Article

Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis

Daniël van der LelieGusto Global LLC, Morrisville, NC, USA. [email protected]Akihiko OkaDepartment of Internal Medicine II, Shimane University Faculty of Medicine, Shimane, JapanSafiyh TaghaviJunji UmenoDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, JapanTing-Jia FanKatherine E. MerrellSarah D. WatsonLisa OuelletteBo LiuDepartments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAMuyiwa AwoniyiDepartments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAYunjia LaiDepartment of Environmental Sciences and Engineering, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USALiang ChiDepartment of Environmental Sciences and Engineering, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAKun LüDepartment of Environmental Sciences and Engineering, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAChristopher S. HenryR. Balfour SartorDepartments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Nature Communicationsjournal2021en

ABI

Abstract

Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability.

Topics

Gut microbiota and health Clostridium difficile and Clostridium perfringens research Gastrointestinal motility and disorders

Identifiers

DOI: 10.1038/s41467-021-23460-x

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