THE MICROBIOME: A POTENTIAL TREASURE TROVE FOR NEW THERAPEUTICS

The host immune system and the microbiota interact constantly. To date, we have discovered the only bacterial structures from the gut flora known to stimulate the immune system during commensalism. Studying a single microbial species amongst the many thousand species known to inhabit the human gut, we have discovered two molecules, one a polysaccharide and the other a glycosphingolipid, with significant therapeutic potential. We have delineated the innate and adaptive cellular mechanisms governing the physiologic immunoregulatory processes stimulated by polysaccharide A (PSA) of Bacteroides fragilis. Immunoregulation by this single bacterial molecule from a commensal organism requires plasmacytoid dendritic cells (PDCs) to induce regulatory T cells. Overturning immunologic paradigms, this zwitterionic polysaccharide was found to be processed and presented by major histocompatibility class II molecules. PSA plays an essential role in shaping mammalian immune development and displays potent immunomodulatory and anti-inflammatory activity, stimulating CD4+ T-cell production of interleukin 10, which protects mice against experimental inflammatory bowel disease and experimental allergic encephalitis. . Natural molecules like PSA have very complex signaling mechanisms to the immune system.

The microbiota also modulate invariant natural killer T (iNKT) cell numbers in the colon. SInce iNKT cells recognize glycosphingolipids presented by CD1d and the Bacteroidetes are among the few microbial phyla with sphingolipids contributing to membrane architecture, we sought to find a molecule within the Bacteroidetes involved in modulating iNKT cell homeostasis.We purified and chemically identified a microbial sphingolipid molecule that when administered to mice actually inhibits iNKT cell numbers in the colon and protects mice egainst experimental ulcerative colitis simulating the observation reported with the entire microbiota.

The finding of these two molecules points to a new direction for therapeutic intervention for inflammatory and possibly other types of diseases.