Identification of novel intestinal microbiome-derived factors that modulate host innate immune responses
Helena Kiefel, Dhwani Haria, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Laurens Kruidenier, Karim Dabbagh and Kareem Graham Second Genome, Inc. 341 Allerton Avenue, South San Francisco, CA 94080
Intestinal microbiome dysbiosis is associated with numerous metabolic and inflammatory disorders. Understanding the interplay between gut microbiome products and host responses therefore offers a rich potential for illuminating regulators and determinants of health and disease. Second Genome has developed a microbiome discovery platform that can identify novel microbial-based factors with potential for modulating host cell behavior. We have leveraged this discovery platform to identify putative secreted factors derived from discrete gut-resident bacterial strains. In in vitro culture systems, these factors induce robust secretion of proinflammatory cytokines (e.g., IL-6, TNF) by mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes. These factors also enhance systemic immune activation when administered in vivo to mice treated with anti-CD3 monoclonal antibodies. Evaluation of select bacterial-derived secreted products in a functional, whole-cell assay revealed that some of these factors may exert their immunomodulatory effects in part by functioning as agonists of specific Toll-like receptors. Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunoregulatory factors. This approach may prove highly useful for uncovering agents with potential for use as therapeutics in disorders of the immune system.