Modulation of Host Immunity by Targeting Gut Microbiota

Abstract

Intestinal microbiota plays a critical role in the modulation of human health. Dysregulation of the commensal flora is closely linked to functional changes of the immune system and subsequently contributes to development of immune disorders. Recently many studies suggested that targeting gut microbiome could be applicable as a therapeutic modality to treat diverse diseases. However, there are many gaps and hurdles to develop microbiome therapeutics for human trials. These include how to control the safety and efficacy of specific microorganisms as there is no approved guidelines to develop the products. Development of probiotics as prophylactic or therapeutic modalities is highly considered to restore homeostasis of host immune system as they are generally recognized as safe (GRAS). Providing tailored probiotic strain(s) is essential to the people who are in the sage of disease development. How to identify and characterize the properties of specific probiotic strains? What are the effector molecules and mode of action of them? How to prove efficacy with clinical relevance? To answer these questions, we have developed and identified different types of probiotic strains that could either induce regulatory T cells (Treg) or suppressing Treg cell activity while activating cytotoxic activity of CD8 T cells. As an example, we have selected Bifidobacterium bifidum PRI1 (Bb PRI1) as a Treg-inducing bacteria based on its IL-10highIL-12low inducing capabilities. Mono-association of Bb PRI1significantly enhanced the generation of induced CD4+Foxp3+ Helioslow Treg (iTreg) cells from the naive CD4+ T cell populations mainly in the lamina propria of the colon. Mechanistically, we identified Bb PRI1-derived capsular polysaccharide (CPS) as the key component that in a TLR2 dependent manner is capable of inducing regulatory DCs, which in turn enhanced iTreg cells generation. These findings provide new insights into the molecular mechanisms by which Treg-inducing probiotics-host interaction could establish immunological homeostasis in the gut. Our studies also provide a proof of concept how specific probiotic strain could modulate host’s immune system.