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

Nat Commun. 2021 May 28;12(1):3105. doi: 10.1038/s41467-021-23460-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / genetics
  • Bacteria / metabolism*
  • Bile Acids and Salts / metabolism
  • Colitis / immunology
  • Colitis / microbiology*
  • Colitis / therapy*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Dysbiosis / microbiology*
  • Dysbiosis / therapy
  • Feces / microbiology
  • Gastrointestinal Microbiome* / immunology
  • Gastrointestinal Microbiome* / physiology
  • Germ-Free Life* / immunology
  • Germ-Free Life* / physiology
  • Homeostasis
  • Humans
  • Inflammation / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout

Substances

  • Bile Acids and Salts
  • Cytokines