Physiologically-Based Modeling and Immunomodulatory Effects of Microbial Metabolite-Delivering Polymeric Nano-Prodrugs

Short-chain fatty acids (SCFAs) are immune tolerance–promoting microbiome-derived metabolites with demonstrated therapeutic potential but limited clinical utility, primarily due to pharmacokinetic limitations such as rapid absorption/metabolism after oral administration. We developed an oral nanoformulation comprised of polymeric SCFA nano-prodrugs (NPs) with prolonged gastrointestinal retention in mice (~12 h), enabling enhanced delivery to the distal gut. A physiologically-based pharmacokinetic (PBPK) model was constructed using experimentally-derived rate constants describing NP transit, release, and SCFA absorption. We then tested a microbiome-focused combination treatment strategy in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Specifically, we first administered vancomycin to deplete pathogenic gut bacteria, then administered immunomodulatory SCFA-NPs. This significantly reduced MHC-II expression on antigen-presenting cells in gut-draining lymph nodes, systemic, and central nervous system (CNS)-draining lymph nodes, and increased MOG-specific regulatory T cells in the CNS-draining lymph nodes, supporting that activation of pro-reparative gut-CNS axis mechanisms may ameliorate CNS autoimmunity.