four class I integrons (LR134330, LS998783, CP065848, LT883143) were co-occurred among contigs from Pseudomonas sp. Chemical fertilizers may shape the resistomes of maize rhizosphere, highlighting that rhizosphere carried multidrug-resistant Pseudomonas isolates, which may pose a risk to animal and human health. This study adds knowledge of long-term chemical fertilization on ARG dissemination in farmland systems and provides information for decision-making in agricultural production and monitoring.
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Affiliation(s)
- Xiaolong Lin
- Key Laboratory of Wetland Ecology and Environment, State Key Laboratory of Black Soils Conservation and Utilization, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102, China; School of Agriculture, Sun Yat-sen University, Guangzhou 510275, China
| | - Guanghui Xu
- Key Laboratory of Wetland Ecology and Environment, State Key Laboratory of Black Soils Conservation and Utilization, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102, China
| | - Yanjun Li
- Key Laboratory of Wetland Ecology and Environment, State Key Laboratory of Black Soils Conservation and Utilization, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102, China
| | - Yong Yu
- Key Laboratory of Wetland Ecology and Environment, State Key Laboratory of Black Soils Conservation and Utilization, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102, China.
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Prosty C, Katergi K, Papenburg J, Lawandi A, Lee TC, Shi H, Burnham P, Swem L, Routy B, Yansouni CP, Cheng MP. Causal role of the gut microbiome in certain human diseases: a narrative review. EGASTROENTEROLOGY 2024; 2:e100086. [PMID: 39944364 PMCID: PMC11770457 DOI: 10.1136/egastro-2024-100086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/16/2024] [Indexed: 03/19/2025]
Abstract
Composed of an elaborate ecosystem of bacteria, fungi, viruses and protozoa residing in the human digestive tract, the gut microbiome influences metabolism, immune modulation, bile acid homeostasis and host defence. Through observational and preclinical data, the gut microbiome has been implicated in the pathogenesis of a spectrum of chronic diseases ranging from psychiatric to gastrointestinal in nature. Until recently, the lack of unequivocal evidence supporting a causal link between gut microbiome and human health outcomes incited controversy regarding its significance. However, recent randomised controlled trial (RCT) evidence in conditions, such as Clostridioides difficile infection, cancer immunotherapy and ulcerative colitis, has supported a causal relationship and has underscored the potential of the microbiome as a therapeutic target. This review delineates the RCT evidence substantiating the potential for a causal relationship between the gut microbiome and human health outcomes, the seminal observational evidence that preceded these RCTs and the remaining knowledge gaps.
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Affiliation(s)
- Connor Prosty
- Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Khaled Katergi
- Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Jesse Papenburg
- Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alexander Lawandi
- Division of Infectious Diseases and Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Todd C Lee
- Division of Infectious Diseases and Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Hao Shi
- Kanvas Biosciences, Princeton, New Jersey, USA
| | | | - Lee Swem
- Kanvas Biosciences, Princeton, New Jersey, USA
| | - Bertrand Routy
- Centre de recherche du Centre Hospitalier de l’Université de Montréal, Universite de Montreal, Montreal, Quebec, Canada
| | - Cedric P Yansouni
- Division of Infectious Diseases and Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
- JD MacLean Centre for Tropical Diseases, McGill University, Montreal, Quebec, Canada
| | - Matthew P Cheng
- Faculty of Medicine, McGill University, Montreal, Quebec, Canada
- Division of Infectious Diseases and Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
- Kanvas Biosciences, Princeton, New Jersey, USA
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Li X, Xiao F, Wang X, Ye L, Xiao Y, Li D, Zhang T, Wang Y. Gut Microbial and Metabolic Features Associated With Clostridioides difficile Infection Recurrence in Children. Open Forum Infect Dis 2024; 11:ofae506. [PMID: 39319090 PMCID: PMC11420671 DOI: 10.1093/ofid/ofae506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 09/02/2024] [Indexed: 09/26/2024] Open
Abstract
Background Recurrent Clostridioides difficile infection (CDI) is a critical clinical issue due to the increase in incidence and difficulty in treatment. We aimed to identify gut microbial and metabolic features associated with disease recurrence in a group of pediatric CDI patients. Methods A total of 84 children with primary CDI were prospectively enrolled in the study. Fecal samples collected at the initial diagnosis were subjected to 16S rRNA gene sequencing and targeted metabolomics analysis to profile the bacterial composition and metabolome. Results Twenty-six of 84 (31.0%) pediatric CDI patients experienced recurrence. The alpha diversity of the fecal microbiota was significantly lower in the recurrent group than in the nonrecurrent group, and the beta diversity was different from that of the nonrecurrent group. Taxonomic profiles revealed that the relative abundances of multiple bacterial taxa significantly differed between the recurrent and nonrecurrent groups. Linear discriminant analysis effect size analysis identified several bacterial genera that discriminated between recurrent and nonrecurrent groups, including Parabacteroides, Coprococcus, Dialister, and Clostridium. Recurrent bacteria presented lower abundances of several short-chain fatty acid (SCFA)-producing bacteria (Faecalibacterium, Butyricicoccus, Clostridium, Roseburia, and Ruminococcus), which were correlated with reduced fecal SCFA levels. In addition, several bile acids, including lithocholic acid (LCA), 12-ketoLCA, trihydroxycholestanoic acid, and deoxycholic acid, were decreased in recurrent patients. Conclusions Our study suggests that the differing gut microbiota profiles in pediatric CDI patients may contribute to disease recurrence by modulating SCFA concentrations and bile acid profiles. The gut microbiota and metabolite signatures may be used to predict disease recurrence in children with CDI.
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Affiliation(s)
- Xiaolu Li
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fangfei Xiao
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xufei Wang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Ye
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongmei Xiao
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Li
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Zhang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Gut Microbiota and Metabolic Research Center, Institute of Pediatric Infection, Immunity and Critical Care Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yizhong Wang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Gut Microbiota and Metabolic Research Center, Institute of Pediatric Infection, Immunity and Critical Care Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Spigaglia P. Clostridioides difficile and Gut Microbiota: From Colonization to Infection and Treatment. Pathogens 2024; 13:646. [PMID: 39204246 PMCID: PMC11357127 DOI: 10.3390/pathogens13080646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/03/2024] Open
Abstract
Clostridioides difficile is the main causative agent of antibiotic-associated diarrhea (AAD) in hospitals in the developed world. Both infected patients and asymptomatic colonized individuals represent important transmission sources of C. difficile. C. difficile infection (CDI) shows a large range of symptoms, from mild diarrhea to severe manifestations such as pseudomembranous colitis. Epidemiological changes in CDIs have been observed in the last two decades, with the emergence of highly virulent types and more numerous and severe CDI cases in the community. C. difficile interacts with the gut microbiota throughout its entire life cycle, and the C. difficile's role as colonizer or invader largely depends on alterations in the gut microbiota, which C. difficile itself can promote and maintain. The restoration of the gut microbiota to a healthy state is considered potentially effective for the prevention and treatment of CDI. Besides a fecal microbiota transplantation (FMT), many other approaches to re-establishing intestinal eubiosis are currently under investigation. This review aims to explore current data on C. difficile and gut microbiota changes in colonized individuals and infected patients with a consideration of the recent emergence of highly virulent C. difficile types, with an overview of the microbial interventions used to restore the human gut microbiota.
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Affiliation(s)
- Patrizia Spigaglia
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Roma, Italy
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van Rossen TM, van Beurden YH, Bogaards JA, Budding AE, Mulder CJJ, Vandenbroucke-Grauls CMJE. Fecal microbiota composition is a better predictor of recurrent Clostridioides difficile infection than clinical factors in a prospective, multicentre cohort study. BMC Infect Dis 2024; 24:687. [PMID: 38987677 PMCID: PMC11238444 DOI: 10.1186/s12879-024-09506-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 06/13/2024] [Indexed: 07/12/2024] Open
Abstract
INTRODUCTION Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea. Fidaxomicin and fecal microbiota transplantation (FMT) are effective, but expensive therapies to treat recurrent CDI (reCDI). Our objective was to develop a prediction model for reCDI based on the gut microbiota composition and clinical characteristics, to identify patients who could benefit from early treatment with fidaxomicin or FMT. METHODS Multicentre, prospective, observational study in adult patients diagnosed with a primary episode of CDI. Fecal samples and clinical data were collected prior to, and after 5 days of CDI treatment. Follow-up duration was 8 weeks. Microbiota composition was analysed by IS-pro, a bacterial profiling technique based on phylum- and species-specific differences in the 16-23 S interspace regions of ribosomal DNA. Bayesian additive regression trees (BART) and adaptive group-regularized logistic ridge regression (AGRR) were used to construct prediction models for reCDI. RESULTS 209 patients were included, of which 25% developed reCDI. Variables related to microbiota composition provided better prediction of reCDI and were preferentially selected over clinical factors in joint prediction models. Bacteroidetes abundance and diversity after start of CDI treatment, and the increase in Proteobacteria diversity relative to baseline, were the most robust predictors of reCDI. The sensitivity and specificity of a BART model including these factors were 95% and 78%, but these dropped to 67% and 62% in out-of-sample prediction. CONCLUSION Early microbiota response to CDI treatment is a better predictor of reCDI than clinical prognostic factors, but not yet sufficient enough to predict reCDI in daily practice.
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Affiliation(s)
- Tessel M van Rossen
- Department of Medical Microbiology & Infection Control, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands.
- Department of Gastroenterology & Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands.
| | - Yvette H van Beurden
- Department of Gastroenterology & Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Johannes A Bogaards
- Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Public Health, Amsterdam, The Netherlands
| | | | - Chris J J Mulder
- Department of Gastroenterology & Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands
| | - Christina M J E Vandenbroucke-Grauls
- Department of Medical Microbiology & Infection Control, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
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Missa KF, Diallo K, Bla KB, Tuo KJ, Gboko KDT, Tiémélé LS, Ouattara AF, Gragnon BG, Ngoi JM, Wilkinson RJ, Awandare GA, Bonfoh B. Association of symptomatic upper respiratory tract infections with the alteration of the oropharyngeal microbiome in a cohort of school children in Côte d'Ivoire. Front Microbiol 2024; 15:1412923. [PMID: 38993497 PMCID: PMC11238735 DOI: 10.3389/fmicb.2024.1412923] [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: 04/08/2024] [Accepted: 05/29/2024] [Indexed: 07/13/2024] Open
Abstract
Introduction The oropharyngeal microbiome plays an important role in protection against infectious agents when in balance. Despite use of vaccines and antibiotic therapy to prevent respiratory tract infections, they remain one of the major causes of mortality and morbidity in Low- and middle-income countries. Hence the need to explore other approaches to prevention by identifying microbial biomarkers that could be leveraged to modify the microbiota in order to enhance protection against pathogenic bacteria. The aim of this study was to analyze the oropharyngeal microbiome (OPM) of schoolchildren in Côte d'Ivoire presenting symptoms of upper respiratory tract infections (URTI) for better prevention strategy. Methods Primary schools' children in Korhogo (n = 37) and Abidjan (n = 39) were followed for six months with monthly oropharyngeal sampling. Clinical diagnostic of URT infection was performed and nucleic acid extracted from oropharyngeal swabs were used for 16S rRNA metagenomic analysis and RT-PCR. Results The clinical examination of children's throat in Abidjan and Korhogo identified respectively 17 (43.59%) and 15 (40.54%) participants with visible symptoms of URTIs, with 26 episodes of infection in Abidjan and 24 in Korhogo. Carriage of Haemophilus influenzae (12%), Streptococcus pneumoniae (6%) and SARS-CoV-2 (6%) was confirmed by PCR. A significant difference in alpha diversity was found between children colonized by S. pneumoniae and those that were not (p = 0.022). There was also a significant difference in alpha diversity between children colonised with H. influenzae and those who were not (p = 0.017). No significant difference was found for SARS-CoV-2. Sphingomonas, Ralstonia and Rothia were significantly enriched in non-carriers of S. pneumoniae; Actinobacillus was significantly enriched in non-carriers of H. influenzae; Actinobacillus and Porphyromonas were significantly enriched in non-carriers of SARS-CoV-2 (p < 0.001). Discussion Nearly 40% of children showed clinical symptoms of infection not related to geographical location. The OPM showed an imbalance during H. influenzae and S. pneumoniae carriage. This study provides a baseline understanding of microbiome markers in URTIs in children for future research, to develop targeted interventions aimed at restoring the microbial balance and reducing the symptoms associated with RTIs.
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Affiliation(s)
- Kouassi Firmin Missa
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
- Laboratoire de Biologie et Santé, UFR Biosciences, Université Félix Houphouët Boigny de Cocody, Abidjan, Côte d'Ivoire
| | - Kanny Diallo
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
- West African Centre for Cell Biology of Infectious Pathogens, Accra, Ghana
| | - Kouakou Brice Bla
- Laboratoire de Biologie et Santé, UFR Biosciences, Université Félix Houphouët Boigny de Cocody, Abidjan, Côte d'Ivoire
| | - Kolotioloman Jérémie Tuo
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
- Laboratoire de Microbiologie, Biotechnologies et Bio-informatique, Institut National Polytechnique Félix Houphouët-Boigny, Yamoussoukro, Côte d'Ivoire
| | - Kossia Debia Thérèse Gboko
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
| | - Laurent-Simon Tiémélé
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
| | - Allassane Foungoye Ouattara
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
- Laboratoire de Cytologie et Biologie Animale, Université Nangui Abrogoua, Abidjan, Côte d'Ivoire
| | - Biego Guillaume Gragnon
- Laboratoire de Cytologie et Biologie Animale, Université Nangui Abrogoua, Abidjan, Côte d'Ivoire
| | | | - Robert J Wilkinson
- Laboratoire National d'Appui au Développement Agricole, Laboratoire Régional de Korhogo, Korhogo, Côte d'Ivoire
- The Francis Crick Institute, London, United Kingdom
- Department of Infectious Disease, Imperial College London, London, United Kingdom
| | - Gordon A Awandare
- West African Centre for Cell Biology of Infectious Pathogens, Accra, Ghana
| | - Bassirou Bonfoh
- Direction de la Recherche et du Développement, Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire
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10
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Davoutis E, Gkiafi Z, Lykoudis PM. Bringing gut microbiota into the spotlight of clinical research and medical practice. World J Clin Cases 2024; 12:2293-2300. [PMID: 38765739 PMCID: PMC11099419 DOI: 10.12998/wjcc.v12.i14.2293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/30/2024] [Accepted: 04/07/2024] [Indexed: 04/29/2024] Open
Abstract
Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical practice. Proteins and metabolites produced by microbiota contribute to immune system development, energy homeostasis and digestion. Exo- and endogenous factors can alter its composition. Disturbance of microbiota, also known as dysbiosis, is associated with various pathological conditions. Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool. GM could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections. Additionally, it can influence response to treatments, including those for cancers, by altering drug bioavailability. A thorough understanding of its function has permitted significant development in therapeutics, such as probiotics and fecal transplantation. Hence, GM should be considered as a ground-breaking biological parameter, and it is advisable to be investigated and reported in literature in a more consistent and systematic way.
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Affiliation(s)
- Efstathia Davoutis
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Zoi Gkiafi
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagis M Lykoudis
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
- Division of Surgery and Interventional Science, University College London, London WC1E 6BT, United Kingdom
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11
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Mpakaniye P, Boven A, Callens S, Engstrand L, Vlieghe E, Brusselaers N. Clostridioides difficile recurrence in individuals with and without cancer: a Swedish population-based cohort study. Infection 2024; 52:649-660. [PMID: 38407777 PMCID: PMC10954957 DOI: 10.1007/s15010-024-02193-1] [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: 12/08/2023] [Accepted: 01/19/2024] [Indexed: 02/27/2024]
Abstract
PURPOSE Patients with cancer are vulnerable to Clostridioides difficile infection (CDI) due to their disease, treatment and regular hospital contact, yet if CDI-recurrence is more common remains unclear, and differences among cancer types remain unexplored. METHODS This Swedish nationwide population-based cohort included all 43,150 individuals with recorded CDI (2006-2019) to assess CDI-recurrence in individuals with and without cancer, with binary multivariable logistic regression, stratified by anatomical location, and survival status. RESULTS Compared to those without cancer (N = 29,543), ongoing cancer (diagnosis < 12 months; N = 3,882) was associated with reduced recurrence (OR = 0.81, 95% CI 0.73-0.89), while there was no association with cancer history (diagnosis ≥ 12 months; N = 9,725). There was an increased 8-week all-cause mortality (Ongoing cancer: OR = 1.58, 95% CI 1.43-1.74; Cancer history: OR = 1.45, 95% CI 1.36-1.55) compared to those without cancer. Among CDI-survivors, those with ongoing cancer presented with a decreased odds of recurrence (OR = 0.84, 95% CI 0.76-0.94), compared to those without cancer history, with no association for those with cancer history (OR = 1.04, 95% CI 0.97-1.1). Large variations were seen across cancer types, with the highest observed proportion of recurrence in oral and mesothelial cancer, and the lowest for esophageal cancer, although no statistically significant OR were found. CONCLUSION The population-based study indicates that individuals with cancer may have fewerrecurrences than expected, yet variations by cancer type were large, and mortality was high.
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Affiliation(s)
- Peace Mpakaniye
- Centre for Translational Microbiome Research, Department Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Global Health Institute, Department of Family Medicine and Population Health, University of Antwerp, Antwerp, Belgium
| | - Annelies Boven
- Centre for Translational Microbiome Research, Department Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Global Health Institute, Department of Family Medicine and Population Health, University of Antwerp, Antwerp, Belgium
- The Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Steven Callens
- General Internal Medicine and Infectious Diseases, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Lars Engstrand
- Centre for Translational Microbiome Research, Department Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Erika Vlieghe
- Global Health Institute, Department of Family Medicine and Population Health, University of Antwerp, Antwerp, Belgium
- Infectious Diseases, Department of General Medicine, Antwerp University Hospital, Antwerp, Belgium
| | - Nele Brusselaers
- Centre for Translational Microbiome Research, Department Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
- Global Health Institute, Department of Family Medicine and Population Health, University of Antwerp, Antwerp, Belgium.
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
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12
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Gurung B, Stricklin M, Wang S. Gut Microbiota-Gut Metabolites and Clostridioides difficile Infection: Approaching Sustainable Solutions for Therapy. Metabolites 2024; 14:74. [PMID: 38276309 PMCID: PMC10819375 DOI: 10.3390/metabo14010074] [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: 12/23/2023] [Revised: 01/06/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and fecal microbiota transplantation, which contribute to recurrent CDIs and potential risks. Therefore, there is an ongoing need to develop new preventative treatment strategies for CDI. Notably, gut microbiota dysbiosis is the primary risk factor for CDI and provides a promising target for developing novel CDI therapy approaches. Along with gut microbiota dysbiosis, a reduction in important gut metabolites like secondary bile acids and short-chain fatty acids (SCFAs) were also seen in patients suffering from CDI. In this review study, we investigated the roles and mechanisms of gut microbiota and gut microbiota-derived gut metabolites, especially secondary bile acids and SCFAs in CDI pathogenesis. Moreover, specific signatures of gut microbiota and gut metabolites, as well as different factors that can modulate the gut microbiota, were also discussed, indicating that gut microbiota modulators like probiotics and prebiotics can be a potential therapeutic strategy for CDI as they can help restore gut microbiota and produce gut metabolites necessary for a healthy gut. The understanding of the associations between gut microbiota-gut metabolites and CDI will allow for developing precise and sustainable approaches, distinct from antibiotics and fecal transplant, for mitigating CDI and other gut microbiota dysbiosis-related diseases.
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Affiliation(s)
- Bijay Gurung
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (B.G.); (M.S.)
- Infectious and Tropical Disease Institute, Ohio University, Athens, OH 45701, USA
- Interdisciplinary Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA
| | - Maranda Stricklin
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (B.G.); (M.S.)
- Infectious and Tropical Disease Institute, Ohio University, Athens, OH 45701, USA
| | - Shaohua Wang
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (B.G.); (M.S.)
- Infectious and Tropical Disease Institute, Ohio University, Athens, OH 45701, USA
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13
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Wu Q, Badu S, So SY, Treangen TJ, Savidge TC. The pan-microbiome profiling system Taxa4Meta identifies clinical dysbiotic features and classifies diarrheal disease. J Clin Invest 2024; 134:e170859. [PMID: 37962956 PMCID: PMC10786686 DOI: 10.1172/jci170859] [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: 03/24/2023] [Accepted: 11/09/2023] [Indexed: 11/16/2023] Open
Abstract
Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and validated Taxa4Meta for accurate taxonomic profiling of 16S rRNA amplicon data acquired from different sequencing strategies. Taxa4Meta offers significant potential in identifying clinical dysbiotic features that can reliably predict human disease, validated comprehensively via reanalysis of individual patient 16S data sets. We leveraged the power of Taxa4Meta's pan-microbiome profiling to generate 16S-based classifiers that exhibited excellent utility for stratification of diarrheal patients with Clostridioides difficile infection, irritable bowel syndrome, or inflammatory bowel diseases, which represent common misdiagnoses and pose significant challenges for clinical management. We believe that Taxa4Meta represents a new "best practices" approach to individual microbiome surveys that can be used to define gut dysbiosis at a population-scale level.
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Affiliation(s)
- Qinglong Wu
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Shyam Badu
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Sik Yu So
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Todd J. Treangen
- Department of Computer Science, Rice University, Houston, Texas, USA
| | - Tor C. Savidge
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
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14
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Ghani R, Chrysostomou D, Roberts LA, Pandiaraja M, Marchesi JR, Mullish BH. Faecal (or intestinal) microbiota transplant: a tool for repairing the gut microbiome. Gut Microbes 2024; 16:2423026. [PMID: 39499189 PMCID: PMC11540080 DOI: 10.1080/19490976.2024.2423026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/07/2024] Open
Abstract
Faecal/intestinal microbiota transplant (FMT/IMT) is an efficacious treatment option for recurrent Clostridioides difficile infection, which has prompted substantial interest in FMT's potential role in the management of a much broader range of diseases associated with the gut microbiome. Despite its promise, the success rates of FMT in these other settings have been variable. This review critically evaluates the current evidence on the impact of clinical, biological, and procedural factors upon the therapeutic efficacy of FMT, and identifies areas that remain nebulous. Due to some of these factors, the optimal therapeutic approach remains unclear; for example, the preferred timing of FMT administration in a heavily antibiotic-exposed hematopoietic cell transplant recipient is not standardized, with arguments that can be made in alternate directions. We explore how these factors may impact upon more informed selection of donors, potential matching of donors to recipients, and aspects of clinical care of FMT recipients. This includes consideration of how gut microbiome composition and functionality may strategically inform donor selection criteria. Furthermore, we review how the most productive advances within the FMT space are those where clinical and translational outcomes are assessed together, and where this model has been used productively in recent years to better understand the contribution of the gut microbiome to human disease, and start the process toward development of more targeted microbiome therapeutics.
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Affiliation(s)
- Rohma Ghani
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
- Department of Infectious Diseases, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Despoina Chrysostomou
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Lauren A Roberts
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Madhumitha Pandiaraja
- Department of Gastroenterology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Julian R. Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Benjamin H. Mullish
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
- Department of Hepatology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
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15
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Vázquez-Cuesta S, Lozano García N, Fernández AI, Olmedo M, Kestler M, Alcalá L, Marín M, Bermejo J, Díaz FFA, Muñoz P, Bouza E, Reigadas E. Microbiome profile and calprotectin levels as markers of risk of recurrent Clostridioides difficile infection. Front Cell Infect Microbiol 2023; 13:1237500. [PMID: 37780848 PMCID: PMC10534046 DOI: 10.3389/fcimb.2023.1237500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/23/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction Clostridioides difficile infection (CDI) is the main cause of nosocomial diarrhoea in developed countries. Recurrent CDI (R-CDI), which affects 20%-30% of patients and significantly increases hospital stay and associated costs, is a key challenge. The main objective of this study was to explore the role of the microbiome and calprotectin levels as predictive biomarkers of R-CDI. Methods We prospectively (2019-2021) included patients with a primary episode of CDI. Clinical data and faecal samples were collected. The microbiome was analysed by sequencing the hypervariable V4 region of the 16S rRNA gene on an Illumina Miseq platform. Results We enrolled 200 patients with primary CDI, of whom 54 developed R-CDI and 146 did not. We analysed 200 primary samples and found that Fusobacterium increased in abundance, while Collinsella, Senegalimassilia, Prevotella and Ruminococcus decreased in patients with recurrent versus non-recurrent disease. Elevated calprotectin levels correlated significantly with R-CDI (p=0.01). We built a risk index for R-CDI, including as prognostic factors age, sex, immunosuppression, toxin B amplification cycle, creatinine levels and faecal calprotectin levels (overall accuracy of 79%). Discussion Calprotectin levels and abundance of microbial genera such as Fusobacterium and Prevotella in primary episodes could be useful as early markers of R-CDI. We propose a readily available model for prediction of R-CDI that can be applied at the initial CDI episode. The use of this tool could help to better tailor treatments according to the risk of R-CDI.
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Affiliation(s)
- Silvia Vázquez-Cuesta
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Biochemistry and Molecular Biology Department, Faculty of Biology, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Nuria Lozano García
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Ana I. Fernández
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - María Olmedo
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Martha Kestler
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Luis Alcalá
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Mercedes Marín
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Javier Bermejo
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Francisco Fernández-Avilés Díaz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Patricia Muñoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Centro de Investigación Biomédica en red de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
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16
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Talathi S, Wilkinson L, Meloni K, Shroyer M, Zhang L, Ding Z, Eipers P, Van Der Pol W, Martin C, Dimmitt R, Yi N, Morrow C, Galloway D. Factors Affecting the Gut Microbiome in Pediatric Intestinal Failure. J Pediatr Gastroenterol Nutr 2023; 77:426-432. [PMID: 37184493 DOI: 10.1097/mpg.0000000000003828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
BACKGROUND There is little data on gut microbiome and various factors that lead to dysbiosis in pediatric intestinal failure (PIF). This study aimed to characterize gut microbiome in PIF and determine factors that may affect microbial composition in these patients. METHODS This is a single-center, prospective cohort study of children with PIF followed at our intestinal rehabilitation program. Stool samples were collected longitudinally at regular intervals over a 1-year period. Medical records were reviewed, and demographic and clinical data were collected. Medication history including the use of acid blockers, scheduled prophylactic antibiotics, and bile acid sequestrants was obtained. Gut microbial diversity among patients was assessed and compared according to various host characteristics of interest. RESULTS The final analysis included 74 specimens from 12 subjects. Scheduled prophylactic antibiotics, presence of central line associated bloodstream infection (CLABSI) at the time of specimen collection, use of acid blockers, and ≥50% calories delivered via parenteral nutrition (PN) was associated with reduced alpha diversity, whereas increasing age was associated with improved alpha diversity at various microbial levels ( P value <0.05). Beta diversity differed with age, presence of CLABSI, use of scheduled antibiotics, acid blockers, percent calories via PN, and presence of oral feeds at various microbial levels ( P value <0.05). Single taxon analysis identified several taxa at several microbial levels, which were significantly associated with various host characteristics. CONCLUSION Gut microbial diversity in PIF subjects is influenced by various factors involved in the rehabilitation process including medications, percent calories received parenterally, CLABSI events, the degree of oral feeding, and age. Additional investigation performed across multiple centers is needed to further understand the impact of these findings on important clinical outcomes in PIF.
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Affiliation(s)
- Saurabh Talathi
- From the Department of Pediatrics, Division of Pediatric Gastroenterology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- the Department of Pediatrics, Division of Pediatric Gastroenterology, The University of Alabama at Birmingham, Birmingham, AL
| | - Linda Wilkinson
- the Department of Surgery, Division of Pediatric Surgery, The University of Alabama at Birmingham, Birmingham, AL
| | - Katie Meloni
- the Department of Clinical Nutrition, Children's of Alabama, Birmingham, AL
| | - Michelle Shroyer
- the Department of Surgery, Division of Pediatric Surgery, The University of Alabama at Birmingham, Birmingham, AL
| | - Li Zhang
- the Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL
| | - Zhenying Ding
- the Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL
| | - Peter Eipers
- the Department of Cell, Developmental, & Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL
| | - William Van Der Pol
- the Biomedical Informatics Center for Clinical and Translational Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Colin Martin
- the Department of Surgery, Division of Pediatric Surgery, The University of Alabama at Birmingham, Birmingham, AL
| | - Reed Dimmitt
- the Department of Pediatrics, Division of Pediatric Gastroenterology, The University of Alabama at Birmingham, Birmingham, AL
| | - Nengjun Yi
- the Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL
| | - Casey Morrow
- the Department of Cell, Developmental, & Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL
| | - David Galloway
- the Department of Pediatrics, Division of Pediatric Gastroenterology, The University of Alabama at Birmingham, Birmingham, AL
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17
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Chen LA, Oliva-Hemker M, Radin A, Weidner M, O’Laughlin BD, Sears CL, Javitt NB, Hourigan SK. Longitudinal Bile Acid Composition Changes Following Faecal Microbiota Transplantation for Clostridioides difficile Infection in Children With and Without Underlying Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1364-1368. [PMID: 36988432 PMCID: PMC10441560 DOI: 10.1093/ecco-jcc/jjad057] [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: 02/04/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND AND AIMS Faecal microbiota transplant [FMT] is effective in treating recurrent Clostridioides difficile infection [CDI] and restores gut microbiota composition. This is unlikely to account for its entire mechanism of efficacy, as studies have shown that factors such as bile acids influence the risk of infection by affecting Clostridioides difficile germination. We therefore aimed to investigate longitudinal changes in the gut bile acid composition after FMT performed for recurrent CDI, in children with and without inflammatory bowel disease [IBD]. METHODS Eight children received FMT; five had underlying IBD. Primary and secondary faecal bile acids were measured by liquid chromatography-mass spectrometry in recipients [pre-FMT and longitudinally post-FMT for up to 6 months] and donors. RESULTS Pre-FMT, recipients had higher primary and lower secondary bile acid proportions compared with donors. Post-FMT, there was a gradual increase of secondary and decrease of primary bile acids. Whereas gut bacterial diversity had been shown to be restored in all children shortly after FMT, normalisation of bile acids to donor levels occurred only by 6 months. In children with IBD, although microbiota diversity returned to pre-FMT levels within 6 months, secondary bile acids remained at donor levels. CONCLUSIONS The differences in bile acid profiles compared with gut bacterial diversity post-FMT suggests that interactions between the two may be more complex than previously appreciated and may contribute to FMT efficacy in different ways. This initial finding demonstrates the need to further investigate gut metabolites in larger cohorts, with longitudinal sampling to understand the mechanisms of FMT effectiveness.
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Affiliation(s)
- Lea Ann Chen
- Division of Gastroenterology and Hepatology, New York University Grossman School of Medicine, New York, NY, USA
| | - Maria Oliva-Hemker
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Arielle Radin
- Division of Gastroenterology and Hepatology, New York University Grossman School of Medicine, New York, NY, USA
| | - Melissa Weidner
- Division of Pediatric Gastroenterology, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Brynn D O’Laughlin
- Division of Pediatric Gastroenterology, Department of Pediatrics, Children’s National Medical Center, Washington, DC, USA
| | - Cynthia L Sears
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Norman B Javitt
- Division of Gastroenterology and Hepatology,New York University Grossman School of Medicine, New York, NY, USA
| | - Suchitra K Hourigan
- Clinical Microbiome Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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18
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Martín R, Rios-Covian D, Huillet E, Auger S, Khazaal S, Bermúdez-Humarán LG, Sokol H, Chatel JM, Langella P. Faecalibacterium: a bacterial genus with promising human health applications. FEMS Microbiol Rev 2023; 47:fuad039. [PMID: 37451743 PMCID: PMC10410495 DOI: 10.1093/femsre/fuad039] [Citation(s) in RCA: 130] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 06/08/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023] Open
Abstract
In humans, many diseases are associated with alterations in gut microbiota, namely increases or decreases in the abundance of specific bacterial groups. One example is the genus Faecalibacterium. Numerous studies have underscored that low levels of Faecalibacterium are correlated with inflammatory conditions, with inflammatory bowel disease (IBD) in the forefront. Its representation is also diminished in the case of several diseases, including colorectal cancer (CRC), dermatitis, and depression. Additionally, the relative presence of this genus is considered to reflect, at least in part, intestinal health status because Faecalibacterium is frequently present at reduced levels in individuals with gastrointestinal diseases or disorders. In this review, we first thoroughly describe updates to the taxonomy of Faecalibacterium, which has transformed a single-species taxon to a multispecies taxon over the last decade. We then explore the links discovered between Faecalibacterium abundance and various diseases since the first IBD-focused studies were published. Next, we examine current available strategies for modulating Faecalibacterium levels in the gut. Finally, we summarize the mechanisms underlying the beneficial effects that have been attributed to this genus. Together, epidemiological and experimental data strongly support the use of Faecalibacterium as a next-generation probiotic (NGP) or live biotherapeutic product (LBP).
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Affiliation(s)
- Rebeca Martín
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - David Rios-Covian
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Eugénie Huillet
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Sandrine Auger
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Sarah Khazaal
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Luis G Bermúdez-Humarán
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Harry Sokol
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012 Paris, France
- Paris Centre for Microbiome Medicine (PaCeMM) FHU, F-75012, Paris, France
| | - Jean-Marc Chatel
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Philippe Langella
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
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19
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Okafor CM, Clogher P, Olson D, Niccolai L, Hadler J. Trends in and Risk Factors for Recurrent Clostridioides difficile Infection, New Haven County, Connecticut, USA, 2015-2020. Emerg Infect Dis 2023; 29. [PMID: 37081745 PMCID: PMC10124664 DOI: 10.3201/eid2905.221294] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023] Open
Abstract
Recurrent Clostridioides difficile infection (RCDI) causes an increased burden on the healthcare system. We calculated RCDI incidence and identified factors associated with RCDI cases in New Haven County, Connecticut, USA, during 2015-2020 by using data from population-based laboratory surveillance. A subset of C. difficile cases had complete chart reviews conducted for RCDI and potentially associated variables. RCDI was defined as a positive C. difficile specimen occurring 2-8 weeks after incident C. difficile infection. We compared cases with and without RCDI by using multiple regression. RCDI occurred in 12.0% of 4,301 chart-reviewed C. difficile cases, showing a U-shaped time trend with a sharp increase in 2020, mostly because of an increase in hospital-onset cases. Malignancy (odds ratio 1.51 [95% CI 1.11-2.07]) and antecedent nitrofurantoin use (odds ratio 2.37 [95% CI 1.23-4.58]) were medical risk factors for RCDI. The 2020 increase may reflect the impact of the COVID-19 pandemic.
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20
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Lindner M, Radke DI, Elke G. [Bacterial gut microbiota-key player in sepsis]. Med Klin Intensivmed Notfmed 2023; 118:107-113. [PMID: 36807754 DOI: 10.1007/s00063-023-00993-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 02/19/2023]
Abstract
The gut microbiota is comprised of over 1200 different bacteria and forms a symbiotic community with the human organism, the holobiont. It plays an important role in the maintenance of homeostasis, e.g., of the immune system and essential metabolic processes. Disturbances in the balance of this reciprocal relationship are called dysbiosis and, in the field of sepsis, are associated with incidence of disease, extent of the systemic inflammatory response, severity of organ dysfunction, and mortality. In addition to providing guiding principles in the fascinating relationship between "human and microbe," this article summarizes recent findings regarding the role of the bacterial gut microbiota in sepsis, which is one a very relevant in intensive care medicine.
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Affiliation(s)
- Matthias Lindner
- Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus 12, 24105, Kiel, Deutschland.
| | - David I Radke
- Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus 12, 24105, Kiel, Deutschland
| | - Gunnar Elke
- Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus 12, 24105, Kiel, Deutschland
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21
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Maciel-Guerra A, Baker M, Hu Y, Wang W, Zhang X, Rong J, Zhang Y, Zhang J, Kaler J, Renney D, Loose M, Emes RD, Liu L, Chen J, Peng Z, Li F, Dottorini T. Dissecting microbial communities and resistomes for interconnected humans, soil, and livestock. THE ISME JOURNAL 2023; 17:21-35. [PMID: 36151458 PMCID: PMC9751072 DOI: 10.1038/s41396-022-01315-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 08/26/2022] [Accepted: 09/01/2022] [Indexed: 12/24/2022]
Abstract
A debate is currently ongoing as to whether intensive livestock farms may constitute reservoirs of clinically relevant antimicrobial resistance (AMR), thus posing a threat to surrounding communities. Here, combining shotgun metagenome sequencing, machine learning (ML), and culture-based methods, we focused on a poultry farm and connected slaughterhouse in China, investigating the gut microbiome of livestock, workers and their households, and microbial communities in carcasses and soil. For both the microbiome and resistomes in this study, differences are observed across environments and hosts. However, at a finer scale, several similar clinically relevant antimicrobial resistance genes (ARGs) and similar associated mobile genetic elements were found in both human and broiler chicken samples. Next, we focused on Escherichia coli, an important indicator for the surveillance of AMR on the farm. Strains of E. coli were found intermixed between humans and chickens. We observed that several ARGs present in the chicken faecal resistome showed correlation to resistance/susceptibility profiles of E. coli isolates cultured from the same samples. Finally, by using environmental sensing these ARGs were found to be correlated to variations in environmental temperature and humidity. Our results show the importance of adopting a multi-domain and multi-scale approach when studying microbial communities and AMR in complex, interconnected environments.
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Affiliation(s)
- Alexandre Maciel-Guerra
- grid.4563.40000 0004 1936 8868School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD UK
| | - Michelle Baker
- grid.4563.40000 0004 1936 8868School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD UK
| | - Yue Hu
- grid.4563.40000 0004 1936 8868School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD UK
| | - Wei Wang
- grid.464207.30000 0004 4914 5614NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021 People’s Republic of China
| | - Xibin Zhang
- grid.508175.eNew Hope Liuhe Co., Ltd., Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Beijing 100102 and Weifang Heshengyuan Food Co. Ltd., Weifang, 262167 People’s Republic of China
| | - Jia Rong
- grid.508175.eNew Hope Liuhe Co., Ltd., Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Beijing 100102 and Weifang Heshengyuan Food Co. Ltd., Weifang, 262167 People’s Republic of China
| | - Yimin Zhang
- grid.440622.60000 0000 9482 4676College of Food Science and Engineering, Shandong Agricultural University, Tai’an, Shandong 271018 People’s Republic of China
| | - Jing Zhang
- grid.464207.30000 0004 4914 5614NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021 People’s Republic of China
| | - Jasmeet Kaler
- grid.4563.40000 0004 1936 8868School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD UK
| | - David Renney
- Nimrod Veterinary Products Limited, 2, Wychwood Court, Cotswold Business Village, Moreton-in-Marsh, GL56 0JQ UK
| | - Matthew Loose
- grid.4563.40000 0004 1936 8868DeepSeq, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH UK
| | - Richard D. Emes
- grid.4563.40000 0004 1936 8868School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD UK
| | - Longhai Liu
- grid.508175.eNew Hope Liuhe Co., Ltd., Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Beijing 100102 and Weifang Heshengyuan Food Co. Ltd., Weifang, 262167 People’s Republic of China
| | - Junshi Chen
- grid.464207.30000 0004 4914 5614NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021 People’s Republic of China
| | - Zixin Peng
- NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, People's Republic of China.
| | - Fengqin Li
- NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, People's Republic of China.
| | - Tania Dottorini
- School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Leicestershire, LE12 5RD, UK.
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22
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Interaction of microbiome and immunity in tumorigenesis and clinical treatment. Biomed Pharmacother 2022; 156:113894. [DOI: 10.1016/j.biopha.2022.113894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 11/15/2022] Open
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23
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Mullish BH, Martinez-Gili L, Chekmeneva E, Correia GDS, Lewis MR, Horneffer-Van Der Sluis V, Roberts LA, McDonald JAK, Pechlivanis A, Walters JRF, McClure EL, Marchesi JR, Allegretti JR. Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection. Aliment Pharmacol Ther 2022; 56:1556-1569. [PMID: 36250604 DOI: 10.1111/apt.17247] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/30/2022] [Accepted: 09/26/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis. AIMS To define stool BA dynamics in patients with primary CDI and to explore signatures predicting recurrence METHODS: Weekly stool samples were collected from patients with primary CDI from the last day of anti-CDI therapy until recurrence or, otherwise, through 8 weeks post-completion. Ultra-high performance liquid chromatography-mass spectrometry was used to profile BAs. Stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence. RESULTS Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post-antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post-treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non-relapsing patients (β = 0.056; likelihood ratio test p = 0.018). A joint longitudinal-survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post-CDI treatment. CONCLUSIONS Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.
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Affiliation(s)
- Benjamin H Mullish
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK.,Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Laura Martinez-Gili
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK.,Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Elena Chekmeneva
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, National Phenome Centre, IRDB Building, Hammersmith House Campus, Imperial College London, London, UK.,Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Gonçalo D S Correia
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, National Phenome Centre, IRDB Building, Hammersmith House Campus, Imperial College London, London, UK.,Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Matthew R Lewis
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, National Phenome Centre, IRDB Building, Hammersmith House Campus, Imperial College London, London, UK.,Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Verena Horneffer-Van Der Sluis
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, National Phenome Centre, IRDB Building, Hammersmith House Campus, Imperial College London, London, UK.,Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.,Department for Diagnostics, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Lauren A Roberts
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - Julie A K McDonald
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
| | - Alexandros Pechlivanis
- Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.,Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Biomic_Auth, Bioanalysis and Omics Laboratory, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Thessaloniki, Greece
| | - Julian R F Walters
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK.,Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Emma L McClure
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Julian R Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - Jessica R Allegretti
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
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24
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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
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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25
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Martinez E, Rodriguez C, Crèvecoeur S, Lebrun S, Delcenserie V, Taminiau B, Daube G. Impact of environmental conditions and gut microbiota on the in vitro germination and growth of Clostridioides difficile. FEMS Microbiol Lett 2022; 369:6692865. [PMID: 36066913 DOI: 10.1093/femsle/fnac087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 08/09/2022] [Accepted: 09/01/2022] [Indexed: 12/13/2022] Open
Abstract
Clostridioides difficile is a spore-forming anaerobic Gram-positive bacterium responsible for a broad spectrum of intestinal symptoms and healthcare-associated diarrhoea. The hypothesis of this work was that different in vitro conditions, notably pH and human faecal microbiota composition, impact the germination and/or the growth of C. difficile. This study aimed to correlate growth kinetics of the bacterium with these two physiochemical parameters by using a static in vitro model. To better understand the initial gut colonisation, several growth curve assays were carried out to monitor the behaviour of the spores and vegetative forms of C. difficile strain 078 under different conditions mimicking the gut environment. When the faeces were added, no spore germination or growth was observed, but C. difficile spores germinated in vitro when the pH was maintained between 6.6 and 6.9 for four different faeces donors. The evolution of microbiota studied by 16S rDNA profiling showed high proportions of Enterobacteriaceae and E. coli/Shigella when C. difficile grew, regardless of the inoculated faeces. This model helped us to understand that the germination and growth of C. difficile are strongly pH dependent, and further research is needed to evaluate the potential impact of the gut microbiota composition on C. difficile.
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Affiliation(s)
- Elisa Martinez
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
| | - Cristina Rodriguez
- Instituto de Investigación Biomédica de Málaga-IBIMA. Málaga, Spain. Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Málaga, 29590, Spain
| | - Sébastien Crèvecoeur
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
| | - Sarah Lebrun
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
| | - Véronique Delcenserie
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
| | - Bernard Taminiau
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
| | - Georges Daube
- Fundamental and Applied Research for Animals & Health (FARAH), Faculté de Médecine Vétérinaire, Département des Sciences des Denrées alimentaires, Université de Liège, Avenue de Cureghem 10, 4000 Liège, Belgique
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26
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Gut Microbiota Composition Associated with Clostridioides difficile Colonization and Infection. Pathogens 2022; 11:pathogens11070781. [PMID: 35890026 PMCID: PMC9322938 DOI: 10.3390/pathogens11070781] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/12/2022] Open
Abstract
Clostridioides difficile is an anaerobic Gram-positive and spore-forming bacterium. The majority of C. difficile strains produce two toxins, A and B, associated with the development of acute diarrhea and/or colitis. In this review, two situations are distinguished: C. difficile infection (CDI) and asymptomatic colonization (AC). The main objective of this review is to explore the available data related to the link between the gut microbiota and the development of CDI. The secondary aim is to provide more information on why some people colonized with toxigenic C. difficile develop an infection while others show no signs of disease. Several factors, such as the use of antibiotics and proton pump inhibitors, hospitalization, and age, predispose individuals to C. difficile colonization and/or C. difficile infection. The gut microbiota of people with AC showed decreased abundances of Prevotella, Alistipes, Bacteroides, Bifidobacterium, Dorea, Coprococcus, and Roseburia. The gut microbiota of people suffering from CDI showed reductions in the abundances of Lachnospiraceae, Ruminococcaceae, Blautia spp., Prevotella spp., Dialister spp., Bifidobacterium spp., Roseburia spp., Anaerostipes spp., Faecalibacterium spp. and Coprococcus spp., in comparison with healthy people. Furthermore, increases in the abundances of Enterococcaceae and Enterococcus were associated with C. difficile infection.
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27
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Hogan CA, Hitchcock MM, Frost S, Kapphahn K, Holubar M, Tompkins LS, Banaei N. Clinical Outcomes of Treated and Untreated C. difficile PCR-Positive/Toxin-Negative Adult Hospitalized Patients: a Quasi-Experimental Noninferiority Study. J Clin Microbiol 2022; 60:e0218721. [PMID: 35611653 PMCID: PMC9199396 DOI: 10.1128/jcm.02187-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/21/2022] [Indexed: 12/31/2022] Open
Abstract
Clostridioides difficile infection (CDI) is routinely diagnosed by PCR, with or without toxin enzyme immunoassay testing. The role of therapy for positive PCR and negative toxin remains unclear. The objective of this study was to determine whether clinical outcomes of PCR+/cycle threshold-based toxin (CT-toxin)- individuals vary by result reporting and treatment strategy. We performed a quasiexperimental noninferiority study comparing clinical outcomes of PCR+/CT-toxin- individuals by reporting PCR result only (most patients treated) with reporting CT-toxin result only (most patients untreated) in a single-center, tertiary academic hospital. The primary outcome was symptomatic PCR+/CT-toxin+ conversion at 8 weeks. Secondary outcomes included 7-day diarrhea resolution, hospital length of stay, and 30-day all-cause mortality. A total of 663 PCR+/CT-toxin- test results were analyzed from 632 individuals with a median age of 61 years (interquartile range [IQR], 44 to 72) and 50.4% immunocompromised. Individuals in the preintervention group were more likely to have received CDI therapy than those in the intervention group (91.5 versus 15.1%; P < 0.001). Symptomatic toxin conversion at 8 weeks and hospital length of stay failed to establish the predefined thresholds for noninferiority. Lack of diarrhea resolution at 7 days and 30-day all-cause mortality was similar and established noninferiority (20.0 versus 13.7%; adjusted odds ratio [aOR], 0.57; 90% confidence interval [CI], 0.32 to 1.01; P = 0.1; and 8.6 versus 6.5%; aOR, 0.46; 90% CI, 0.20 to 1.04; P = 0.12). These data support the safety of withholding antibiotics for selected hospitalized individuals with suspected CDI but negative toxin.
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Affiliation(s)
- Catherine A. Hogan
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
- Clinical Microbiology Laboratory, Stanford Health Care, Stanford, California, USA
| | - Matthew M. Hitchcock
- Department of Medicine, Division of Infectious Diseases, Central Virginia VA Health Care System, Richmond, Virginia, USA
- Department of Internal Medicine, Division of Infectious Diseases, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Spencer Frost
- Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Kristopher Kapphahn
- Quantitative Sciences Unit, Stanford University School of Medicine, Stanford, California, USA
| | - Marisa Holubar
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
- Department of Quality, Patient Safety and Effectiveness, Stanford University School of Medicine, Stanford, California, USA
| | - Lucy S. Tompkins
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Niaz Banaei
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
- Clinical Microbiology Laboratory, Stanford Health Care, Stanford, California, USA
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
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28
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Dawkins JJ, Allegretti JR, Gibson TE, McClure E, Delaney M, Bry L, Gerber GK. Gut metabolites predict Clostridioides difficile recurrence. MICROBIOME 2022; 10:87. [PMID: 35681218 PMCID: PMC9178838 DOI: 10.1186/s40168-022-01284-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 05/02/2022] [Indexed: 05/10/2023]
Abstract
BACKGROUND Clostridioides difficile infection (CDI) is the most common hospital acquired infection in the USA, with recurrence rates > 15%. Although primary CDI has been extensively linked to gut microbial dysbiosis, less is known about the factors that promote or mitigate recurrence. Moreover, previous studies have not shown that microbial abundances in the gut measured by 16S rRNA amplicon sequencing alone can accurately predict CDI recurrence. RESULTS We conducted a prospective, longitudinal study of 53 non-immunocompromised participants with primary CDI. Stool sample collection began pre-CDI antibiotic treatment at the time of diagnosis, and continued up to 8 weeks post-antibiotic treatment, with weekly or twice weekly collections. Samples were analyzed using (1) 16S rRNA amplicon sequencing, (2) liquid chromatography/mass-spectrometry metabolomics measuring 1387 annotated metabolites, and (3) short-chain fatty acid profiling. The amplicon sequencing data showed significantly delayed recovery of microbial diversity in recurrent participants, and depletion of key anaerobic taxa at multiple time-points, including Clostridium cluster XIVa and IV taxa. The metabolomic data also showed delayed recovery in recurrent participants, and moreover mapped to pathways suggesting distinct functional abnormalities in the microbiome or host, such as decreased microbial deconjugation activity, lowered levels of endocannabinoids, and elevated markers of host cell damage. Further, using predictive statistical/machine learning models, we demonstrated that the metabolomic data, but not the other data sources, can accurately predict future recurrence at 1 week (AUC 0.77 [0.71, 0.86; 95% interval]) and 2 weeks (AUC 0.77 [0.69, 0.85; 95% interval]) post-treatment for primary CDI. CONCLUSIONS The prospective, longitudinal, and multi-omic nature of our CDI recurrence study allowed us to uncover previously unrecognized dynamics in the microbiome and host presaging recurrence, and, in particular, to elucidate changes in the understudied gut metabolome. Moreover, we demonstrated that a small set of metabolites can accurately predict future recurrence. Our findings have implications for development of diagnostic tests and treatments that could ultimately short-circuit the cycle of CDI recurrence, by providing candidate metabolic biomarkers for diagnostics development, as well as offering insights into the complex microbial and metabolic alterations that are protective or permissive for recurrence. Video Abstract.
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Affiliation(s)
- Jennifer J. Dawkins
- Department of Pathology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
- Harvard-MIT Health Sciences & Technology, Harvard Medical School, MIT, Cambridge, MA USA
| | - Jessica R. Allegretti
- Massachusetts Host-Microbiome Center, Boston, MA USA
- Division of Gastroenterology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
| | - Travis E. Gibson
- Department of Pathology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
| | - Emma McClure
- Division of Gastroenterology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
| | - Mary Delaney
- Massachusetts Host-Microbiome Center, Boston, MA USA
| | - Lynn Bry
- Department of Pathology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
- Massachusetts Host-Microbiome Center, Boston, MA USA
| | - Georg K. Gerber
- Department of Pathology, Brigham & Woman’s Hospital, Harvard Medical School, Boston, MA USA
- Harvard-MIT Health Sciences & Technology, Harvard Medical School, MIT, Cambridge, MA USA
- Massachusetts Host-Microbiome Center, Boston, MA USA
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29
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Hazleton KZ, Martin CG, Orlicky DJ, Arnolds KL, Nusbacher NM, Moreno-Huizar N, Armstrong M, Reisdorph N, Lozupone CA. Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice. NPJ Biofilms Microbiomes 2022; 8:15. [PMID: 35365681 PMCID: PMC8975876 DOI: 10.1038/s41522-022-00276-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/21/2022] [Indexed: 11/15/2022] Open
Abstract
Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea, and emerging evidence has linked dietary components with CDI pathogenesis, suggesting that dietary modulation may be an effective strategy for prevention. Here, we show that mice fed a high-fat/low-fiber “Western-type” diet (WD) had dramatically increased mortality in a murine model of antibiotic-induced CDI compared to a low-fat/low-fiber (LF/LF) diet and standard mouse chow controls. We found that the WD had a pro- C. difficile bile acid composition that was driven in part by higher levels of primary bile acids that are produced to digest fat, and a lower level of secondary bile acids that are produced by the gut microbiome. This lack of secondary bile acids was associated with a greater disturbance to the gut microbiome with antibiotics in both the WD and LF/LF diet compared to mouse chow. Mice fed the WD also had the highest level of toxin TcdA just prior to the onset of mortality, but not of TcdB or increased inflammation. These findings indicate that dietary intervention to decrease fat may complement previously proposed dietary intervention strategies to prevent CDI in high-risk individuals.
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Affiliation(s)
- Keith Z Hazleton
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition. University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.,Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA.,Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Arizona, Tucson, AZ, 85719, USA
| | - Casey G Martin
- Department of Immunology and Microbiology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - David J Orlicky
- Department of Pathology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Kathleen L Arnolds
- Department of Immunology and Microbiology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nichole M Nusbacher
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nancy Moreno-Huizar
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Michael Armstrong
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nichole Reisdorph
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Catherine A Lozupone
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.
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30
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Roles of Microbiota in Cancer: From Tumor Development to Treatment. JOURNAL OF ONCOLOGY 2022; 2022:3845104. [PMID: 35342407 PMCID: PMC8941494 DOI: 10.1155/2022/3845104] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 12/11/2022]
Abstract
Cancer as a second leading cause of death arises from multifactorial pathology. The association of microbiota and their products with various pathologic conditions including cancer is receiving significant attention over the past few years. Mounting evidence showed that human microbiota is an emerging target in tumor onset, progression, prevention, and even diagnosis. Accordingly, modulating this composition might influence the response to tumor therapy and therapeutic resistance as well. Through this review, one could conceive of complex interaction between the microbiome and cancer in either positive or negative manner by which may hold potential for finding novel preventive and therapeutic strategies against cancer.
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31
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Blount K, Jones C, Walsh D, Gonzalez C, Shannon WD. Development and Validation of a Novel Microbiome-Based Biomarker of Post-antibiotic Dysbiosis and Subsequent Restoration. Front Microbiol 2022; 12:781275. [PMID: 35058900 PMCID: PMC8764365 DOI: 10.3389/fmicb.2021.781275] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/18/2021] [Indexed: 11/23/2022] Open
Abstract
Background: The human gut microbiota are important to health and wellness, and disrupted microbiota homeostasis, or “dysbiosis,” can cause or contribute to many gastrointestinal disease states. Dysbiosis can be caused by many factors, most notably antibiotic treatment. To correct dysbiosis and restore healthier microbiota, several investigational microbiota-based live biotherapeutic products (LBPs) are in formal clinical development. To better guide and refine LBP development and to better understand and manage the risks of antibiotic administration, biomarkers that distinguish post-antibiotic dysbiosis from healthy microbiota are needed. Here we report the development of a prototype Microbiome Health Index for post-Antibiotic dysbiosis (MHI-A). Methods: MHI-A was developed and validated using longitudinal gut microbiome data from participants in clinical trials of RBX2660 and RBX7455 – investigational LBPs in development for reducing recurrent Clostridioides difficile infections (rCDI). The MHI-A algorithm relates the relative abundances of microbiome taxonomic classes that changed the most after RBX2660 or RBX7455 treatment, that strongly correlated with clinical response, and that reflect biological mechanisms believed important to rCDI. The diagnostic utility of MHI-A was reinforced using publicly available microbiome data from healthy or antibiotic-treated populations. Results: MHI-A has high accuracy to distinguish post-antibiotic dysbiosis from healthy microbiota. MHI-A values were consistent across multiple healthy populations and were significantly shifted by antibiotic treatments known to alter microbiota compositions, shifted less by microbiota-sparing antibiotics. Clinical response to RBX2660 and RBX7455 correlated with a shift of MHI-A from dysbiotic to healthy values. Conclusion: MHI-A is a promising biomarker of post-antibiotic dysbiosis and subsequent restoration. MHI-A may be useful for rank-ordering the microbiota-disrupting effects of antibiotics and as a pharmacodynamic measure of microbiota restoration.
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Affiliation(s)
- Ken Blount
- Rebiotix Inc., a Ferring Company, Roseville, MN, United States
| | - Courtney Jones
- Rebiotix Inc., a Ferring Company, Roseville, MN, United States
| | - Dana Walsh
- Rebiotix Inc., a Ferring Company, Roseville, MN, United States
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32
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Liao W, Khan I, Huang G, Chen S, Liu L, Leong WK, Li XA, Wu J, Wendy Hsiao WL. Bifidobacterium animalis: the missing link for the cancer-preventive effect of Gynostemma pentaphyllum. Gut Microbes 2022; 13:1847629. [PMID: 33228450 PMCID: PMC8381792 DOI: 10.1080/19490976.2020.1847629] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer (CRC) ranks the third most common cancer type in both men and women. Besides the known genetic and epigenetic changes in the gut epithelial cells, we now know that disturbed gut microbes could also contribute to the onset and progression of CRC. Hence, keeping a balanced gut microbiota (GM) has become a novel pursue in the medical field, particularly in the area of gastrointestinal disorders. Gynostemma pentaphyllum (Gp) is a dietary herbal medicine. In our previous study, Gp saponins (GpS) displayed prebiotic and cancer-preventive properties through the modulation of GM in ApcMin/+ mice. However, the specific group(s) of GM links to the health effects of GpS remains unknown. To track down the missing link, we first investigated and found that inoculation with fecal materials from GpS-treated ApcMin/+ mice effectively reduces polyps in ApcMin/+ mice. From the same source of the fecal sample, we successfully isolated 16 bacterial species. Out of the 16 bacteria, Bifidobacterium animalis stands out as the responder to the GpS-growth stimulus. Biochemical and RNAseq analysis demonstrated that GpS enhanced expressions of a wide range of genes encoding biogenesis and metabolic pathways in B. animalis culture. Moreover, we found that colonization of B. animalis markedly reduces the polyp burden in ApcMin/+ mice. These findings reveal a mutualistic interaction between the prebiotic and a probiotic to achieve anticancer and cancer-preventive activities. Our result, for the first time, unveils the anticancer function of B. animalis and extend the probiotic horizon of B. animalis.
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Affiliation(s)
- Weilin Liao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Imran Khan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Guoxin Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Shengshuang Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Wai Kit Leong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Xiao Ang Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - Jianlin Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
| | - W. L. Wendy Hsiao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR,CONTACT W. L. Wendy Hsiao State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR
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33
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Machine Learning Approaches to Investigate Clostridioides difficile Infection and Outcomes: A Systematic Review. Int J Med Inform 2022; 160:104706. [DOI: 10.1016/j.ijmedinf.2022.104706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/21/2021] [Accepted: 01/22/2022] [Indexed: 11/20/2022]
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34
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Schupack DA, Mars RAT, Voelker DH, Abeykoon JP, Kashyap PC. The promise of the gut microbiome as part of individualized treatment strategies. Nat Rev Gastroenterol Hepatol 2022; 19:7-25. [PMID: 34453142 PMCID: PMC8712374 DOI: 10.1038/s41575-021-00499-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2021] [Indexed: 02/07/2023]
Abstract
Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.
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Affiliation(s)
- Daniel A Schupack
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ruben A T Mars
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Dayne H Voelker
- Division of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jithma P Abeykoon
- Division of Hematology and Oncology, Mayo Clinic, Rochester, MN, USA
| | - Purna C Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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35
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Turjeman S, Koren O. Using the microbiome in clinical practice. Microb Biotechnol 2022; 15:129-134. [PMID: 34767683 PMCID: PMC8719822 DOI: 10.1111/1751-7915.13971] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 10/31/2021] [Indexed: 12/13/2022] Open
Affiliation(s)
| | - Omry Koren
- Azrieli Faculty of MedicineBar‐Ilan UniversitySafedIsrael
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36
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Huang X, Li M, Hou S, Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021; 59:101. [PMID: 34738624 PMCID: PMC8577795 DOI: 10.3892/ijo.2021.5281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
A large body of evidence has revealed that the microbiome serves a role in all aspects of cancer, particularly cancer treatment. To date, studies investigating the relationship between the microbiome and systemic therapy for pancreatic ductal adenocarcinoma (PDAC) are lacking. PDAC is a high‑mortality malignancy (5‑year survival rate; <9% for all stages). Systemic therapy is one of the most important treatment choices for all patients; however, resistance or toxicity can affect its efficacy. Studies have supported the hypothesis that the microbiome is closely associated with the response to systemic therapy in PDAC, including the induction of drug resistance, or toxicity and therapy‑related changes in microbiota composition. The present review comprehensively summarized the role of the microbiome in systemic therapy for PDAC and the associated molecular mechanisms in an attempt to provide a novel direction for the improvement of treatment response and proposed potential directions for in‑depth research.
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Affiliation(s)
| | | | - Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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37
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Ke S, Pollock NR, Wang XW, Chen X, Daugherty K, Lin Q, Xu H, Garey KW, Gonzales-Luna AJ, Kelly CP, Liu YY. Integrating gut microbiome and host immune markers to understand the pathogenesis of Clostridioides difficile infection. Gut Microbes 2021; 13:1-18. [PMID: 34132169 PMCID: PMC8210874 DOI: 10.1080/19490976.2021.1935186] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile (C.difficile) infection is the most common cause of healthcare-associated infection and an important cause of morbidity and mortality among hospitalized patients. A comprehensive understanding of C.difficile infection (CDI) pathogenesis is crucial for disease diagnosis, treatment, and prevention. Here, we characterized gut microbial compositions and a broad panel of innate and adaptive immunological markers in 243 well-characterized human subjects (including 187 subjects with both microbiota and immune marker data), who were divided into four phenotype groups: CDI, Asymptomatic Carriage, Non-CDI Diarrhea, and Control. We found that the interactions between gut microbiota and host immune markers are very sensitive to the status of C.difficile colonization and infection. We demonstrated that incorporating both gut microbiome and host immune marker data into classification models can better distinguish CDI from other groups than can either type of data alone. Our classification models display robust diagnostic performance to differentiate CDI from Asymptomatic carriage (AUC~0.916), Non-CDI Diarrhea (AUC~0.917), or Non-CDI that combines all other three groups (AUC~0.929). Finally, we performed symbolic classification using selected features to derive simple mathematic formulas that explicitly quantify the interactions between the gut microbiome and host immune markers. These findings support the potential roles of gut microbiota and host immune markers in the pathogenesis of CDI. Our study provides new insights for a microbiome-immune marker-derived signature to diagnose CDI and design therapeutic strategies for CDI.
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Affiliation(s)
- Shanlin Ke
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MassachusettsUSA,School of Animal Science and Technology, State Key Laboratory of Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University 330045, China
| | - Nira R. Pollock
- Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA,Department of Laboratory Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Xu-Wen Wang
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MassachusettsUSA
| | - Xinhua Chen
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Kaitlyn Daugherty
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Qianyun Lin
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Hua Xu
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Kevin W. Garey
- Department of Pharmacy Practice and Translation Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Anne J. Gonzales-Luna
- Department of Pharmacy Practice and Translation Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Ciarán P. Kelly
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA,Ciarán P. Kelly Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MassachusettsUSA
| | - Yang-Yu Liu
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MassachusettsUSA,CONTACT Yang-Yu Liu Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MassachusettsUSA
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38
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Gupta VK, Cunningham KY, Hur B, Bakshi U, Huang H, Warrington KJ, Taneja V, Myasoedova E, Davis JM, Sung J. Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis. Genome Med 2021; 13:149. [PMID: 34517888 PMCID: PMC8439035 DOI: 10.1186/s13073-021-00957-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Rapid advances in the past decade have shown that dysbiosis of the gut microbiome is a key hallmark of rheumatoid arthritis (RA). Yet, the relationship between the gut microbiome and clinical improvement in RA disease activity remains unclear. In this study, we explored the gut microbiome of patients with RA to identify features that are associated with, as well as predictive of, minimum clinically important improvement (MCII) in disease activity. METHODS We conducted a retrospective, observational cohort study on patients diagnosed with RA between 1988 and 2014. Whole metagenome shotgun sequencing was performed on 64 stool samples, which were collected from 32 patients with RA at two separate time-points approximately 6-12 months apart. The Clinical Disease Activity Index (CDAI) of each patient was measured at both time-points to assess achievement of MCII; depending on this clinical status, patients were distinguished into two groups: MCII+ (who achieved MCII; n = 12) and MCII- (who did not achieve MCII; n = 20). Multiple linear regression models were used to identify microbial taxa and biochemical pathways associated with MCII while controlling for potentially confounding factors. Lastly, a deep-learning neural network was trained upon gut microbiome, clinical, and demographic data at baseline to classify patients according to MCII status, thereby enabling the prediction of whether a patient will achieve MCII at follow-up. RESULTS We found age to be the largest determinant of the overall compositional variance in the gut microbiome (R2 = 7.7%, P = 0.001, PERMANOVA). Interestingly, the next factor identified to explain the most variance in the gut microbiome was MCII status (R2 = 3.8%, P = 0.005). Additionally, by looking at patients' baseline gut microbiome profiles, we observed significantly different microbiome traits between patients who eventually showed MCII and those who did not. Taxonomic features include alpha- and beta-diversity measures, as well as several microbial taxa, such as Coprococcus, Bilophila sp. 4_1_30, and Eubacterium sp. 3_1_31. Notably, patients who achieved clinical improvement had higher alpha-diversity in their gut microbiomes at both baseline and follow-up visits. Functional profiling identified fifteen biochemical pathways, most of which were involved in the biosynthesis of L-arginine, L-methionine, and tetrahydrofolate, to be differentially abundant between the MCII patient groups. Moreover, MCII+ and MCII- groups showed significantly different fold-changes (from baseline to follow-up) in eight microbial taxa and in seven biochemical pathways. These results could suggest that, depending on the clinical course, gut microbiomes not only start at different ecological states, but also are on separate trajectories. Finally, the neural network proved to be highly effective in predicting which patients will achieve MCII (balanced accuracy = 90.0%, leave-one-out cross-validation), demonstrating potential clinical utility of gut microbiome profiles. CONCLUSIONS Our findings confirm the presence of taxonomic and functional signatures of the gut microbiome associated with MCII in RA patients. Ultimately, modifying the gut microbiome to enhance clinical outcome may hold promise as a future treatment for RA.
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Affiliation(s)
- Vinod K Gupta
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Surgery Research, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Kevin Y Cunningham
- Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, MN, USA
| | - Benjamin Hur
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Surgery Research, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Utpal Bakshi
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Surgery Research, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Harvey Huang
- Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, MN, USA
| | - Kenneth J Warrington
- Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Veena Taneja
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Elena Myasoedova
- Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
| | - John M Davis
- Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jaeyun Sung
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
- Division of Surgery Research, Department of Surgery, Mayo Clinic, Rochester, MN, USA.
- Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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Dong J, Li Y, Xiao H, Cui M, Fan S. Commensal microbiota in the digestive tract: a review of its roles in carcinogenesis and radiotherapy. Cancer Biol Med 2021; 19:j.issn.2095-3941.2020.0476. [PMID: 34369136 PMCID: PMC8763002 DOI: 10.20892/j.issn.2095-3941.2020.0476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/27/2021] [Indexed: 11/11/2022] Open
Abstract
The human microflora is a complex ecosystem composed of diverse microorganisms mainly distributed in the epidermal and mucosal habitats of the entire body, including the mouth, lung, intestines, skin, and vagina. These microbial communities are involved in many essential functions, such as metabolism, immunity, host nutrition, and diseases. Recent studies have focused on the microbiota associated with cancers, particularly the oral and intestinal microbiota. Radiotherapy, the most effective cytotoxic modality available for solid tumors, contributes to the treatment of cancer patients. Mounting evidence supports that the microbiota plays pivotal roles in the efficacy and prognosis of tumor radiotherapy. Here, we review current research on the microbiota and cancer development, and describe knowledge gaps in the study of radiotherapy and the microbiota. Better understanding of the effects of the microbiome in tumorigenesis and radiotherapy will shed light on future novel prevention and treatment strategies based on modulating the microbiome in cancer patients.
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Affiliation(s)
- Jiali Dong
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Yuan Li
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Huiwen Xiao
- Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Ming Cui
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
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Buckley AM, Moura IB, Arai N, Spittal W, Clark E, Nishida Y, Harris HC, Bentley K, Davis G, Wang D, Mitra S, Higashiyama T, Wilcox MH. Trehalose-Induced Remodelling of the Human Microbiota Affects Clostridioides difficile Infection Outcome in an In Vitro Colonic Model: A Pilot Study. Front Cell Infect Microbiol 2021; 11:670935. [PMID: 34277467 PMCID: PMC8284250 DOI: 10.3389/fcimb.2021.670935] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/02/2021] [Indexed: 12/19/2022] Open
Abstract
Within the human intestinal tract, dietary, microbial- and host-derived compounds are used as signals by many pathogenic organisms, including Clostridioides difficile. Trehalose has been reported to enhance virulence of certain C. difficile ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from C. difficile infection (CDI). Here, we make preliminary observations on how trehalose supplementation affects the microbiota in an in vitro model and show that trehalose-induced changes can reduce the outgrowth of C. difficile, preventing simulated CDI. Three clinically reflective human gut models simulated the effects of sugar (trehalose or glucose) or saline ingestion on the microbiota. Models were instilled with sugar or saline and further exposed to C. difficile spores. The recovery of the microbiota following antibiotic treatment and CDI induction was monitored in each model. The human microbiota remodelled to utilise the bioavailable trehalose. Clindamycin induction caused simulated CDI in models supplemented with either glucose or saline; however, trehalose supplementation did not result in CDI, although limited spore germination did occur. The absence of CDI in trehalose model was associated with enhanced abundances of Finegoldia, Faecalibacterium and Oscillospira, and reduced abundances of Klebsiella and Clostridium spp., compared with the other models. Functional analysis of the microbiota in the trehalose model revealed differences in the metabolic pathways, such as amino acid metabolism, which could be attributed to prevention of CDI. Our data show that trehalose supplementation remodelled the microbiota, which prevented simulated CDI, potentially due to enhanced recovery of nutritionally competitive microbiota against C. difficile.
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Affiliation(s)
- Anthony M. Buckley
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Ines B. Moura
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Norie Arai
- R&D Division, Hayashibara Co. Ltd./NAGASE Group, Okayama, Japan
| | - William Spittal
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Emma Clark
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | | | - Hannah C. Harris
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Karen Bentley
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Georgina Davis
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Dapeng Wang
- LeedsOmics, University of Leeds, Leeds, United Kingdom
| | - Suparna Mitra
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | | | - Mark H. Wilcox
- Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
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Tariq R, Saha S, Solanky D, Pardi DS, Khanna S. Predictors and Management of Failed Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection. J Clin Gastroenterol 2021; 55:542-547. [PMID: 32701563 DOI: 10.1097/mcg.0000000000001398] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND GOALS Clostridioides difficile infection (CDI) recurs in 10% to 15% after fecal microbiota transplantation (FMT). We identify predictors, and describe management and outcome of patients with recurrent CDI after FMT in a predominantly outpatient cohort. METHODS A nested case-control study of patients undergoing FMT for recurrent CDI from August 2012 to January 2017 was performed. FMT failure was defined as recurrent diarrhea with positive C. difficile stool test during follow-up (≥2 mo). Controls (patients without FMT failures) were matched to cases 1:1 for sex and timing of FMT±1 month. RESULTS Overall, 522 patients underwent FMT; 70 [13.4%; median age 53.8 years (range, 18 to 89 y), 54.3% females] recurred within a median 5.6 months (range, 0.2 to 34.9 mo). Number of prior CDI episodes, prior CDI treatment, and prior CDI-related hospitalizations were similar in cases and controls. Systemic antibiotics after FMT (54.3% vs. 21.4%, P<0.0001), inflammatory bowel disease (IBD) (34.3% vs. 15.7%, P=0.01), pseudomembranes at FMT (4.3% vs. 0%, P=0.03), and poor bowel preparation (68.5% vs. 31.4%, P=0.01) were associated with FMT failure. On multivariate analysis, IBD [odds ratio (OR) 4.34; 95% confidence interval (CI), 1.24-15.15], systemic antibiotics (OR 7.39; 95% CI, 3.02-18.07), and poor bowel preparation (OR 3.84; 95% CI, 1.59-9.28) predicted FMT failure with an area under the curve of 0.78. Among FMT failures, 37 (52.8%) were managed with antibiotics, 32 (45.7%) with repeat FMT after antibiotics and 1 with colectomy. CONCLUSIONS Use of systemic antibiotics, IBD, and poor bowel preparation predict FMT failure. Patients with FMT failure can be managed with antibiotics and/or repeat FMT.
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Affiliation(s)
- Raseen Tariq
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
- Department of Medicine, Rochester General Hospital, Rochester, NY
| | - Srishti Saha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Dipesh Solanky
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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42
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Yan D, Huang YD, Chen YB, Lv T, Zhu CX, Huang JR, Li LJ. Prediction of Clostridium difficile infection based on gut microbial traits in patients with Clostridium difficile colonization. Hepatobiliary Pancreat Dis Int 2021; 20:298-300. [PMID: 33810987 DOI: 10.1016/j.hbpd.2021.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 03/08/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yan-Di Huang
- Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yun-Bo Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Tao Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chun-Xia Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian-Rong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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43
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Fu Y, Luo Y, Grinspan AM. Epidemiology of community-acquired and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol 2021; 14:17562848211016248. [PMID: 34093740 PMCID: PMC8141977 DOI: 10.1177/17562848211016248] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile infection is a leading cause of healthcare-associated infections with significant morbidity and mortality. For the past decade, the bulk of infection prevention and epidemiologic surveillance efforts have been directed toward mitigating hospital-acquired C. difficile. However, the incidence of community-associated infection is on the rise. Patients with community-associated C. difficile tend to be younger and have lower mortality rate. Rates of recurrent C. difficile infection overall have decreased in the United States, but future research and public health endeavors are needed to standardize and improve disease detection, stratify risk factors in large-scale population studies, and to identify regional and local variations in strain types, reservoirs and transmission routes to help characterize and combat the changing epidemiology of C. difficile.
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Affiliation(s)
- Yichun Fu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuying Luo
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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44
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Lousada MB, Lachnit T, Edelkamp J, Rouillé T, Ajdic D, Uchida Y, Di Nardo A, Bosch TCG, Paus R. Exploring the human hair follicle microbiome. Br J Dermatol 2021; 184:802-815. [PMID: 32762039 DOI: 10.1111/bjd.19461] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2020] [Indexed: 12/31/2022]
Abstract
Human hair follicles (HFs) carry complex microbial communities that differ from the skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively ultraviolet light-protected environment, part of which is immune-privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria (such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci), viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, and examine hair growth-modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome.
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Affiliation(s)
- M B Lousada
- Monasterium Laboratory, Münster, Germany
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - T Lachnit
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - J Edelkamp
- Monasterium Laboratory, Münster, Germany
| | - T Rouillé
- Monasterium Laboratory, Münster, Germany
| | - D Ajdic
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Y Uchida
- Monasterium Laboratory, Münster, Germany
| | - A Di Nardo
- Department of Dermatology, University of California, San Diego, CA, USA
| | - T C G Bosch
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - R Paus
- Monasterium Laboratory, Münster, Germany
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
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Berkell M, Mysara M, Xavier BB, van Werkhoven CH, Monsieurs P, Lammens C, Ducher A, Vehreschild MJGT, Goossens H, de Gunzburg J, Bonten MJM, Malhotra-Kumar S. Microbiota-based markers predictive of development of Clostridioides difficile infection. Nat Commun 2021; 12:2241. [PMID: 33854066 PMCID: PMC8047037 DOI: 10.1038/s41467-021-22302-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare-costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treatment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enterococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI.
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Affiliation(s)
- Matilda Berkell
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium
| | - Mohamed Mysara
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium
- Microbiology Unit, Interdisciplinary Biosciences, Belgian Nuclear Research Centre, SCK-CEN, Mol, Belgium
| | - Basil Britto Xavier
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium
| | - Cornelis H van Werkhoven
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Pieter Monsieurs
- Microbiology Unit, Interdisciplinary Biosciences, Belgian Nuclear Research Centre, SCK-CEN, Mol, Belgium
- Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
| | - Christine Lammens
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium
| | | | - Maria J G T Vehreschild
- Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
- German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany
- Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Herman Goossens
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium
| | | | - Marc J M Bonten
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Surbhi Malhotra-Kumar
- Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium.
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Niu H, Zhou X, Zhang X, Liu T, Wu Y, Lyu L, Liang C, Chen S, Gong P, Zhang J, Han X, Jiang S, Zhang L. Breast milk contains probiotics with anti-infantile diarrhoea effects that may protect infants as they change to solid foods. Environ Microbiol 2021; 23:1750-1764. [PMID: 33684236 DOI: 10.1111/1462-2920.15390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 01/04/2021] [Indexed: 12/20/2022]
Abstract
Infants often experience complementary food-induced diarrhoea (CFID), which occurs when infants switch from breast milk to solid foods. The relative abundances of Prevotella and Rothia were higher in stools of infants with CFID, while the relative abundances of Enterococcus and Escherichia were higher in healthy infants. The abundance of Lactobacillus spp. normally found in breast milk fed to infants with CFID was significantly reduced, and Enterococcus spp. were less abundant when diarrhoea occurred. Furthermore, Lactobacillus and Enterococcus were present as shared bacteria in both mother and infant, and they were considered potential anti-CFID probiotics as their relative abundances in breast milk were negatively correlated to infant CFID. Kyoto encyclopedia of genes and genomes (KEGG) functional analysis showed that the function of amino acid metabolism differed between infants with CFID and healthy infants. Therefore, CFID might be related to the decomposition of proteins in food supplements. The screening revealed seven hydrolytic casein and five hydrolytic casein and rice protein isolates from 320 suspected Lactobacillus and Enterococcus isolates. The animal experiments demonstrated that a mixture of five isolates effectively hydrolysed the casein and rice protein and prevented diarrhoea in young rats. Thus, the occurrence of CFID was found to be closely related to the intestinal and breast milk microbiota, and bacteria that could assist in the digestion of cereal proteins were involved in CFID.
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Affiliation(s)
- Haiyue Niu
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | | | | | - Tongjie Liu
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, China
| | - Yifan Wu
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Linzheng Lyu
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Cong Liang
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Shiwei Chen
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Pimin Gong
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, China
| | - Jiliang Zhang
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Xue Han
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China
| | - Shilong Jiang
- Heilongjiang Feihe Dairy Co. Ltd., Beijing, 100015, China
| | - Lanwei Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, China
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Engevik MA, Danhof HA, Auchtung J, Endres BT, Ruan W, Bassères E, Engevik AC, Wu Q, Nicholson M, Luna RA, Garey KW, Crawford SE, Estes MK, Lux R, Yacyshyn MB, Yacyshyn B, Savidge T, Britton RA, Versalovic J. Fusobacteriumnucleatum Adheres to Clostridioides difficile via the RadD Adhesin to Enhance Biofilm Formation in Intestinal Mucus. Gastroenterology 2021; 160:1301-1314.e8. [PMID: 33227279 PMCID: PMC7956072 DOI: 10.1053/j.gastro.2020.11.034] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Although Clostridioides difficile infection (CDI) is known to involve the disruption of the gut microbiota, little is understood regarding how mucus-associated microbes interact with C difficile. We hypothesized that select mucus-associated bacteria would promote C difficile colonization and biofilm formation. METHODS To create a model of the human intestinal mucus layer and gut microbiota, we used bioreactors inoculated with healthy human feces, treated with clindamycin and infected with C difficile with the addition of human MUC2-coated coverslips. RESULTS C difficile was found to colonize and form biofilms on MUC2-coated coverslips, and 16S rRNA sequencing showed a unique biofilm profile with substantial cocolonization with Fusobacterium species. Consistent with our bioreactor data, publicly available data sets and patient stool samples showed that a subset of patients with C difficile infection harbored high levels of Fusobacterium species. We observed colocalization of C difficile and F nucleatum in an aggregation assay using adult patients and stool of pediatric patients with inflammatory bowel disease and in tissue sections of patients with CDI. C difficile strains were found to coaggregate with F nucleatum subspecies in vitro; an effect that was inhibited by blocking or mutating the adhesin RadD on Fusobacterium and removal of flagella on C difficile. Aggregation was shown to be unique between F nucleatum and C difficile, because other gut commensals did not aggregate with C difficile. Addition of F nucleatum also enhanced C difficile biofilm formation and extracellular polysaccharide production. CONCLUSIONS Collectively, these data show a unique interaction of between pathogenic C difficile and F nucleatum in the intestinal mucus layer.
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Affiliation(s)
- Melinda A. Engevik
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
| | - Heather A. Danhof
- Department of Molecular Virology and Microbiology, Baylor
College of Medicine
| | - Jennifer Auchtung
- Department of Molecular Virology and Microbiology, Baylor
College of Medicine,Department of Food Science and Technology, University of
Nebraska-Lincoln
| | - Bradley T. Endres
- Department of Pharmacy Practice and Translational Research,
University of Houston College of Pharmacy
| | - Wenly Ruan
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
| | - Eugénie Bassères
- Department of Pharmacy Practice and Translational Research,
University of Houston College of Pharmacy
| | - Amy C. Engevik
- Department of Surgical Sciences, Vanderbilt University
Medical Center
| | - Qinglong Wu
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
| | | | - Ruth Ann Luna
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
| | - Kevin W. Garey
- Department of Pharmacy Practice and Translational Research,
University of Houston College of Pharmacy
| | - Sue E. Crawford
- Department of Molecular Virology and Microbiology, Baylor
College of Medicine
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor
College of Medicine,Department of Surgical Sciences, Vanderbilt University
Medical Center
| | - Renate Lux
- Department of Periodontics, University of California Los
Angeles School of Dentistry
| | - Mary Beth Yacyshyn
- Department of Medicine Division of Digestive Diseases
University of Cincinnati College of Medicine
| | - Bruce Yacyshyn
- Department of Medicine Division of Digestive Diseases
University of Cincinnati College of Medicine
| | - Tor Savidge
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
| | - Robert A. Britton
- Department of Molecular Virology and Microbiology, Baylor
College of Medicine
| | - James Versalovic
- Department of Pathology & Immunology, Baylor College of
Medicine,Texas Children’s Microbiome Center, Department of
Pathology, Texas Children's Hospital
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Sehgal K, Khanna S. Gut microbiome and Clostridioides difficile infection: a closer look at the microscopic interface. Therap Adv Gastroenterol 2021; 14:1756284821994736. [PMID: 33747125 PMCID: PMC7905718 DOI: 10.1177/1756284821994736] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/19/2021] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of Clostridioides difficile infection (CDI) was recognized with its link to the use of antimicrobials. Antimicrobials significantly alter gut microbiota structure and composition, which led to the discovery of the association of this gut perturbation with the development of CDI. A number of factors implicated in its pathogenesis, such as advancing age, proton-pump inhibitors, and gastrointestinal diseases, are linked to gut microbiota perturbations. In an effort to better understand CDI, a multitude of studies have tried to ascertain protective and predictive microbial footprints linked with CDI. It has further been realized that CDI in itself can alter the gut microbiome. Its spore-forming capability poses as an impediment in the management of the infection and contributes to its recurrence. Antibiotic therapies used for its management have also been linked to gut microbiota changes, making its treatment a little more challenging. In an effort to exploit and utilize this association, gut microbial restoration therapies, particularly in the form of fecal microbial transplant, are increasingly being put to use and are proving to be beneficial. In this review, we summarize the association of the gut microbiome and microbial perturbation with initial and recurrent CDI.
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Affiliation(s)
- Kanika Sehgal
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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49
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Henson MA. Computational modeling of the gut microbiota reveals putative metabolic mechanisms of recurrent Clostridioides difficile infection. PLoS Comput Biol 2021; 17:e1008782. [PMID: 33617526 PMCID: PMC7932513 DOI: 10.1371/journal.pcbi.1008782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 03/04/2021] [Accepted: 02/05/2021] [Indexed: 12/16/2022] Open
Abstract
Approximately 30% of patients who have Clostridioides difficile infection (CDI) will suffer at least one incident of reinfection. While the underlying causes of CDI recurrence are poorly understood, interactions between C. difficile and commensal gut bacteria are thought to play an important role. In this study, an in silico pipeline was used to process 16S rRNA gene amplicon sequence data of 225 stool samples from 93 CDI patients into sample-specific models of bacterial community metabolism. Clustered metabolite production rates generated from post-diagnosis samples generated a high Enterobacteriaceae abundance cluster containing disproportionately large numbers of recurrent samples and patients. This cluster was predicted to have significantly reduced capabilities for secondary bile acid synthesis but elevated capabilities for aromatic amino acid catabolism. When applied to 16S sequence data of 40 samples from fecal microbiota transplantation (FMT) patients suffering from recurrent CDI and their stool donors, the community modeling method generated a high Enterobacteriaceae abundance cluster with a disproportionate large number of pre-FMT samples. This cluster also was predicted to exhibit reduced secondary bile acid synthesis and elevated aromatic amino acid catabolism. Collectively, these in silico predictions suggest that Enterobacteriaceae may create a gut environment favorable for C. difficile spore germination and/or toxin synthesis.
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Affiliation(s)
- Michael A. Henson
- Department of Chemical Engineering and Institute for Applied Life Sciences, University of Massachusetts, Amherst, Massachusetts, United States of America
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50
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van Rossen TM, van Dijk LJ, Heymans MW, Dekkers OM, Vandenbroucke-Grauls CMJE, van Beurden YH. External validation of two prediction tools for patients at risk for recurrent Clostridioides difficile infection. Therap Adv Gastroenterol 2021; 14:1756284820977385. [PMID: 33456500 PMCID: PMC7797589 DOI: 10.1177/1756284820977385] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/03/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND One in four patients with primary Clostridioides difficile infection (CDI) develops recurrent CDI (rCDI). With every recurrence, the chance of a subsequent CDI episode increases. Early identification of patients at risk for rCDI might help doctors to guide treatment. The aim of this study was to externally validate published clinical prediction tools for rCDI. METHODS The validation cohort consisted of 129 patients, diagnosed with CDI between 2018 and 2020. rCDI risk scores were calculated for each individual patient in the validation cohort using the scoring tools described in the derivation studies. Per score value, we compared the average predicted risk of rCDI with the observed number of rCDI cases. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC). RESULTS Two prediction tools were selected for validation (Cobo 2018 and Larrainzar-Coghen 2016). The two derivation studies used different definitions for rCDI. Using Cobo's definition, rCDI occurred in 34 patients (26%) of the validation cohort: using the definition of Larrainzar-Coghen, we observed 19 recurrences (15%). The performance of both prediction tools was poor when applied to our validation cohort. The estimated AUC was 0.43 [95% confidence interval (CI); 0.32-0.54] for Cobo's tool and 0.42 (95% CI; 0.28-0.56) for Larrainzar-Coghen's tool. CONCLUSION Performance of both prediction tools was disappointing in the external validation cohort. Currently identified clinical risk factors may not be sufficient for accurate prediction of rCDI.
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Affiliation(s)
- Tessel M. van Rossen
- Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Microbiology and Infection Control, Amsterdam Infection and Immunity Institute, Amsterdam UMC location VUmc, PK 2X132, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
| | - Laura J. van Dijk
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands
| | - Martijn W. Heymans
- Amsterdam UMC, Vrije Universiteit Amsterdam, Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
| | - Olaf M. Dekkers
- Leiden University Medical Center, Clinical Epidemiology, Leiden, The Netherlands
| | - Christina M. J. E. Vandenbroucke-Grauls
- Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Microbiology and Infection Control, Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands
| | - Yvette H. van Beurden
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands
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