Svetlana F Lima1, Lasha Gogokhia2, Monica Viladomiu1, Lance Chou1, Gregory Putzel1, Wen-Bing Jin1, Silvia Pires1, Chun-Jun Guo1, Ylaine Gerardin3, Carl V Crawford4, Vinita Jacob5, Ellen Scherl5, Su-Ellen Brown6, John Hambor6, Randy S Longman7. 1. Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, New York; Division of Gastroenterology and Hepatology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York. 2. Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, New York; Division of Gastroenterology and Hepatology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York; St. Mary's Hospital, Department of Medicine, Waterbury, Connecticut. 3. Finch Therapeutics, Somerville, Massachusetts. 4. Division of Gastroenterology and Hepatology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York. 5. Division of Gastroenterology and Hepatology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York; Jill Roberts Center for IBD, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York. 6. Boehringer Ingelheim SHINE Program, Ridgefield, Connecticut. 7. Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, New York; Division of Gastroenterology and Hepatology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York; Jill Roberts Center for IBD, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York. Electronic address: ral2006@med.cornell.edu.
Abstract
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC. METHODS: Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A-coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity. RESULTS: Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin (IL) 10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models. CONCLUSIONS: This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384.
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC. METHODS: Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A-coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity. RESULTS: Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin (IL) 10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models. CONCLUSIONS: This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384.
Authors: Noortje G Rossen; Susana Fuentes; Mirjam J van der Spek; Jan G Tijssen; Jorn H A Hartman; Ann Duflou; Mark Löwenberg; Gijs R van den Brink; Elisabeth M H Mathus-Vliegen; Willem M de Vos; Erwin G Zoetendal; Geert R D'Haens; Cyriel Y Ponsioen Journal: Gastroenterology Date: 2015-03-30 Impact factor: 22.682
Authors: Vinita Jacob; Carl Crawford; Shirley Cohen-Mekelburg; Monica Viladomiu; Gregory G Putzel; Yecheskel Schneider; Fatiha Chabouni; Sarah OʼNeil; Brian Bosworth; Viola Woo; Nadim J Ajami; Joseph F Petrosino; Ylaine Gerardin; Zain Kassam; Mark Smith; Iliyan D Iliev; Gregory F Sonnenberg; David Artis; Ellen Scherl; Randy S Longman Journal: Inflamm Bowel Dis Date: 2017-06 Impact factor: 5.325
Authors: Valentin Mocanu; Zhengxiao Zhang; Edward C Deehan; Dina H Kao; Naomi Hotte; Shahzeer Karmali; Daniel W Birch; Kalutota K Samarasinghe; Jens Walter; Karen L Madsen Journal: Nat Med Date: 2021-07-05 Impact factor: 53.440
Authors: Christian Quast; Elmar Pruesse; Pelin Yilmaz; Jan Gerken; Timmy Schweer; Pablo Yarza; Jörg Peplies; Frank Oliver Glöckner Journal: Nucleic Acids Res Date: 2012-11-28 Impact factor: 16.971
Authors: Changsheng Xing; Yang Du; Tianhao Duan; Kelly Nim; Junjun Chu; Helen Y Wang; Rong-Fu Wang Journal: Front Immunol Date: 2022-07-29 Impact factor: 8.786
Authors: John Gubatan; Theresa Louise Boye; Michelle Temby; Raoul S Sojwal; Derek R Holman; Sidhartha R Sinha; Stephan R Rogalla; Ole Haagen Nielsen Journal: Microorganisms Date: 2022-07-07