Title | Transferable Immunoglobulin A-Coated Odoribacter splanchnicus in Responders to Fecal Microbiota Transplantation for Ulcerative Colitis Limits Colonic Inflammation. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Lima SF, Gogokhia L, Viladomiu M, Chou L, Putzel G, Jin W-B, Pires S, Guo C-J, Gerardin Y, Crawford CV, Jacob V, Scherl E, Brown S-E, Hambor J, Longman RS |
Journal | Gastroenterology |
Volume | 162 |
Issue | 1 |
Pagination | 166-178 |
Date Published | 2022 01 |
ISSN | 1528-0012 |
Keywords | Animals, Bacteroidetes, Clinical Trials as Topic, Colitis, Colitis, Ulcerative, Colon, Disease Models, Animal, Fecal Microbiota Transplantation, Forkhead Transcription Factors, Gastrointestinal Microbiome, Germ-Free Life, Humans, Immunity, Mucosal, Immunoglobulin A, Intestinal Mucosa, Intraepithelial Lymphocytes, Metagenome, Metagenomics, Mice, Inbred C57BL, Mice, Knockout, Nuclear Receptor Subfamily 1, Group F, Member 3, T-Lymphocytes, Regulatory, Treatment Outcome |
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. |
DOI | 10.1053/j.gastro.2021.09.061 |
Alternate Journal | Gastroenterology |
PubMed ID | 34606847 |
PubMed Central ID | PMC8678328 |
Grant List | R01 DK114252 / DK / NIDDK NIH HHS / United States R01 DK120985 / DK / NIDDK NIH HHS / United States R01 DK128257 / DK / NIDDK NIH HHS / United States |