Rationally Selected Probiotics as Immunomodulatory Biologics

Abstract

The intestinal microbiota may play a critical role in the modulation of human health. Dysregulation of the commensal flora, in both diversity and composition, is intimately linked to functional changes of the immune system and subsequently contributes to development of immune disorders. Although probiotics are considered as prophylactic or therapeutic modalities to restore homeostasis of the gut microbiota, efficacy of probiotics is strain specific with great variations within the same species. To identify regulatory T cell (Treg)-inducing probiotic strains, we have screened several hundred strains of bacteria. Among the several hundred strains screened, Bifidobacterium bifidum PRI1 (Bb PRI1) was selected based on its IL-10highIL-12low inducing capabilities in mixed mesenteric lymphocyte cultures. Mono-association of Bb PRI1 significantly enhanced the generation of induced CD4+Foxp3+ Helioslow Treg (iTreg) cells in a DC-dependent manner. These iTreg cells express enhanced levels of CTLA4 and IL-10 and exhibit activated Treg cell phenotypes. Cell surface beta-glucan/galactan polysacchaccharides (CSGG) of Bb PRI1 were identified as key components for Treg induction. CSGG efficiently recapitulated the activity of whole bacteria and acted via regulatory dendritic cells. Treg cells induced by Bb PRI1 or purified CSGG display stable and robust suppressive capacity towards experimental colitis. Collectively our study establishes CSGG as a novel functional component of Treg-inducing bacteria, underscoring potential applicability of CSGG-producing probiotics as modulators of diverse hyper-immune disorders. These findings provide new insights into the molecular mechanisms by which iTreg-inducing probiotics-host interaction could establish immunological homeostasis in the gut. This study was supported from the Institute for Basic Science (IBS; IBS-R005), Republic of Korea.