A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory <i>Clostridioides difficile</i> Infection
Tanya M. Monaghan,
Niharika A. Duggal,
Elisa Rosati,
Ruth Griffin,
Jamie Hughes,
Brandi Roach,
David Y. Yang,
Christopher Wang,
Karen Wong,
Lynora Saxinger,
Maja Pučić-Baković,
Frano Vučković,
Filip Klicek,
Gordan Lauc,
Paddy Tighe,
Benjamin H. Mullish,
Jesus Miguens Blanco,
Julie A. K. McDonald,
Julian R. Marchesi,
Ning Xue,
Tania Dottorini,
Animesh Acharjee,
Andre Franke,
Yingrui Li,
Gane Ka-Shu Wong,
Christos Polytarchou,
Tung On Yau,
Niki Christodoulou,
Maria Hatziapostolou,
Minkun Wang,
Lindsey A. Russell,
Dina H. Kao
Affiliations
Tanya M. Monaghan
NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham NG7 2UH, UK
Niharika A. Duggal
MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Elisa Rosati
Institute of Clinical Molecular Biology, Universitätsklinikum Schleswig-Holstein, Christian-Albrecht University of Kiel, 24105 Kiel, Germany
Ruth Griffin
Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
Jamie Hughes
Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
Brandi Roach
Division of Gastroenterology, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
David Y. Yang
Division of Gastroenterology, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
Christopher Wang
Division of Gastroenterology, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
Karen Wong
Division of Gastroenterology, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
Lynora Saxinger
Division of Infectious Diseases, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
Maja Pučić-Baković
Glycoscience Research Laboratory, Genos Ltd., Borongajska cesta 83H, 10000 Zagreb, Croatia
Frano Vučković
Glycoscience Research Laboratory, Genos Ltd., Borongajska cesta 83H, 10000 Zagreb, Croatia
Filip Klicek
Glycoscience Research Laboratory, Genos Ltd., Borongajska cesta 83H, 10000 Zagreb, Croatia
Gordan Lauc
Glycoscience Research Laboratory, Genos Ltd., Borongajska cesta 83H, 10000 Zagreb, Croatia
Paddy Tighe
School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
Benjamin H. Mullish
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
Jesus Miguens Blanco
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
Julie A. K. McDonald
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
Julian R. Marchesi
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
Ning Xue
School of Veterinary Medicine and Science, University of Nottingham, Nottingham NG7 2UH, UK
Tania Dottorini
School of Veterinary Medicine and Science, University of Nottingham, Nottingham NG7 2UH, UK
Animesh Acharjee
College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, Birmingham B15 2TT, UK
Andre Franke
Institute of Clinical Molecular Biology, Universitätsklinikum Schleswig-Holstein, Christian-Albrecht University of Kiel, 24105 Kiel, Germany
Yingrui Li
Shenzhen Digital Life Institute, Shenzhen 518016, China
Gane Ka-Shu Wong
Department of Biological Sciences, Department of Medicine, University of Alberta, Edmonton, AB T6G 2E1, Canada
Christos Polytarchou
Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Tung On Yau
Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Niki Christodoulou
Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Maria Hatziapostolou
Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Minkun Wang
Shenzhen Digital Life Institute, Shenzhen 518016, China
Lindsey A. Russell
Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
Dina H. Kao
Division of Gastroenterology, Department of Medicine, University of Alberta; Edmonton, Alberta, AB T6G 2G3, Canada
Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies.
