Abstract 1490: Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling

Abstract

Abstract The gut microbiome is a key contributor to the maintenance of host physiology. At the same time, increasing evidence implicates microbiome dysbiosis as a key determinant of numerous metabolic and inflammatory disorders. It is, therefore, of paramount importance to understand the interactions between the host and gut microbiota. Second Genome has developed a proprietary, bioinformatics-driven discovery platform to identify novel microbiome-derived peptides with the potential to modulate host immune responses. We have leveraged this platform to evaluate immunomodulatory functions of novel, secreted peptides derived from gut-resident bacterial species Bifidobacterium longum and Bifidobacterium breve. Previously, the microbial genus Bifidobacterium (‘Bifido’) has been shown to be associated with enhanced dendritic cell functions and antitumor effects. Here, we identify Bifido-derived peptides that are putative agonists of certain murine and human Toll-like receptors (TLRs). These peptides induce secretion of pro-inflammatory cytokines such as TNF-α and IL-6 by in vitro-generated mouse dendritic cells and peritoneal macrophages in a TLR4 and CD14-dependent manner. One of the peptides, SG-A, also induces secretion of Th1-type cytokines and chemokines such as IL-21, GRO-α, and IP-10 by human monocytes and monocyte-derived dendritic cells. Moreover, in vivo administration of SG-A in mice elicited a systemic pro-inflammatory immune response in the absence of any secondary stimulus. Collectively, our results demonstrate the ability of a novel bacterial-derived peptide to engage the host innate immune system. Moreover, our findings validate the potential of the Second Genome discovery platform for identification of novel microbiome-derived agents that: i) have the ability to modulate host cell functions; and ii) may be developed into therapeutic agents for immune and inflammatory disorders. Citation Format: Dhwani Haria, Helena Kiefel, Yuliya Katlinskaya, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1490.