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Morales C, Ballestero L, Del Río P, Barbero-Herranz R, Olavarrieta L, Gómez-Artíguez L, Galeano J, Avendaño-Ortiz J, Basterra J, Del Campo R. Should the Faecal Microbiota Composition Be Determined to Certify a Faecal Donor? Diagnostics (Basel) 2024; 14:2635. [PMID: 39682542 DOI: 10.3390/diagnostics14232635] [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: 10/20/2024] [Revised: 11/10/2024] [Accepted: 11/15/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES Faecal microbiota transplantation (FMT) is considered a safe and effective therapy for recurrent Clostridioides difficile infection. It is the only current clinical indication for this technique, although numerous clinical research studies and trials propose its potential usefulness for treating other pathologies. Donor selection is a very rigorous process, based on a personal lifestyle interview and the absence of known pathogens in faeces and serum, leading to only a few volunteers finally achieving the corresponding certification. However, despite the high amount of data generated from the ongoing research studies relating microbiota and health, there is not yet a consensus defining what is a "healthy" microbiota. To date, knowledge of the composition of the microbiota is not a requirement to be a faecal donor. The aim of this work was to evaluate whether the analysis of the composition of the microbiota by massive sequencing of 16S rDNA could be useful in the selection of the faecal donors. METHODS Samples from 10 certified donors from Mikrobiomik Healthcare Company were collected and sequenced using 16S rDNA in a MiSeq (Illumina) platform. Alpha (Chao1 and Shannon indices) and beta diversity (Bray-Curtis) were performed using the bioinformatic web server Microbiome Analyst. The differences in microbial composition at the genera and phyla levels among the donors were evaluated. RESULTS The microbial diversity metric by alpha diversity indexes showed that most donors exhibited a similar microbial diversity and richness, whereas beta diversity by 16S rDNA sequencing revealed significant inter-donor differences, with a more stable microbial composition over time in some donors. The phyla Bacillota and Bacteroidota were predominant in all donors, while the density of other phyla, such as Actinomycota and Pseudomonota, varied among individuals. Each donor exhibited a characteristic genera distribution pattern; however, it was possible to define a microbiome core consisting of the genera Agathobacter, Eubacterium, Bacteroides, Clostridia UCG-014 and Akkermansia. Conclusions: The results suggest that donor certification does not need to rely exclusively on their microbiota composition, as it is unique to each donor. While one donor showed greater microbial diversity and richness, clear criteria for microbial normality and health have yet to be established. Therefore, donor certification should focus more on clinical and lifestyle aspects.
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Affiliation(s)
- Celia Morales
- Mikrobiomik Healthcare Company, 48160 Vizcaya, Spain
| | - Luna Ballestero
- Servicio de Microbiología, Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | | | - Raquel Barbero-Herranz
- Servicio de Microbiología, Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Leticia Olavarrieta
- Unidad Central de Apoyo (UCA-GT), Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | | | - Javier Galeano
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
| | - José Avendaño-Ortiz
- Servicio de Microbiología, Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
- Ciber en Enfermedades Infecciosas CIBERINFEC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan Basterra
- Mikrobiomik Healthcare Company, 48160 Vizcaya, Spain
| | - Rosa Del Campo
- Servicio de Microbiología, Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
- Ciber en Enfermedades Infecciosas CIBERINFEC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Facultad de Ciencias de la Salud, Universidad Alfonso X El Sabio, 28691 Villanueva de la Cañada, Spain
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Woelfel S, Silva MS, Stecher B. Intestinal colonization resistance in the context of environmental, host, and microbial determinants. Cell Host Microbe 2024; 32:820-836. [PMID: 38870899 DOI: 10.1016/j.chom.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 06/15/2024]
Abstract
Microbial communities that colonize the human gastrointestinal (GI) tract defend against pathogens through a mechanism known as colonization resistance (CR). Advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced our understanding of the underlying mechanisms and the intricate microbial interactions involved in CR. Rather than being attributed to specific microbial clades, CR is now understood to arise from a dynamic interplay between microbes and the host and is shaped by metabolic, immune, and environmental factors. This evolving perspective underscores the significance of contextual factors, encompassing microbiome composition and host conditions, in determining CR. This review highlights recent research that has shifted its focus toward elucidating how these factors interact to either promote or impede enteric infections. It further discusses future research directions to unravel the complex relationship between host, microbiota, and environmental determinants in safeguarding against GI infections to promote human health.
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Affiliation(s)
- Simon Woelfel
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany
| | - Marta Salvado Silva
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany
| | - Bärbel Stecher
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site LMU Munich, Munich, Germany.
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Vendrik KE, Chernova VO, Kuijper EJ, Terveer EM, van Hilten JJ, Contarino MF. Safety and feasibility of faecal microbiota transplantation for patients with Parkinson's disease: a protocol for a self-controlled interventional donor-FMT pilot study. BMJ Open 2023; 13:e071766. [PMID: 37798034 PMCID: PMC10565159 DOI: 10.1136/bmjopen-2023-071766] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/30/2023] [Indexed: 10/07/2023] Open
Abstract
INTRODUCTION Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson's disease (PD) via the gut-brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy. METHODS AND ANALYSIS We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor-recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months. ETHICS AND DISSEMINATION This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences. TRIAL REGISTRATION NUMBER International Clinical Trial Registry Platform: NL9438.
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Affiliation(s)
- Karuna Ew Vendrik
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Vlada O Chernova
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ed J Kuijper
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Elisabeth M Terveer
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Jacobus J van Hilten
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | - Maria Fiorella Contarino
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Neurology, Haga Teaching hospital, The Hague, The Netherlands
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Jess AT, Eskander GH, Vu MH, Michail S. Short-Chain Fatty Acid Levels after Fecal Microbiota Transplantation in a Pediatric Cohort with Recurrent Clostridioides difficile Infection. Metabolites 2023; 13:1039. [PMID: 37887364 PMCID: PMC10608736 DOI: 10.3390/metabo13101039] [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: 08/17/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Though antibiotics are the mainstay treatment for Clostridioides difficile, a large population of individuals infected will experience recurrence. In turn, fecal microbiota transplantation (FMT) has emerged as a promising treatment for recurrent C. difficile infection (rCDI). Mechanistically, by providing a healthy, diverse flora to the infected individual, FMT "resets" the underlying gut microbiome dysbiosis associated with rCDI. A proposed mechanism through which this occurs is via microbiome metabolites such as short-chain fatty acids (SCFAs); however, this has not been previously studied in pediatric patients. Using mass spectroscopy, we quantified pre- and post-transplant levels of acetate, isovalerate, butyrate, formate, and propionate in pediatric patients diagnosed with rCDI (n = 9). We compared pre- and post-transplant levels within the rCDI cohort at 1, 3, 6, and 12 months post-transplant and correlated these levels with healthy controls (n = 19). We witnessed a significant difference in the combined SCFA levels and the individual levels of acetate, butyrate, isovalerate, and propionate in the pre-treatment rCDI cohort compared to the healthy controls. In addition, there was a significant increase in combined SCFA levels at 12 months post-transplant within the rCDI group compared to that of their pre-transplant levels, and, more specifically, acetate, propionate, and isovalerate increased from pre-transplant to 12 months post-transplant. The longitudinal aspect of this study allowed us to identify mechanisms that contribute to the durability of responses to FMT, as well as characterize the unique patterns of short-chain fatty acid level recovery in rCDI pediatric patients.
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Affiliation(s)
- Alison T. Jess
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA;
| | - George Hany Eskander
- School of Medicine & Health Sciences, George Washington University, Washington, DC 20052, USA;
| | - My H. Vu
- Biostatistics Core, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA;
| | - Sonia Michail
- Division of Gastroenterology, Children’s Hospital of Los Angeles, Los Angeles, CA 90027, USA
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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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Shtossel O, Turjeman S, Riumin A, Goldberg MR, Elizur A, Bekor Y, Mor H, Koren O, Louzoun Y. Recipient-independent, high-accuracy FMT-response prediction and optimization in mice and humans. MICROBIOME 2023; 11:181. [PMID: 37580821 PMCID: PMC10424414 DOI: 10.1186/s40168-023-01623-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 07/14/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Some microbiota compositions are associated with negative outcomes, including among others, obesity, allergies, and the failure to respond to treatment. Microbiota manipulation or supplementation can restore a community associated with a healthy condition. Such interventions are typically probiotics or fecal microbiota transplantation (FMT). FMT donor selection is currently based on donor phenotype, rather than the anticipated microbiota composition in the recipient and associated health benefits. However, the donor and post-transplant recipient conditions differ drastically. We here propose an algorithm to identify ideal donors and predict the expected outcome of FMT based on donor microbiome alone. We also demonstrate how to optimize FMT for different required outcomes. RESULTS We show, using multiple microbiome properties, that donor and post-transplant recipient microbiota differ widely and propose a tool to predict the recipient post-transplant condition (engraftment success and clinical outcome), using only the donors' microbiome and, when available, demographics for transplantations from humans to either mice or other humans (with or without antibiotic pre-treatment). We validated the predictor using a de novo FMT experiment highlighting the possibility of choosing transplants that optimize an array of required goals. We then extend the method to characterize a best-planned transplant (bacterial cocktail) by combining the predictor and a generative genetic algorithm (GA). We further show that a limited number of taxa is enough for an FMT to produce a desired microbiome or phenotype. CONCLUSIONS Off-the-shelf FMT requires recipient-independent optimized FMT selection. Such a transplant can be from an optimal donor or from a cultured set of microbes. We have here shown the feasibility of both types of manipulations in mouse and human recipients. Video Abstract.
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Affiliation(s)
- Oshrit Shtossel
- Department of Mathematics, Bar-Ilan University, Ramat Gan, 52900, Israel.
| | - Sondra Turjeman
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Alona Riumin
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Michael R Goldberg
- Yitzhak Shamir Medical Center (Assaf Harofeh), Zerifin, Israel
- Department of Pediatrics, Sackler Faculty of Medicine, Tel Aviv, Israel
| | - Arnon Elizur
- Yitzhak Shamir Medical Center (Assaf Harofeh), Zerifin, Israel
- Department of Pediatrics, Sackler Faculty of Medicine, Tel Aviv, Israel
| | - Yarin Bekor
- Department of Mathematics, Bar-Ilan University, Ramat Gan, 52900, Israel
| | - Hadar Mor
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Omry Koren
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Yoram Louzoun
- Department of Mathematics, Bar-Ilan University, Ramat Gan, 52900, Israel.
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Wu Q, Boonma P, Badu S, Yalcinkaya N, So SY, Garey KW, Williams K, Arnold LE, Shulman RJ, Kellermayer R, Savidge TC. Donor-recipient specificity and age-dependency in fecal microbiota therapy and probiotic resolution of gastrointestinal symptoms. NPJ Biofilms Microbiomes 2023; 9:54. [PMID: 37537181 PMCID: PMC10400536 DOI: 10.1038/s41522-023-00421-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/20/2023] [Indexed: 08/05/2023] Open
Abstract
Fecal microbiota transplantation (FMT) has proven to be an effective treatment for recurrent Clostridioides difficile infection (rCDI) in both adult and pediatric patients. However, as microbiome development is a critical factor in children, it remains unclear whether adult fecal donors can provide age-appropriate functional restoration in pediatric patients. To address this issue, we conducted an integrated systems approach and found that concordant donor strain engraftment, along with metabolite restoration, are associated with FMT outcomes in both adult and pediatric rCDI patients. Although functional restoration after FMT is not strain-specific, specialized metabolic functions are retained in pediatric patients when adult fecal donors are used. Furthermore, we demonstrated broad utility of high-resolution variant-calling by linking probiotic-strain engraftment with improved gastrointestinal symptoms in adults with irritable bowel syndrome and in children with autism spectrum disorder. Our findings emphasize the importance of strain-level identification when assessing the efficacy of probiotics and microbiota-based therapeutics.
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Affiliation(s)
- Qinglong Wu
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Prapaporn Boonma
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA
- Faculty of Medicine, King Mongkut's Institute of Technology Ladkrabang, Bangkok, Thailand
| | - Shyam Badu
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Nazli Yalcinkaya
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Sik Yu So
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Kevin W Garey
- Department of Pharmacy Practice and Translational Research, College of Pharmacy, University of Houston, Houston, TX, USA
| | - Kent Williams
- Department of Pediatrics, Ohio State University & Nationwide Children's Hospital, Columbus, OH, USA
| | - L Eugene Arnold
- Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, USA
| | - Robert J Shulman
- Department of Pediatrics, Baylor College of Medicine & Texas Children's Hospital, Houston, TX, USA
| | - Richard Kellermayer
- Department of Pediatrics, Baylor College of Medicine & Texas Children's Hospital, Houston, TX, USA
| | - Tor C Savidge
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
- Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TX, USA.
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Gonzales-Luna AJ, Carlson TJ, Garey KW. Gut microbiota changes associated with Clostridioides difficile infection and its various treatment strategies. Gut Microbes 2023; 15:2223345. [PMID: 37318134 DOI: 10.1080/19490976.2023.2223345] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/01/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023] Open
Abstract
Human gut microbiota are critical to both the development of and recovery from Clostridioides difficile infection (CDI). Antibiotics are the mainstay of CDI treatment, yet inherently cause further imbalances in the gut microbiota, termed dysbiosis, complicating recovery. A variety of microbiota-based therapeutic approaches are in use or in development to limit disease- and treatment-associated dysbiosis and improve rates of sustained cure. These include the recently FDA-approved fecal microbiota, live-jslm (formerly RBX2660) and fecal microbiota spores, live-brpk (formerly SER-109), which represent a new class of live biotherapeutic products (LBPs), traditional fecal microbiota transplantation (FMT), and ultra-narrow-spectrum antibiotics. Here, we aim to review the microbiome changes associated with CDI as well as a variety of microbiota-based treatment approaches.
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Affiliation(s)
- Anne J Gonzales-Luna
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Travis J Carlson
- Department of Clinical Sciences, High Point University Fred Wilson School of Pharmacy, High Point, NC, USA
| | - Kevin W Garey
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
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Ouyang J, Yan J, Zhou X, Isnard S, Harypursat V, Cui H, Routy JP, Chen Y. Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV. Front Immunol 2023; 14:1173956. [PMID: 37153621 PMCID: PMC10160480 DOI: 10.3389/fimmu.2023.1173956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.
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Affiliation(s)
- Jing Ouyang
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiangyu Yan
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, BC, Canada
| | - Vijay Harypursat
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
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10
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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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11
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Podlesny D, Durdevic M, Paramsothy S, Kaakoush NO, Högenauer C, Gorkiewicz G, Walter J, Fricke WF. Identification of clinical and ecological determinants of strain engraftment after fecal microbiota transplantation using metagenomics. Cell Rep Med 2022; 3:100711. [PMID: 35931074 PMCID: PMC9418803 DOI: 10.1016/j.xcrm.2022.100711] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/27/2022] [Accepted: 07/14/2022] [Indexed: 11/01/2022]
Abstract
Fecal microbiota transplantation (FMT) is a promising therapeutic approach for microbiota-associated pathologies, but our understanding of the post-FMT microbiome assembly process and its ecological and clinical determinants is incomplete. Here we perform a comprehensive fecal metagenome analysis of 14 FMT trials, involving five pathologies and >250 individuals, and determine the origins of strains in patients after FMT. Independently of the underlying clinical condition, conspecific coexistence of donor and recipient strains after FMT is uncommon and donor strain engraftment is strongly positively correlated with pre-FMT recipient microbiota dysbiosis. Donor strain engraftment was enhanced through antibiotic pretreatment and bowel lavage and dependent on donor and recipient ɑ-diversity; strains from relatively abundant species were more likely and from predicted oral, oxygen-tolerant, and gram-positive species less likely to engraft. We introduce a general mechanistic framework for post-FMT microbiome assembly in alignment with ecological theory, which can guide development of optimized, more targeted, and personalized FMT therapies.
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Affiliation(s)
- Daniel Podlesny
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany.
| | - Marija Durdevic
- Institute of Pathology, Medical University of Graz, Graz, Austria; Theodor Escherich Laboratory for Medical Microbiome Research, Medical University of Graz, Graz, Austria
| | - Sudarshan Paramsothy
- Department of Gastroenterology and Hepatology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Concord Clinical School, University of Sydney, Sydney, NSW, Australia
| | | | - Christoph Högenauer
- Institute of Pathology, Medical University of Graz, Graz, Austria; Theodor Escherich Laboratory for Medical Microbiome Research, Medical University of Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Gregor Gorkiewicz
- Institute of Pathology, Medical University of Graz, Graz, Austria; Theodor Escherich Laboratory for Medical Microbiome Research, Medical University of Graz, Graz, Austria; BioTechMed, Interuniversity Cooperation, Graz, Austria
| | - Jens Walter
- APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland
| | - W Florian Fricke
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
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12
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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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13
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Button JE, Autran CA, Reens AL, Cosetta CM, Smriga S, Ericson M, Pierce JV, Cook DN, Lee ML, Sun AK, Alousi AM, Koh AY, Rechtman DJ, Jenq RR, McKenzie GJ. Dosing a synbiotic of human milk oligosaccharides and B. infantis leads to reversible engraftment in healthy adult microbiomes without antibiotics. Cell Host Microbe 2022; 30:712-725.e7. [PMID: 35504279 DOI: 10.1016/j.chom.2022.04.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/11/2022] [Accepted: 04/07/2022] [Indexed: 11/30/2022]
Abstract
Predictable and sustainable engraftment of live biotherapeutic products into the human gut microbiome is being explored as a promising way to modulate the human gut microbiome. We utilize a synbiotic approach pairing the infant gut microbe Bifidobacterium longum subspecies infantis (B. infantis) and human milk oligosaccharides (HMO). B. infantis, which is typically absent in adults, engrafts into healthy adult microbiomes in an HMO-dependent manner at a relative abundance of up to 25% of the bacterial population without antibiotic pretreatment or adverse effects. Corresponding changes in metabolites are detected. Germ-free mice transplanted with dysbiotic human microbiomes also successfully engraft with B. infantis in an HMO-dependent manner, and the synbiotic augments butyrate levels both in this in vivo model and in in vitro cocultures of the synbiotic with specific Firmicutes species. Finally, the synbiotic inhibits the growth of enteropathogens in vitro. Our findings point to a potential safe mechanism for ameliorating dysbioses characteristic of numerous human diseases.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Adam K Sun
- Prolacta Bioscience, Duarte, CA 91010, USA
| | - Amin M Alousi
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Andrew Y Koh
- Department of Pediatrics, Division of Hematology/Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | | | - Robert R Jenq
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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14
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Podlesny D, Arze C, Dörner E, Verma S, Dutta S, Walter J, Fricke WF. Metagenomic strain detection with SameStr: identification of a persisting core gut microbiota transferable by fecal transplantation. MICROBIOME 2022; 10:53. [PMID: 35337386 PMCID: PMC8951724 DOI: 10.1186/s40168-022-01251-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/24/2022] [Indexed: 05/13/2023]
Abstract
BACKGROUND The understanding of how microbiomes assemble, function, and evolve requires metagenomic tools that can resolve microbiota compositions at the strain level. However, the identification and tracking of microbial strains in fecal metagenomes is challenging and available tools variably classify subspecies lineages, which affects their applicability to infer microbial persistence and transfer. RESULTS We introduce SameStr, a bioinformatic tool that identifies shared strains in metagenomes by determining single-nucleotide variants (SNV) in species-specific marker genes, which are compared based on a maximum variant profile similarity. We validated SameStr on mock strain populations, available human fecal metagenomes from healthy individuals and newly generated data from recurrent Clostridioides difficile infection (rCDI) patients treated with fecal microbiota transplantation (FMT). SameStr demonstrated enhanced sensitivity to detect shared dominant and subdominant strains in related samples (where strain persistence or transfer would be expected) when compared to other tools, while being robust against false-positive shared strain calls between unrelated samples (where neither strain persistence nor transfer would be expected). We applied SameStr to identify strains that are stably maintained in fecal microbiomes of healthy adults over time (strain persistence) and that successfully engraft in rCDI patients after FMT (strain engraftment). Taxonomy-dependent strain persistence and engraftment frequencies were positively correlated, indicating that a specific core microbiota of intestinal species is adapted to be competitive both in healthy microbiomes and during post-FMT microbiome assembly. We explored other use cases for strain-level microbiota profiling, as a metagenomics quality control measure and to identify individuals based on the persisting core gut microbiota. CONCLUSION SameStr provides for a robust identification of shared strains in metagenomic sequence data with sufficient specificity and sensitivity to examine strain persistence, transfer, and engraftment in human fecal microbiomes. Our findings identify a persisting healthy adult core gut microbiota, which should be further studied to shed light on microbiota contributions to chronic diseases. Video abstract.
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Affiliation(s)
- Daniel Podlesny
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany.
| | - Cesar Arze
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany
- Current address: Ring Therapeutics, Cambridge, MA, USA
| | - Elisabeth Dörner
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany
| | - Sandeep Verma
- Division of Gastroenterology, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Sudhir Dutta
- Division of Gastroenterology, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Jens Walter
- APC Microbiome Ireland, School of Microbiology, and Department of Medicine, University College Cork, Cork, Ireland
| | - W Florian Fricke
- Department of Microbiome Research and Applied Bioinformatics, University of Hohenheim, Stuttgart, Germany.
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
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15
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Fecal 1H-NMR Metabolomics: A Comparison of Sample Preparation Methods for NMR and Novel in Silico Baseline Correction. Metabolites 2022; 12:metabo12020148. [PMID: 35208222 PMCID: PMC8875708 DOI: 10.3390/metabo12020148] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 11/17/2022] Open
Abstract
Analysis of enteric microbiota function indirectly through the fecal metabolome has the potential to be an informative diagnostic tool. However, metabolomic analysis of feces is hampered by high concentrations of macromolecules such as proteins, fats, and fiber in samples. Three methods—ultrafiltration (UF), Bligh–Dyer (BD), and no extraction (samples added directly to buffer, vortexed, and centrifuged)—were tested on multiple rat (n = 10) and chicken (n = 8) fecal samples to ascertain whether the methods worked equally well across species and individuals. An in silico baseline correction method was evaluated to determine if an algorithm could produce spectra similar to those obtained via UF. For both rat and chicken feces, UF removed all macromolecules and produced no baseline distortion among samples. By contrast, the BD and no extraction methods did not remove all the macromolecules and produced baseline distortions. The application of in silico baseline correction produced spectra comparable to UF spectra. In the case of no extraction, more intense peaks were produced. This suggests that baseline correction may be a cost-effective method for metabolomic analyses of fecal samples and an alternative to UF. UF was the most versatile and efficient extraction method; however, BD and no extraction followed by baseline correction can produce comparable results.
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16
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Spindelboeck W, Halwachs B, Bayer N, Huber-Krassnitzer B, Schulz E, Uhl B, Gaksch L, Hatzl S, Bachmayr V, Kleissl L, Kump P, Deutsch A, Stary G, Greinix H, Gorkiewicz G, Högenauer C, Neumeister P. Antibiotic use and ileocolonic immune cells in patients receiving fecal microbiota transplantation for refractory intestinal GvHD: a prospective cohort study. Ther Adv Hematol 2022; 12:20406207211058333. [PMID: 34987741 PMCID: PMC8721365 DOI: 10.1177/20406207211058333] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/13/2021] [Indexed: 02/02/2023] Open
Abstract
Introduction Treatment-refractory, acute graft-versus-host disease (GvHD) of the lower gastrointestinal tract (GI) after allogeneic hematopoietic stem cell transplantation is life threatening and lacks effective treatment options. While fecal microbiota transplantation (FMT) was shown to ameliorate GI-GvHD, its mechanisms of action and the factors influencing the treatment response in humans remain unclear.The objective of this study is to assess response to FMT treatment, factors influencing response, and to study the mucosal immune cell composition in treatment-refractory GI-GvHD. Methods Consecutive patients with treatment-refractory GI-GvHD were treated with up to six endoscopically applied FMTs. Results We observed the response to FMT in four out of nine patients with severe, treatment refractory GI-GvHD, associated with a significant survival benefit (p = 0.017). The concomitant use of broad-spectrum antibiotics was the main factor associated with FMT failure (p = 0.048). In addition, antibiotic administration hindered the establishment of donor microbiota after FMT. Unlike in non-responders, the microbiota characteristics (e.g. α- and β-diversity, abundance of anaerobe butyrate-producers) in responders were more significantly similar to those of FMT donors. During active refractory GI-GvHD, an increased infiltrate of T cells, mainly Th17 and CD8+ T cells, was observed in the ileocolonic mucosa of patients, while the number of immunomodulatory cells such as regulatory T-cells and type 3 innate lymphoid cells decreased. After FMT, a change in immune cell patterns was induced, depending on the clinical response. Conclusion This study increases the knowledge about the crucial effects of antibiotics in patients given FMT for treatment refractory GI-GvHD and defines the characteristic alterations of ileocolonic mucosal immune cells in this setting.
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Affiliation(s)
- Walter Spindelboeck
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Bettina Halwachs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Nadine Bayer
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Bianca Huber-Krassnitzer
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Eduard Schulz
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Barbara Uhl
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Lukas Gaksch
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Stefan Hatzl
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Victoria Bachmayr
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Lisa Kleissl
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Patrizia Kump
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander Deutsch
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Hildegard Greinix
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Christoph Högenauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Peter Neumeister
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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17
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He R, Li P, Wang J, Cui B, Zhang F, Zhao F. The interplay of gut microbiota between donors and recipients determines the efficacy of fecal microbiota transplantation. Gut Microbes 2022; 14:2100197. [PMID: 35854629 PMCID: PMC9302524 DOI: 10.1080/19490976.2022.2100197] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 06/02/2022] [Accepted: 07/01/2022] [Indexed: 02/04/2023] Open
Abstract
Fecal microbiota transplantation (FMT) is a promising treatment for microbiota dysbiosis associated diseases, such as Clostridioides difficile infection (CDI) and inflammatory bowel disease (IBD). The engraftment of donor bacteria is essential for the effectiveness of FMT, which to some extent depends on the matching of donors and recipients. However, how different types of donor-derived bacteria affect FMT efficacy has not been fully dissected. We recruited two longitudinal IBD cohorts of 103 FMT recipients and further analyzed 1,280 microbiota datasets from 14 public CDI and IBD studies to uncover the effect of donor-derived microbiota in recipients. We found that two enterotypes, RCPT/E and RCPT/B (dominated by Enterobacteriaceae and Bacteroides, respectively), consistently exist in both CDI and IBD patients. Based on a time-course-based multi-cohort analysis of FMT fecal samples, we observed the interplay between recipient and donor-derived microbiota during FMT, in which the FMT outcome was significantly associated with the enterotype and microbiota distance between donor and recipient after FMT. We proposed a new measurement, the ratio of colonizers to residents after FMT (C2R), to quantify the engraftment of donor-derived bacteria in the recipients, and then constructed an enterotype-based statistical model for donor-recipient matching, which was validated by both cross-validation and an additional IBD FMT cohort (n = 42). We believe that with the accumulation of FMT multi-omics datasets, machine learning-based methods will be helpful for rational donor selection for improving efficacy and precision FMT practices.
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Affiliation(s)
- Ruiqiao He
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Pan Li
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jinfeng Wang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - Bota Cui
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Faming Zhang
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fangqing Zhao
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
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18
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Bilsen MP, Lambregts MM, van Prehn J, Kuijper EJ. Faecal microbiota replacement to eradicate antimicrobial resistant bacteria in the intestinal tract - a systematic review. Curr Opin Gastroenterol 2022; 38:15-25. [PMID: 34636363 PMCID: PMC8654246 DOI: 10.1097/mog.0000000000000792] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Antimicrobial resistance is a rising threat to global health and is associated with increased mortality. Intestinal colonisation with multidrug-resistant organisms (MDRO) can precede invasive infection and facilitates spread within communities and hospitals. Novel decolonisation strategies, such as faecal microbiota transplantation (FMT), are being explored. The purpose of this review is to provide an update on how the field of FMT for MDRO decolonisation has developed during the past year and to assess the efficacy of FMT for intestinal MDRO decolonisation. RECENT FINDINGS Since 2020, seven highly heterogenous, small, nonrandomised cohort studies and five case reports have been published. In line with previous literature, decolonisation rates ranged from 20 to 90% between studies and were slightly higher for carbapenem-resistant Enterobacteriaceae than vancomycin-resistant Enterococcus. Despite moderate decolonisation rates in two studies, a reduction in MDRO bloodstream and urinary tract infections was observed. SUMMARY AND IMPLICATIONS Although a number of smaller cohort studies show some effect of FMT for MDRO decolonisation, questions remain regarding the true efficacy of FMT (taking spontaneous decolonisation into account), the optimal route of administration, the role of antibiotics pre and post-FMT and the efficacy in different patient populations. The observed decrease in MDRO infections post-FMT warrants further research.
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Affiliation(s)
| | | | - Joffrey van Prehn
- Department of Medical Microbiology, Leiden University Medical Centre, Leiden
| | - Ed J. Kuijper
- Department of Medical Microbiology, Leiden University Medical Centre, Leiden
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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19
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Yan J, Ouyang J, Isnard S, Zhou X, Harypursat V, Routy JP, Chen Y. Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review. Front Immunol 2021; 12:741658. [PMID: 34975838 PMCID: PMC8718428 DOI: 10.3389/fimmu.2021.741658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.
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Affiliation(s)
- Jiangyu Yan
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network (CTN), Canadian Institutes of Health Research (CIHR), Vancouver, BC, Canada
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Vijay Harypursat
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Yaokai Chen
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
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20
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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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21
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The Role of Fecal Microbiota Transplantation in the Treatment of Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10184055. [PMID: 34575166 PMCID: PMC8465860 DOI: 10.3390/jcm10184055] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
The exact pathogenesis of inflammatory bowel disease (IBD) is still not completely understood. It is hypothesized that a genetic predisposition leads to an exaggerated immune response to an environmental trigger, leading to uncontrolled inflammation. As there is no known causative treatment, current management strategies for inflammatory bowel disease focus on correcting the excessive immune response to environmental (including microbial) triggers. In recent years, there has been growing interest in new avenues of treatment, including targeting the microbial environment itself. Fecal microbiota transplantation (FMT) is a novel treatment modality showing promising results in early studies. The article discusses the rationale for the use of FMT in inflammatory bowel disease and the yet-unresolved questions surrounding its optimal use in practice.
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Verma S, Dutta SK, Firnberg E, Phillips L, Vinayek R, Nair PP. Identification and engraftment of new bacterial strains by shotgun metagenomic sequence analysis in patients with recurrent Clostridioides difficile infection before and after fecal microbiota transplantation and in healthy human subjects. PLoS One 2021; 16:e0251590. [PMID: 34252073 PMCID: PMC8274925 DOI: 10.1371/journal.pone.0251590] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/29/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Recurrent Clostridioides diffícile infection (RCDI) is associated with major bacterial dysbiosis and colitis. Fecal microbiota transplantation (FMT) is a highly effective therapeutic modality for RCDI. While several studies have identified bacterial species associated with resolution of symptoms in patients, characterization of the fecal microbiome at the bacterial strain level in RCDI patients before and after FMT and healthy donors, has been lacking. The aim of this study was to examine the ability of bacterial strains from healthy donors to engraft in the gastrointestinal tract of patients with RCDI following FMT. METHODS Fecal samples were collected from 22 patients with RCDI before and after FMT and their corresponding healthy donors. Total DNA was extracted from each sample and analyzed by shotgun metagenomic sequencing. The Cosmos-ID analysis platform was used for taxonomic assignment of sequences and calculation of the relative abundance (RA) of bacterial species and strains. From these data, the total number of bacterial strains (BSI), Shannon diversity index, dysbiosis index (DI), and bacterial engraftment factor, were calculated for each strain. FINDINGS A marked reduction (p<0·0001) in the RA of total and specific bacterial strains, especially from phylum Firmicutes, was observed in RCDI patients prior to FMT. This change was associated with an increase in the DI (p<0·0001) and in pathobiont bacterial strains from phylum Proteobacteria, such as Escherichia coli O157:H7 and Klebsiella pneumoniae UCI 34. BSI was significantly lower in this group of patients as compared to healthy donors and correlated with the Shannon Index. (p<0·0001). Identification and engraftment of bacterial strains from healthy donors revealed a greater diversity and higher relative abundance of short-chain fatty acid (SCFA)-producing bacterial strains, including Lachnospiraceae bacterium 5_1_63FAA_u_t, Dorea formicigenerans ATCC 27755, Anaerostipes hadrusand others, in RCDI patients after FMT. INTERPRETATION These observations identify a group of SCFA-producing bacterial strains from healthy donors that engraft well in patients with RCDI following FMT and are associated with complete resolution of clinical symptoms and bacterial dysbiosis.
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Affiliation(s)
- Sandeep Verma
- Division of Gastroenterology, Sinai Hospital, Baltimore MD, United States of America
| | - Sudhir K. Dutta
- Division of Gastroenterology, Sinai Hospital, Baltimore MD, United States of America
- University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Elad Firnberg
- Division of Gastroenterology, Sinai Hospital, Baltimore MD, United States of America
| | - Laila Phillips
- Division of Gastroenterology, Sinai Hospital, Baltimore MD, United States of America
| | - Rakesh Vinayek
- Division of Gastroenterology, Sinai Hospital, Baltimore MD, United States of America
| | - Padmanabhan P. Nair
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Noninvasive Technologies, Elkridge, MD, United States of America
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23
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Chiu CW, Tsai PJ, Lee CC, Ko WC, Hung YP. Application of Microbiome Management in Therapy for Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents. Pathogens 2021; 10:pathogens10060649. [PMID: 34073695 PMCID: PMC8225043 DOI: 10.3390/pathogens10060649] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/02/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Oral vancomycin and metronidazole, though they are the therapeutic choice for Clostridioides difficile infections (CDIs), also markedly disturb microbiota, leading to a prolonged loss of colonization resistance to C. difficile after therapy; as a result, their use is associated with a high treatment failure rate and high recurrent rate. An alternative for CDIs therapy contains the delivery of beneficial (probiotic) microorganisms into the intestinal tract to restore the microbial balance. Recently, mixture regimens containing Lactobacillus species, Saccharomyces boulardii, or Clostridium butyricum have been extensively studied for the prophylaxis of CDIs. Fecal microbiota transplantation (FMT), the transfer of (processed) fecal material from healthy donors to patients for treating CDIs, combined with vancomycin was recommended as the primary therapy for multiple recurrent CDIs (rCDIs). Either probiotics or FMT have been utilized extensively in preventing or treating CDIs, aiming at less disturbance in the microbiota to prevent rCDIs after therapy cessation. Otherwise, many newly developed therapeutic agents have been developed and aim to preserve microbiota during CDI treatment to prevent disease recurrence and might be useful in clinical patients with rCDIs in the future.
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Affiliation(s)
- Chun-Wei Chiu
- Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan;
| | - Pei-Jane Tsai
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Medical College, Tainan 704, Taiwan;
| | - Ching-Chi Lee
- Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wen-Chien Ko
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
- Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Correspondence: (W.-C.K.); (Y.-P.H.)
| | - Yuan-Pin Hung
- Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan;
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
- Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Correspondence: (W.-C.K.); (Y.-P.H.)
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24
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Fujimoto K, Kimura Y, Allegretti JR, Yamamoto M, Zhang YZ, Katayama K, Tremmel G, Kawaguchi Y, Shimohigoshi M, Hayashi T, Uematsu M, Yamaguchi K, Furukawa Y, Akiyama Y, Yamaguchi R, Crowe SE, Ernst PB, Miyano S, Kiyono H, Imoto S, Uematsu S. Functional Restoration of Bacteriomes and Viromes by Fecal Microbiota Transplantation. Gastroenterology 2021; 160:2089-2102.e12. [PMID: 33577875 PMCID: PMC8684800 DOI: 10.1053/j.gastro.2021.02.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/27/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become a serious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of successful FMT. METHODS The human intestinal bacteriomes and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based host bacteria-phage associations in samples from recipients before and after FMT and in donor samples were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated. RESULTS Metagenomic sequencing of both the viromes and bacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes in recipients after FMT compared with those before FMT. In particular, many Proteobacteria, the fecal abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased in recipients. Most temperate phages also behaved in parallel with the host bacteria that were altered by FMT. Furthermore, the identification of bacterial and viral gene functions before and after FMT revealed that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented. CONCLUSIONS The coordinated action of phages and their host bacteria restored the recipients' intestinal flora. These findings show that the restoration of intestinal microflora functions reflects the success of FMT.
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Affiliation(s)
- Kosuke Fujimoto
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan,Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan,Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yasumasa Kimura
- Division of Systems Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Jessica R. Allegretti
- Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Mako Yamamoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yao-zhong Zhang
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Kotoe Katayama
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Georg Tremmel
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yunosuke Kawaguchi
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan
| | - Masaki Shimohigoshi
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan
| | - Tetsuya Hayashi
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan
| | - Miho Uematsu
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yutaka Akiyama
- Department of Computer Science, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan
| | - Rui Yamaguchi
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Sheila E. Crowe
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Peter B. Ernst
- Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California San Diego, San Diego, La Jolla, California,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, La Jolla, California,Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, La Jolla, California
| | - Satoru Miyano
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Hiroshi Kiyono
- Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California San Diego, San Diego, La Jolla, California,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, La Jolla, California,Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
| | - Satoshi Uematsu
- Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan; Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
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25
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Gal A, Barko PC, Biggs PJ, Gedye KR, Midwinter AC, Williams DA, Burchell RK, Pazzi P. One dog's waste is another dog's wealth: A pilot study of fecal microbiota transplantation in dogs with acute hemorrhagic diarrhea syndrome. PLoS One 2021; 16:e0250344. [PMID: 33872339 PMCID: PMC8055013 DOI: 10.1371/journal.pone.0250344] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 04/05/2021] [Indexed: 01/04/2023] Open
Abstract
Canine acute hemorrhagic diarrhea syndrome (AHDS) has been associated in some studies with Clostridioides perfringens overgrowth and toxin-mediated necrosis of the intestinal mucosa. We aimed to determine the effect of a single fecal microbiota transplantation (FMT) on clinical scores and fecal microbiomes of 1 and 7 dogs with AHDS from New Zealand and South Africa. We hypothesized that FMT would improve AHDS clinical scores and increase microbiota alpha-diversity and short-chain fatty acid (SCFA)-producing microbial communities’ abundances in dogs with AHDS after FMT. We sequenced the V3-V4 region of the 16S-rRNA gene in the feces of AHDS FMT-recipients and sham-treated control dogs, and their healthy donors at admission, discharge, and 30 days post-discharge. There were no significant differences in median AHDS clinical scores between FMT-recipients and sham-treated controls at admission or discharge (P = 0.22, P = 0.41). At admission, the Shannon diversity index (SDI) was lower in AHDS dogs than healthy donors (P = 0.002). The SDI did not change from admission to 30 days in sham-treated dogs yet increased in FMT-recipients from admission to discharge (P = 0.04) to levels not different than donors (P = 0.33) but significantly higher than sham-treated controls (P = 0.002). At 30 days, the SDI did not differ between FMT recipients, sham-treated controls, and donors (P = 0.88). Principal coordinate analysis of the Bray-Curtis index separated post-FMT and donor dogs from pre-FMT and sham-treated dogs (P = 0.009) because of increased SCFA-producing genera’s abundances after FMT. A single co-abundance subnetwork contained many of the same OTUs found to be differentially abundant in FMT-recipients, and the abundance of this module was increased in FMT-recipients at discharge and 30 days, compared to sham-treated controls. We conclude in this small pilot study FMT did not have any clinical benefit. A single FMT procedure has the potential to increase bacterial communities of SCFA-producing genera important for intestinal health up to 30 days post-FMT.
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Affiliation(s)
- Arnon Gal
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- * E-mail:
| | - Patrick C. Barko
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Patrick J. Biggs
- Molecular Epidemiology & Public Health Laboratory, Infectious Disease Research Centre, School of Veterinary Science, Massey University, Palmerston North, New Zealand
- Bioinformatics and Statistics Group, School of Fundamental Sciences, Massey University, Palmerston North, New Zealand
| | - Kristene R. Gedye
- Molecular Epidemiology & Public Health Laboratory, Infectious Disease Research Centre, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Anne C. Midwinter
- Molecular Epidemiology & Public Health Laboratory, Infectious Disease Research Centre, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - David A. Williams
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Richard K. Burchell
- North Coast Veterinary and Referral Centre, Sunshine Coast, Queensland, Australia
| | - Paolo Pazzi
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
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26
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Björkqvist O, Rangel I, Serrander L, Magnusson C, Halfvarson J, Norén T, Bergman-Jungeström M. Faecalibacterium prausnitzii increases following fecal microbiota transplantation in recurrent Clostridioides difficile infection. PLoS One 2021; 16:e0249861. [PMID: 33836037 PMCID: PMC8034738 DOI: 10.1371/journal.pone.0249861] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/26/2021] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Fecal microbiota transplantation (FMT) is a highly effective treatment for Clostridioides difficile infection (CDI). However, the fecal transplant's causal components translating into clearance of the CDI are yet to be identified. The commensal bacteria Faecalibacterium prausnitzii may be of great interest in this context, since it is one of the most common species of the healthy gut microbiota and produces metabolites with anti-inflammatory properties. Although there is mounting evidence that F. prausnitzii is an important regulator of intestinal homeostasis, data about its role in CDI and FMT are relatively scarce. METHODS Stool samples from patients with recurrent CDI were collected to investigate the relative abundance of F. prausnitzii before and after FMT. Twenty-one patients provided fecal samples before the FMT procedure, at 2 weeks post-FMT, and at 2-4 months post-FMT. The relative abundance of F. prausnitzii was determined using quantitative polymerase chain reaction. RESULTS The abundance of F. prausnitzii was elevated in samples (N = 9) from donors compared to pre-FMT samples (N = 15) from patients (adjusted P<0.001). No significant difference in the abundance of F. prausnitzii between responders (N = 11) and non-responders (N = 4) was found before FMT (P = 0.85). In patients with CDI, the abundance of F. prausnitzii significantly increased in the 2 weeks post-FMT samples (N = 14) compared to the pre-FMT samples (N = 15, adjusted P<0.001). The increase persisted 2-4 months post-FMT (N = 15) compared to pre-FMT samples (N = 15) (adjusted P<0.001). CONCLUSIONS FMT increases the relative abundance of F. prausnitzii in patients with recurrent CDI, and this microbial shift remains several months later. The baseline abundance of F. prausnitzii in donors or recipients was not associated with future treatment response, although a true predictive capacity cannot be excluded because of the limited sample size. Further studies are needed to discern whether F. prausnitzii plays an active role in the resolution of CDI.
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Affiliation(s)
- Olle Björkqvist
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- * E-mail:
| | - Ignacio Rangel
- School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Lena Serrander
- Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Cecilia Magnusson
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Infectious Diseases, Region Jönköping County, Jönköping, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Torbjörn Norén
- Faculty of Medicine and Health, Department of Laboratory Medicine, National Reference Laboratory for Clostridioides Difficile, Clinical Microbiology, Örebro University, Örebro, Sweden
| | - Malin Bergman-Jungeström
- Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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27
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A prospective study of the adaptive changes in the gut microbiome during standard-of-care chemoradiotherapy for gynecologic cancers. PLoS One 2021; 16:e0247905. [PMID: 33662003 PMCID: PMC7932122 DOI: 10.1371/journal.pone.0247905] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 02/16/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND A diverse and abundant gut microbiome can improve cancer patients' treatment response; however, the effect of pelvic chemoradiotherapy (CRT) on gut diversity and composition is unclear. The purpose of this prospective study was to identify changes in the diversity and composition of the gut microbiome during and after pelvic CRT. MATERIALS AND METHODS Rectal swabs from 58 women with cervical, vaginal, or vulvar cancer from two institutions were prospectively analyzed before CRT (baseline), during CRT (weeks 1, 3, and 5), and at first follow-up (week 12) using 16Sv4 rRNA gene sequencing of the V4 hypervariable region of the bacterial 16S rRNA marker gene. 42 of these patients received antibiotics during the study period. Observed operational taxonomic units (OTUs; representative of richness) and Shannon, Simpson, Inverse Simpson, and Fisher diversity indices were used to characterize alpha (within-sample) diversity. Changes over time were assessed using a paired t-test, repeated measures ANOVA, and linear mixed modeling. Compositional changes in specific bacteria over time were evaluated using linear discriminant analysis effect size. RESULTS Gut microbiome richness and diversity levels continually decreased throughout CRT (mean Shannon diversity index, 2.52 vs. 2.91; all P <0.01), but were at or near baseline levels in 60% of patients by week 12. Patients with higher gut diversity at baseline had the steepest decline in gut microbiome diversity. Gut microbiome composition was significantly altered during CRT, with increases in Proteobacteria and decreases in Clostridiales, but adapted after CRT, with increases in Bacteroides species. CONCLUSION After CRT, the diversity of the gut microbiomes in this population tended to return to baseline levels by the 12 week follow-up period, but structure and composition remained significantly altered. These changes should be considered when designing studies to analyze the gut microbiome in patients who receive pelvic CRT for gynecologic cancers.
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28
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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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29
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Zhou J, Tripathi M, Sinha RA, Singh BK, Yen PM. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. HEPATOMA RESEARCH 2021; 7:11. [PMID: 33490737 PMCID: PMC7116620 DOI: 10.20517/2394-5079.2020.134] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.
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Affiliation(s)
- Jin Zhou
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Madhulika Tripathi
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Brijesh Kumar Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Paul M. Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
- Duke Molecular Physiology Institute, Durham, NC 27701, USA
- Duke University School of Medicine, Durham, NC 27710, USA
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Frigerio J, Agostinetto G, Galimberti A, De Mattia F, Labra M, Bruno A. Tasting the differences: Microbiota analysis of different insect-based novel food. Food Res Int 2020; 137:109426. [DOI: 10.1016/j.foodres.2020.109426] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/18/2020] [Accepted: 06/05/2020] [Indexed: 01/04/2023]
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Britton GJ, Contijoch EJ, Spindler MP, Aggarwala V, Dogan B, Bongers G, San Mateo L, Baltus A, Das A, Gevers D, Borody TJ, Kaakoush NO, Kamm MA, Mitchell H, Paramsothy S, Clemente JC, Colombel JF, Simpson KW, Dubinsky MC, Grinspan A, Faith JJ. Defined microbiota transplant restores Th17/RORγt + regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas. Proc Natl Acad Sci U S A 2020; 117:21536-21545. [PMID: 32817490 PMCID: PMC7474624 DOI: 10.1073/pnas.1922189117] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.
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Affiliation(s)
- Graham J Britton
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Eduardo J Contijoch
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Matthew P Spindler
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Varun Aggarwala
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Belgin Dogan
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
| | - Gerold Bongers
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | | | - Andrew Baltus
- Janssen Human Microbiome Institute, Janssen Research and Development, Cambridge, MA 02142
| | - Anuk Das
- Janssen Human Microbiome Institute, Janssen Research and Development, Cambridge, MA 02142
| | - Dirk Gevers
- Janssen Human Microbiome Institute, Janssen Research and Development, Cambridge, MA 02142
| | | | - Nadeem O Kaakoush
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Michael A Kamm
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, VIC 3065, Australia
- Department of Medicine, St Vincent's Hospital, Melbourne, VIC 3065, Australia
- Department of Gastroenterology, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Hazel Mitchell
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Sudarshan Paramsothy
- Concord Clinical School, University of Sydney, Sydney, NSW 2050, Australia
- Department of Gastroenterology & Hepatology, Macquarie University Hospital, Sydney, NSW 2109, Australia
| | - Jose C Clemente
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Kenneth W Simpson
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
| | - Marla C Dubinsky
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ari Grinspan
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jeremiah J Faith
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Identification of Simplified Microbial Communities That Inhibit Clostridioides difficile Infection through Dilution/Extinction. mSphere 2020; 5:5/4/e00387-20. [PMID: 32727857 PMCID: PMC7392540 DOI: 10.1128/msphere.00387-20] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal microbiome plays an important role in limiting susceptibility to infection with Clostridioides difficile To better understand the ecology of bacteria important for C. difficile colonization resistance, we developed an experimental platform to simplify complex communities of fecal bacteria through dilution and rapidly screen for their ability to resist C. difficile colonization after challenge, as measured by >100-fold reduction in levels of C. difficile in challenged communities. We screened 76 simplified communities diluted from cultures of six fecal donors and identified 24 simplified communities that inhibited C. difficile colonization in vitro Sequencing revealed that simplified communities were composed of 19 to 67 operational taxonomic units (OTUs) and could be partitioned into four distinct community types. One simplified community could be further simplified from 56 to 28 OTUs through dilution and retain the ability to inhibit C. difficile We tested the efficacy of seven simplified communities in a humanized microbiota mouse model. We found that four communities were able to significantly reduce the severity of the initial C. difficile infection and limit susceptibility to disease relapse. Analysis of fecal microbiomes from treated mice demonstrated that simplified communities accelerated recovery of indigenous bacteria and led to stable engraftment of 19 to 22 OTUs from simplified communities. Overall, the insights gained through the identification and characterization of these simplified communities increase our understanding of the microbial dynamics of C. difficile infection and recovery.IMPORTANCEClostridioides difficile is the leading cause of antibiotic-associated diarrhea and a significant health care burden. Fecal microbiota transplantation is highly effective at treating recurrent C. difficile disease; however, uncertainties about the undefined composition of fecal material and potential long-term unintended health consequences remain. These concerns have motivated studies to identify new communities of microbes with a simpler composition that will be effective at treating disease. This work describes a platform for rapidly identifying and screening new simplified communities for efficacy in treating C. difficile infection. Four new simplified communities of microbes with potential for development of new therapies to treat C. difficile disease are identified. While this platform was developed and validated to model infection with C. difficile, the underlying principles described in the paper could be easily modified to develop therapeutics to treat other gastrointestinal diseases.
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A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression. J Clin Med 2020; 9:jcm9051369. [PMID: 32392712 PMCID: PMC7291163 DOI: 10.3390/jcm9051369] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/24/2020] [Accepted: 05/03/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.
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Kester JC, Brubaker DK, Velazquez J, Wright C, Lauffenburger DA, Griffith LG. Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms. Antimicrob Agents Chemother 2020; 64:e01404-19. [PMID: 31988098 PMCID: PMC7179307 DOI: 10.1128/aac.01404-19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 01/04/2020] [Indexed: 12/16/2022] Open
Abstract
A clinically relevant risk factor for Clostridioides difficile-associated disease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibiotics have been shown to disrupt the structure of the gut microbiota, some antibiotics appear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects. We examined cell biological effects of antibiotic exposure that may be involved in bacterial pathogenesis using an in vitro germfree human colon epithelial culture model. We found a marked loss of mucosal barrier and immune function with exposure to the CDAD-associated antibiotics clindamycin and ciprofloxacin, distinct from the results of pretreatment with an antibiotic unassociated with CDAD, tigecycline, which did not reduce innate immune or mucosal barrier functions. Importantly, pretreatment with CDAD-associated antibiotics sensitized mucosal barriers to C. difficile toxin activity in primary cell-derived enteroid monolayers. These data implicate commensal-independent gut mucosal barrier changes in the increased risk of CDAD with specific antibiotics and warrant further studies in in vivo systems. We anticipate this work to suggest potential avenues of research for host-directed treatment and preventive therapies for CDAD.
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Affiliation(s)
- Jemila C Kester
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Douglas K Brubaker
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Jason Velazquez
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Charles Wright
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Linda G Griffith
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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35
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Hasan RA, Koh AY, Zia A. The gut microbiome and thromboembolism. Thromb Res 2020; 189:77-87. [PMID: 32192995 DOI: 10.1016/j.thromres.2020.03.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 01/09/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
The gut microbiome plays a critical role in various inflammatory conditions, and its modulation is a potential treatment option for these conditions. The role of the gut microbiome in the pathogenesis of thromboembolism has not been fully elucidated. In this review, we summarize the evidence linking the gut microbiome to the pathogenesis of arterial and venous thrombosis. In a human host, potentially pathogenic bacteria are normal residents of the human gut microbiome, but significantly outnumbered by commensal anaerobic bacteria. Several disease states with an increased risk of venous thromboembolism (VTE) are associated with an imbalance in the gut microbiome characterized by a decrease in commensal anaerobic bacteria and an increase in the abundance of pathogenic bacteria of which the most common is the gram-negative Enterobacteriaceae (ENTERO) family. Bacterial lipopolysaccharides (LPS), the glycolipids found on the outer membrane of gram-negative bacteria, is one of the links between the microbiome and hypercoagulability. LPS binds to toll-like receptors to activate endothelial cells and platelets, leading to activation of the coagulation cascade. Bacteria in the microbiome can also metabolite compounds in the diet to produce important metabolites like trimethylamine-N-oxide (TMAO). TMAO causes platelet hyperreactivity, promotes thrombus formation and is associated with cardiovascular disease. Modulating the gut microbiome to target LPS and TMAO levels may be an innovative approach for decreasing the risk of thrombosis.
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Affiliation(s)
- Rida Abid Hasan
- Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Andrew Y Koh
- Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Ayesha Zia
- Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
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36
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Dorsaz S, Charretier Y, Girard M, Gaïa N, Leo S, Schrenzel J, Harbarth S, Huttner B, Lazarevic V. Changes in Microbiota Profiles After Prolonged Frozen Storage of Stool Suspensions. Front Cell Infect Microbiol 2020; 10:77. [PMID: 32185143 PMCID: PMC7058979 DOI: 10.3389/fcimb.2020.00077] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/17/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction: Fecal microbiota transplantation (FMT) is recommended as safe and effective treatment for recurrent Clostridioides difficile infections. Freezing the FMT preparation simplifies the process, allowing a single stool sample to be used for multiple receivers and over an extended period of time. We aimed to assess the effect of long-term frozen storage on bacterial taxonomic profiles of a stool suspension prepared for FMT. Methods: DNA was extracted from a stool suspension before freezing and sequentially during the 18-month storage period at -80°C. Two different protocols were used for DNA extraction. The first relied on a classical mechanical and chemical cell disruption to extract both intra- and extracellular DNA; the second included specific pre-treatments aimed at removing free DNA and DNA from human and damaged bacterial cells. Taxonomic profiling of bacterial communities was performed by sequencing of V3-V4 16S rRNA gene amplicons. Results: Microbiota profiles obtained by whole DNA extraction procedure remained relatively stable during frozen storage. When DNA extraction procedure included specific pre-treatments, microbiota similarity between fresh and frozen samples progressively decreased with longer frozen storage times; notably, the abundance of Bacteroidetes decreased in a storage duration-dependent manner. The abundance of Firmicutes, the main butyrate producers in the colon, were not much affected by frozen storage for up to 1 year. Conclusion: Our data show that metataxonomic analysis of frozen stool suspensions subjected to specific pre-treatments prior to DNA extractions might provide an interesting indication of bacterial resistance to stress conditions and thus of chances of survival in FMT recipients.
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Affiliation(s)
- Stéphane Dorsaz
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Yannick Charretier
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Myriam Girard
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Nadia Gaïa
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Stefano Leo
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Jacques Schrenzel
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.,Bacteriology Laboratory, Division of Laboratory Medicine, Department of Diagnostics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Stephan Harbarth
- Infection Control Program, Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Benedikt Huttner
- Infection Control Program, Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Vladimir Lazarevic
- Genomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
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Xi D, Michail S. Fecal microbiota transplantation in children does not significantly alter body mass index. Transl Pediatr 2019; 8:398-401. [PMID: 31993353 PMCID: PMC6970120 DOI: 10.21037/tp.2019.09.05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Fecal microbiota transplantation (FMT) is nowadays a promising therapy for Clostridium difficile infection (CDI) and a potential treatment for ulcerative colitis. However, it is still unclear whether the changes in intestinal microbiome will affect energy homeostasis or metabolism. This brings an intriguing question whether FMT from healthy donors affects recipient's body mass index (BMI). METHODS In our randomized placebo-controlled study children patients with CDI or ulcerative colitis were randomly divided into control and FMT groups. The change of post-FMT BMI percentile at 1, 3, 6, 12 months was calculated. The age range of CDI cohort was 1 to 17 years, while the range was 8 to 21 years for ulcerative colitis cohort. RESULTS We found that the BMI percentile was insignificantly changed by ‒0.7%, ‒1.8%, 1.3%, 4.6% in CDI, while by 3.6%, ‒3.3%, 3.7%, 7.1% in ulcerative colitis at 1, 3, 6, 12 months after FMT ("‒" means decrease). CONCLUSIONS We concluded that FMT from healthy donors does not significantly alter BMI in children with CDI and ulcerative colitis over 12 months.
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Affiliation(s)
- Dong Xi
- Division of Gastroenterology, Hepatology and Nutrition, Miller Children's Hospital and the University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Sonia Michail
- Division of Gastroenterology, Hepatology and Nutrition, Miller Children's Hospital and the University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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Kumar A, Ellermann M, Sperandio V. Taming the Beast: Interplay between Gut Small Molecules and Enteric Pathogens. Infect Immun 2019; 87:e00131-19. [PMID: 31262983 PMCID: PMC6704596 DOI: 10.1128/iai.00131-19] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The overuse of antibiotics has led to the evolution of drug-resistant bacteria that are becoming increasingly dangerous to human health. According to the Centers for Disease Control and Prevention, antibiotic-resistant bacteria cause at least 2 million illnesses and 23,000 deaths in the United States annually. Traditionally, antibiotics are bactericidal or bacteriostatic agents that place selective pressure on bacteria, leading to the expansion of antibiotic-resistant strains. In addition, antibiotics that are effective against some pathogens can also exacerbate their pathogenesis and may lead to severe progression of the disease. Therefore, alternative strategies are needed to treat antibiotic-resistant bacterial infections. One novel approach is to target bacterial virulence to prevent or limit pathogen colonization, while also minimizing tissue damage and disease comorbidities in the host. This review focuses on the interactions between enteric pathogens and naturally occurring small molecules in the human gut as potential therapeutic targets for antivirulence strategies. Individual small molecules in the intestines modulate enteric pathogen virulence and subsequent intestinal fitness and colonization. Targeted interruption of pathogen sensing of these small molecules could therefore attenuate their virulence. This review highlights the paths of discovery for new classes of antimicrobials that could potentially mitigate the urgent problem of antibiotic resistance.
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Affiliation(s)
- Aman Kumar
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Melissa Ellermann
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Vanessa Sperandio
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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39
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Hourigan SK, Ahn M, Gibson KM, Pérez-Losada M, Felix G, Weidner M, Leibowitz I, Niederhuber JE, Sears CL, Crandall KA, Oliva-Hemker M. Fecal Transplant in Children With Clostridioides difficile Gives Sustained Reduction in Antimicrobial Resistance and Potential Pathogen Burden. Open Forum Infect Dis 2019; 6:ofz379. [PMID: 31660343 PMCID: PMC6790402 DOI: 10.1093/ofid/ofz379] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 08/22/2019] [Indexed: 12/19/2022] Open
Abstract
Background Fecal microbiota transplantation (FMT) treats Clostridioides difficile infection (CDI). Little is known regarding the changes in antimicrobial resistance (AMR) genes and potential pathogen burden that occur in pediatric recipients of FMT. The aim of this study was to investigate changes in AMR genes, potential pathogens, species, and functional pathways with FMT in children. Methods Nine children with recurrent CDI underwent FMT. Stool was collected from donor and recipient pre-FMT and longitudinally post-FMT for up to 24 weeks. Shotgun metagenomic sequencing was performed. Reads were analyzed using PathoScope 2.0. Results All children had resolution of CDI. AMR genes decreased post-FMT (P < .001), with a sustained decrease in multidrug resistance genes (P < .001). Tetracycline resistance genes increased post-FMT (P < .001). Very low levels of potential pathogens were identified in donors and recipients, with an overall decrease post-FMT (P < .001). Prevotella sp. 109 expanded in all recipients post-FMT, and no recipients had any clinical infection. Alpha diversity was lower in recipients vs donors pre-FMT (P < .001), with an increase post-FMT (P ≤ .002) that was sustained. Beta diversity differed significantly in pre- vs post-FMT recipient samples (P < .001). Bacterial species Faecalibacterium prausnitzii and Bacteroides ovatus showed higher abundance in donors than recipients (P = .008 and P = .040, respectively), with expansion post-FMT. Biosynthetic pathways predominated in the donor and increased in the recipient post-FMT. Conclusions FMT for CDI in children decreases AMR genes and potential pathogens and changes microbiota composition and function. However, acquisition of certain AMR genes post-FMT combined with low levels of potential pathogens found in donors suggests that further study is warranted regarding screening donors using metagenomics sequencing before FMT.
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Affiliation(s)
- Suchitra K Hourigan
- Inova Translational Medicine Institute, Falls Church, Virginia.,Inova Children's Hospital, Falls Church, Virginia.,Pediatric Specialists of Virginia, Fairfax, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michelle Ahn
- Computational Biology Institute and, Washington, DC
| | | | - Marcos Pérez-Losada
- Computational Biology Institute and, Washington, DC.,Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC.,CIBIO-InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto, Campus Agrário de Vairão, Vairão, Portugal
| | - Grace Felix
- Pediatric Specialists of Virginia, Fairfax, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Melissa Weidner
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ian Leibowitz
- Pediatric Specialists of Virginia, Fairfax, Virginia
| | - John E Niederhuber
- Inova Translational Medicine Institute, Falls Church, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland.,Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, Virginia
| | - Cynthia L Sears
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Keith A Crandall
- Computational Biology Institute and, Washington, DC.,Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC
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40
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Mouzaki M, Loomba R. Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention. Therap Adv Gastroenterol 2019; 12:1756284819858470. [PMID: 31258623 PMCID: PMC6591661 DOI: 10.1177/1756284819858470] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/08/2019] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is diagnosed across the age spectrum and contributes to significant morbidity and mortality. The pathophysiology of NAFLD is not entirely understood; however, recent evidence has implicated the intestinal microbiome. Through the effects on host appetite, energy expenditure, digestion, gene expression, intestinal permeability, as well as immune activation, a dysbiotic microbiome can contribute to the development and progression of the hepatocellular steatosis, inflammation and fibrosis seen in the context of NAFLD. As such, intestinal microbiota and products of their metabolism have been targeted as treatment approaches for NAFLD.
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Affiliation(s)
- Marialena Mouzaki
- Steatohepatitis Center, Cincinnati Children’s
Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
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41
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Nie P, Li Z, Wang Y, Zhang Y, Zhao M, Luo J, Du S, Deng Z, Chen J, Wang Y, Chen S, Wang L. Gut microbiome interventions in human health and diseases. Med Res Rev 2019; 39:2286-2313. [PMID: 30994937 DOI: 10.1002/med.21584] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/27/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023]
Abstract
Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome-based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.
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Affiliation(s)
- Pengqing Nie
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Zhiqiang Li
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Yimeng Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Yubing Zhang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Mengna Zhao
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Jie Luo
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Shiming Du
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Zixin Deng
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Jincao Chen
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Yunfu Wang
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Shi Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Lianrong Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.,Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.,Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
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Chen T, Liu AB, Sun S, Ajami NJ, Ross MC, Wang H, Zhang L, Reuhl K, Kobayashi K, Onishi JC, Zhao L, Yang CS. Green Tea Polyphenols Modify the Gut Microbiome in db/db Mice as Co-Abundance Groups Correlating with the Blood Glucose Lowering Effect. Mol Nutr Food Res 2019; 63:e1801064. [PMID: 30667580 DOI: 10.1002/mnfr.201801064] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/07/2019] [Indexed: 01/04/2023]
Abstract
SCOPE The effects of green tea polyphenols, Polyphenon E (PPE), and black tea polyphenols, theaflavins (TFs), on gut microbiota and development of diabetes in db/db mice are investigated and compared. METHODS AND RESULTS Supplementation of PPE (0.1%) in the diet of female db/db mice for 7 weeks decreases fasting blood glucose levels and mesenteric fat while increasing the serum level of insulin, possibly through protection against β-cell damage. However, TFs are less or not effective. Microbiome analysis through 16S rRNA gene sequencing shows that PPE and TFs treatments significantly alter the bacterial community structure in the cecum and colon, but not in the ileum. The key bacterial phylotypes responding to the treatments are then clustered into 11 co-abundance groups (CAGs). CAGs 6 and 7, significantly increased by PPE but not by TFs, are negatively associated with blood glucose levels. The operational taxonomic units in these CAGs are from two different phyla, Firmicutes and Bacteroidetes. CAG 10, decreased by PPE and TFs, is positively associated with blood glucose levels. CONCLUSION Gut microbiota respond to tea polyphenol treatments as CAGs instead of taxa. Some of the CAGs associated with the blood glucose lowering effect are enriched by PPE, but not TFs.
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Affiliation(s)
- Tingting Chen
- Department of Chemical Biology, The State University of New Jersey, Piscataway, NJ, USA
| | - Anna B Liu
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Shili Sun
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Nadim J Ajami
- The Alkek Center for Metagenomics and Microbiome Research, Molecular Virology and Microbiology Department, Baylor College of Medicine, Houston, TX, USA
| | - Matthew C Ross
- The Alkek Center for Metagenomics and Microbiome Research, Molecular Virology and Microbiology Department, Baylor College of Medicine, Houston, TX, USA
| | - Hong Wang
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Le Zhang
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Kenneth Reuhl
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, The State University of New Jersey, Piscataway, NJ, USA
| | - Koichi Kobayashi
- Department of Microbial Pathogenesis & Immunology, Texas A&M Health Science Center, College Station, TX, USA
| | - Janet C Onishi
- Department of Chemical Biology, The State University of New Jersey, Piscataway, NJ, USA
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Chung S Yang
- Department of Chemical Biology, The State University of New Jersey, Piscataway, NJ, USA
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Wilson BC, Vatanen T, Cutfield WS, O'Sullivan JM. The Super-Donor Phenomenon in Fecal Microbiota Transplantation. Front Cell Infect Microbiol 2019; 9:2. [PMID: 30719428 PMCID: PMC6348388 DOI: 10.3389/fcimb.2019.00002] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/03/2019] [Indexed: 12/13/2022] Open
Abstract
Fecal microbiota transplantation (FMT) has become a highly effective bacteriotherapy for recurrent Clostridium difficile infection. Meanwhile the efficacy of FMT for treating chronic diseases associated with microbial dysbiosis has so far been modest with a much higher variability in patient response. Notably, a number of studies suggest that FMT success is dependent on the microbial diversity and composition of the stool donor, leading to the proposition of the existence of FMT super-donors. The identification and subsequent characterization of super-donor gut microbiomes will inevitably advance our understanding of the microbial component of chronic diseases and allow for more targeted bacteriotherapy approaches in the future. Here, we review the evidence for super-donors in FMT and explore the concept of keystone species as predictors of FMT success. Possible effects of host-genetics and diet on FMT engraftment and maintenance are also considered. Finally, we discuss the potential long-term applicability of FMT for chronic disease and highlight how super-donors could provide the basis for dysbiosis-matched FMTs.
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Affiliation(s)
- Brooke C. Wilson
- The Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Tommi Vatanen
- The Liggins Institute, University of Auckland, Auckland, New Zealand
- The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Wayne S. Cutfield
- The Liggins Institute, University of Auckland, Auckland, New Zealand
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Hernández M, de Frutos M, Rodríguez-Lázaro D, López-Urrutia L, Quijada NM, Eiros JM. Fecal Microbiota of Toxigenic Clostridioides difficile-Associated Diarrhea. Front Microbiol 2019; 9:3331. [PMID: 30697203 PMCID: PMC6341279 DOI: 10.3389/fmicb.2018.03331] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/21/2018] [Indexed: 12/18/2022] Open
Abstract
Clostridioides difficile infection (CDI) is currently one of the most important causes of infectious diarrhea in developed countries and the main cause in healthcare settings. Here, we characterized the gut microbiota from the feces of 57 patients with diarrhea from nosocomial and community-acquired CDI. We performed an ecological analysis by high-throughput sequencing of the V3-V4 region of 16S rRNA amplicons and evaluated the association of the various ecological profiles with CDI risk factors. Among all samples Bacteroidaceae 31.01%, Enterobacteriaceae 9.82%, Lachnospiraceae 9.33%, Tannerellaceae 6,16%, and Ruminococcaceae 5.64%, were the most abundant families. A reduced abundance of Bacteroides was associated with a poor CDI prognosis, with severe diarrhea and a high incidence of recurrence. This reduction was associated with a weakened host immune system and previous aggressive antibiotherapy. Peptostreptococcaceae family was 1.56% overall and within the family the only identified member was the genus Clostridioides, positively correlated with the presence of Akkermansia that may be predictive of the presence of a CDI. Finally, a relevant aspect that must be considered in clinical practice is the misdiagnosis of CDI, as patients with a stool sample that tests positive for C. difficile are usually diagnosed with CDI and subsequently treated as such. However, co-infection with other pathogenic agents often plays an important role in the development of diarrhea, and must be considered when prescribing antibiotic treatment.
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Affiliation(s)
- Marta Hernández
- Laboratorio de Biología Molecular y Microbiología, Instituto Tecnológico Agrario de Castilla y León, Valladolid, Spain
- Área de Microbiología, Departamento de Biotecnología y Ciencia de los Alimentos, Universidad de Burgos, Burgos, Spain
| | | | - David Rodríguez-Lázaro
- Área de Microbiología, Departamento de Biotecnología y Ciencia de los Alimentos, Universidad de Burgos, Burgos, Spain
| | | | - Narciso M. Quijada
- Laboratorio de Biología Molecular y Microbiología, Instituto Tecnológico Agrario de Castilla y León, Valladolid, Spain
- Área de Microbiología, Departamento de Biotecnología y Ciencia de los Alimentos, Universidad de Burgos, Burgos, Spain
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45
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Ling Z, Liu X, Guo S, Cheng Y, Shao L, Guan D, Cui X, Yang M, Xu X. Role of Probiotics in Mycoplasma pneumoniae Pneumonia in Children: A Short-Term Pilot Project. Front Microbiol 2019; 9:3261. [PMID: 30687259 PMCID: PMC6334620 DOI: 10.3389/fmicb.2018.03261] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 12/14/2018] [Indexed: 12/12/2022] Open
Abstract
Mycoplasma pneumoniae is one of the most common pathogens causing community-acquired pneumonia in children. Mycoplasma pneumoniae pneumonia (MPP) can be successfully treated with azithromycin; however, antibiotic-associated diarrhea (AAD) is a common adverse effect. Increasing evidence suggests that some probiotics may prevent the development of AAD. The present study determined the effects of probiotics (live Clostridium butyricum plus Bifidobacterium infantis) on the prevention and treatment of AAD in children with MPP when co-administered with intravenous azithromycin. Fifty-five children with MPP were enrolled and received azithromycin (10 mg/kg/day; once daily for 7 days) combined with probiotics (starting on the third day of azithromycin treatment; 1,500 mg three times daily); 50 healthy children served as controls. At the end of the trial, the incidence of AAD, fecal microbiota, intestinal mucosal barriers, and systemic inflammation were analyzed using recommended systems biology techniques. No cases of AAD or other adverse events occurred in children with MPP after co-administration of probiotics with azithromycin. A live C. butyricum plus B. infantis preparation partly reconstructed the gut microbiota, especially restoration of bacterial diversity. The indicators of intestinal mucosal barrier function, such as D-lactate, endotoxin, and diamine oxidase, were significantly improved and the systemic inflammation (interleukin 10) was attenuated after probiotic therapy. The present study indicated that co-administration of probiotics with azithromycin is a promising therapy for MPP treatment which could prevent and treat AAD effectively.
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Affiliation(s)
- Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xia Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shu Guo
- Department of Gastroenterology, Affiliated Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Yiwen Cheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Shao
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dexiu Guan
- Department of Gastroenterology, Affiliated Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Xiaoshuang Cui
- Department of Gastroenterology, Affiliated Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Mingming Yang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiwei Xu
- Department of Gastroenterology, Affiliated Beijing Children’s Hospital, Capital Medical University, Beijing, China
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46
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Qualitative and Quantitative DNA- and RNA-Based Analysis of the Bacterial Stomach Microbiota in Humans, Mice, and Gerbils. mSystems 2018; 3:mSystems00262-18. [PMID: 30505943 PMCID: PMC6247015 DOI: 10.1128/msystems.00262-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
Clinical stomach interventions, such as acid inhibition or bypass surgery, have been linked to fecal microbiota alterations. We demonstrate that the stomach microbiota largely overlaps those of adjacent gastrointestinal locations and identify gradual decreases and increases in the relative abundances of specific bacteria within the stomach, suggesting selective enrichment and depletion. Moreover, similarities between stomach and esophagus samples are proportional to the concentrations of Streptococcus (Firmicutes) in the stomach. The relative abundance of Firmicutes in the stomach, compared to that of Bacteroidetes, is increased in RNA relative to DNA, indicating higher transcriptional activity. Moreover, increased absolute bacterial loads are associated with decreased relative abundance of Firmicutes and higher relative abundance of Bacteroidetes. Our findings characterize the stomach microbiota as influenced by Bacteroidetes influx against a background of transcriptionally more active Firmicutes. Human, mouse, and gerbil stomach microbiotas differ at lower taxonomic levels, which might affect the utility of these model organisms. Clinical interventions in the stomach have been linked to fecal microbiota alterations, suggesting a function of the stomach in gastrointestinal (GI) homeostasis. We sought to determine the taxonomic bacterial biogeography of the upper GI tract, including different sites within the human stomach (cardia, corpus, and antrum), adjacent upstream (esophagus) and downstream (duodenum) locations, and luminal contents (aspirate), as well as whole-stomach samples from mice and gerbils. Qualitative and quantitative DNA- and RNA-based taxonomic microbiota analyses were combined to study the relationship of relative and absolute bacterial abundances and transcriptionally active bacterial microbiota components in the stomach of humans and mice. Stomach microbiota compositions resembled those of esophagus and duodenum. However, along the descending GI tract, the relative abundances of specific oropharyngeal commensals decreased (Streptococcus) or increased (Rothia mucilaginosa, Porphyromonas, and Lachnospiraceae). Furthermore, the compositional similarity (weighted UniFrac) between stomach aspirates and esophageal biopsy samples increased with gastric Streptococcus relative abundance. In both human aspirate and mouse stomach samples, Firmicutes were more abundant among transcriptionally active bacteria than Bacteroidetes. The relative abundance of Firmicutes in the stomach was negatively correlated and that of Bacteroidetes was positively correlated with absolute bacterial abundance, suggesting a disproportionate increase of Bacteroidetes over Firmicutes at higher bacterial densities. Human, mouse, and gerbil stomach samples showed similarities at higher taxonomic levels but differences at lower taxonomic levels. Our findings suggest selective enrichment and depletion of specific bacterial taxa in the stomach and Firmicutes being transcriptionally more active than Bacteroidetes that increase in relative abundance with total bacterial load. IMPORTANCE Clinical stomach interventions, such as acid inhibition or bypass surgery, have been linked to fecal microbiota alterations. We demonstrate that the stomach microbiota largely overlaps those of adjacent gastrointestinal locations and identify gradual decreases and increases in the relative abundances of specific bacteria within the stomach, suggesting selective enrichment and depletion. Moreover, similarities between stomach and esophagus samples are proportional to the concentrations of Streptococcus (Firmicutes) in the stomach. The relative abundance of Firmicutes in the stomach, compared to that of Bacteroidetes, is increased in RNA relative to DNA, indicating higher transcriptional activity. Moreover, increased absolute bacterial loads are associated with decreased relative abundance of Firmicutes and higher relative abundance of Bacteroidetes. Our findings characterize the stomach microbiota as influenced by Bacteroidetes influx against a background of transcriptionally more active Firmicutes. Human, mouse, and gerbil stomach microbiotas differ at lower taxonomic levels, which might affect the utility of these model organisms.
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47
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Balakrishnan B, Taneja V. Microbial modulation of the gut microbiome for treating autoimmune diseases. Expert Rev Gastroenterol Hepatol 2018; 12:985-996. [PMID: 30146910 DOI: 10.1080/17474124.2018.1517044] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Many studies have shown the relationship between autoimmune diseases and the gut microbiome in humans: those with autoimmune conditions display gut microbiome dysbiosis. The big question that needs to be addressed is if restoring eubiosis of the gut microbiota can help suppress the autoimmune condition by activating various immune regulatory mechanisms. Inducing these self-healing mechanisms should prolong good health in affected individuals. Area covered: Here, we review the available clinical and preclinical studies that have used selective bacteria for modulating gut microbiota for treating autoimmune diseases. The potential bacterial candidates and their mechanism of action in treating autoimmune diseases will be discussed. We searched for genetically modified and potential probiotics for diseases and discuss the most likely candidates. Expert commentary: To achieve eubiosis, manipulation of the gut microbiota must occur in some form. Several approaches for modulating gut microbiota include prebiotic diets, antimicrobial interventions, fecal microbiota transplants, and selective probiotics. One novel approach showing promising results is the use of selective bacterial candidates to modulate microbial composition. Use of single microbe for treatment has an advantage as compared to multi-species as microbes grow at different rates and if needed, a single microbe is easy to target.
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Affiliation(s)
| | - Veena Taneja
- a Department of Immunology , Mayo Clinic , Rochester , MN , USA
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48
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Seekatz AM, Theriot CM, Rao K, Chang YM, Freeman AE, Kao JY, Young VB. Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Anaerobe 2018; 53:64-73. [PMID: 29654837 PMCID: PMC6185828 DOI: 10.1016/j.anaerobe.2018.04.001] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 02/06/2023]
Abstract
A significant proportion of individuals develop recurrent Clostridium difficile infection (CDI) following initial disease. Fecal microbiota transplantation (FMT), a highly effective treatment method for recurrent CDI, has been demonstrated to induce microbiota recovery. One of the proposed functions associated with restoration of colonization resistance against C. difficile has been recovery of bile acid metabolism. In this study, we aimed to assess recovery of short chain fatty acids (SCFAs) in addition to bile acids alongside microbial community structure in six patients with recurrent CDI following treatment with FMT over time. Using 16S rRNA gene-based sequencing, we observed marked similarity of the microbiota between recipients following FMT (n = 6, sampling up to 6 months post-FMT) and their respective donors. Sustained increases in the levels of the SCFAs butyrate, acetate, and propionate were observed post-FMT, and variable recovery over time was observed in the secondary bile acids deoxycholate and lithocholate. To correlate these changes with specific microbial taxa at an individual level, we applied a generalized estimating equation approach to model metabolite concentrations with the presence of specific members of the microbiota. Metabolites that increased following FMT were associated with bacteria classified within the Lachnospiraceae, Ruminococcaceae, and unclassified Clostridiales families. In contrast, members of these taxa were inversely associated with primary bile acids. The longitudinal aspect of this study allowed us to characterize individualized patterns of recovery, revealing variability between and within patients following FMT.
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Affiliation(s)
- Anna M Seekatz
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Casey M Theriot
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Krishna Rao
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Yu-Ming Chang
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Alison E Freeman
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - John Y Kao
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Vincent B Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.
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49
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The Use of Microbiome Restoration Therapeutics to Eliminate Intestinal Colonization With Multidrug-Resistant Organisms. Am J Med Sci 2018; 356:433-440. [PMID: 30384952 DOI: 10.1016/j.amjms.2018.08.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 08/27/2018] [Indexed: 12/17/2022]
Abstract
Antibiotic resistance (AR) has been described by the World Health Organization as an increasingly serious threat to global public health. Many mechanisms of AR have become widespread due to global selective pressures such as widespread antibiotic use. The intestinal tract is an important reservoir for many multidrug-resistant organisms (MDROs), and next-generation sequencing has expanded understanding of the resistome, defined as the comprehensive sum of genetic determinants of AR. Intestinal decolonization has been explored as a strategy to eradicate MDROs with selective digestive tract decontamination and probiotics being notable examples with mixed results. This review focuses on fecal microbiota transplantation and the early evidence supporting its efficacy in decolonizing MDROs and potential mechanisms of action to reduce AR genes. Current evidence suggests that fecal microbiota transplantation may have promise in restoring healthy microbial diversity and reducing AR, and clinical trials are underway to better characterize its safety and efficacy.
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50
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Brown JRM, Flemer B, Joyce SA, Zulquernain A, Sheehan D, Shanahan F, O'Toole PW. Changes in microbiota composition, bile and fatty acid metabolism, in successful faecal microbiota transplantation for Clostridioides difficile infection. BMC Gastroenterol 2018; 18:131. [PMID: 30153805 PMCID: PMC6114236 DOI: 10.1186/s12876-018-0860-5] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 08/15/2018] [Indexed: 12/12/2022] Open
Abstract
Background Alteration of the gut microbiota by repeated antibiotic treatment increases susceptibility to Clostridioides difficile infection. Faecal microbiota transplantation from donors with a normal microbiota effectively treats C. difficile infection. Methods The study involved 10 patients with recurrent C. difficile infection, nine of whom received transplants from individual donors and one who received a donor unit from a stool bank (OpenBiome). Results All individuals demonstrated enduring post-transplant resolution of C. difficile- associated diarrhoea. Faecal microbiota diversity of recipients significantly increased, and the composition of the microbiota resembled that of the donor. Patients with C. difficile infection exhibited significantly lower faecal levels of secondary/ bile acids and higher levels of primary bile acids. Levels of secondary bile acids were restored in all transplant recipients, but to a lower degree with the OpenBiome transplant. The abundance increased of bacterial genera known from previous studies to confer resistance to growth and germination of C. difficile. These were significantly negatively associated with primary bile acid levels and positively related with secondary bile acid levels. Although reduced levels of the short chain fatty acids, butyrate, propionate and acetate, have been previously reported, here we report elevations in SCFA, pyruvic and lactic fatty acids, saturated, ω-6, monounsaturated, ω-3 and ω-6 polyunsaturated fatty acids (PUFA) in C. difficile infection. This potentially indicates one or a combination of increased dietary FA intake, microbial modification of FAs or epithelial cell damage and inflammatory cell recruitment. No reversion to donor FA profile occurred post-FMT but ω-3 to ω-6 PUFA ratios were altered in the direction of the donor. Archaeal metabolism genes were found in some samples post FMT. Conclusion A consistent metabolic signature was identified in the post-transplant microbiota, with reduced primary bile acids and substantial restoration of secondary bile acid production capacity. Total FA levels were unchanged but the ratio of inflammatory to non-inflammatory FAs decreased. Electronic supplementary material The online version of this article (10.1186/s12876-018-0860-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jillian R-M Brown
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland
| | - Burkhardt Flemer
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland
| | - Susan A Joyce
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, National University of Ireland, Cork, Ireland
| | - Akbar Zulquernain
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - Donal Sheehan
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - Fergus Shanahan
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - Paul W O'Toole
- APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland. .,School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
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