Deciphering and Exploiting the chemical features of Silent Lipopolysaccharides: a gift from gut microbiota

Gut Microbiota is a key actor for human health, driving many physiological and pathological processes, including immune system development and modulation. How this massive population of microorganisms, most of which are bacteria, establishes commensal, mutualistic or pathogenic interactions with the human host despite the vigilance of the immune system, is still obscure and requires an in-depth study. The story gets more intricate considering that gut is home for a myriad of Gram-negative bacteria whose outer membrane main constituent is the lipopolysaccharide (LPS). Due to its chemical structure, LPS is considered a potent elicitor of immune inflammatory reactions in mammals, being usually associated to perilous bacteria and detrimental outcomes for human health. Nevertheless, LPS also decorates the membrane of harmless and beneficial Gram-negatives of gut microbiota. How LPS is tolerated and remains (apparently) silent in the gut is a major unsolved question representing a frontier in our understanding of innate immunity. DEBUGGING-LPS project will contribute to answer this question, starting from the assumption that the chemistry of LPS is the real message taken from human host of the bacterial interaction, either beneficial or harmful. Strategically based on my expertise in organic chemistry, and integrating synthetic chemistry and cellular immunology studies, DEBUGGING-LPS will decrypt the 'chemical language' spoken by LPS in the gut. This project will deliver a clear picture of the chemistry at the basis of the difference between 'good' and 'bad' LPS, providing tools for the exploitation of the acquired knowledge to create novel therapeutics for resolving/mitigating immune disorders. DEBUGGING-LPS has been conceived to go beyond the state-of-the-art, breaking the dogma of LPS as an enemy, leaving space for a new vision of this glycomolecule: i.e. no longer as a toxic bacterial product rather as an immune signal vital for the proper functioning of our body.