Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis
Daniël van der Lelie, Akihiko Oka, Safiyh Taghavi, Junji Umeno, Ting-Jia Fan, Katherine E. Merrell, Sarah D. Watson, Lisa Ouellette, Bo Liu, Muyiwa Awoniyi, Yunjia Lai, Liang Chi, Kun Lü, Christopher S. Henry, R. Balfour Sartor
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.