Targeting the GUT-CNS axis via distal GUT-delivered short-chain fatty acids to treat CNS autoimmunity

The National Institute of Allergy and Infectious Diseases awarded the University of Washington $136,563 on November 28, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop and test a nanoparticle formulation for selective delivery of short-chain fatty acids to the distal gut as a treatment for multiple sclerosis-related central nervous system autoimmunity.

The project targets the gut-central nervous system axis by addressing translational barriers to oral short-chain fatty acid (SCFA) therapy. Free SCFAs, which demonstrate immunomodulatory potential in preclinical and clinical studies of multiple sclerosis, suffer from rapid absorption, unclear therapeutic site of action, rapid metabolism requiring clinically unfeasible dosing, and poor organoleptic properties that compromise patient compliance. The recipient will develop an innovative nanoparticle formulation engineered to deliver SCFAs to the distal gut in a sustained manner, circumventing these limitations. Aim 1 establishes pharmacokinetic properties of SCFA-nanoparticles and develops a physiologically-based pharmacokinetic model to narrow the translational gap characteristic of oral nanoparticles and enable rational prediction of human behavior. Aim 2 characterizes therapeutic efficacy in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis to determine whether gut-specific SCFA delivery can ameliorate central nervous system autoimmunity.

Work is performed in Seattle, Washington. The period of performance runs through September 15, 2028. The award is a Project Grant, an assistance type supporting investigator-initiated research at the University of Washington's Office of Sponsored Programs.

Abstract

Short-chain fatty acids (scfas) are immunoregulatory metabolites normally produced in high levels by the GUT microbiome. Compromised scfa production upon GUT dysbiosis has recently been associated with multiple sclerosis (MS), a chronic neurodegenerative disease mediated by autoimmune reactions against myelin in the central nervous system (CNS). Both preclinical and clinical evidence show that orally administered scfas can ameliorate CNS autoimmunity, offering a promising approach toward restoring immune homeostasis in MS by leveraging the immunomodulatory activity of the microbiome. However, these studies have employed free scfas, which currently have limited translational potential. As free scfas are rapidly absorbed, their oral administration yields simultaneous exposure in the GUT, circulation, and CNS, making IT unclear where their primary therapeutic actions occur. Moreover, their rapid metabolism requiring clinically unfeasible dosing regimens and foul organoleptic properties pose major challenges for patient compliance. This project was designed to address these barriers to clinical translation using an innovative nanoparticle (NP) formulation that selectively delivers scfas to the distal GUT in a sustained manner. Aim 1 will establish the PK properties of scfa-NPS and develop a physiologically-based pharmacokinetic (pbpk) model of scfa-NP delivery. This work has the potential narrow the translational GAP characteristic of oral NPS by enabling rational predictions of their behavior in humans. Then, aim 2 will characterize the therapeutic efficacy of scfa-NPS in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to determine whether GUT-specific scfa delivery can ameliorate CNS autoimmunity for the first time. Further, as effective MS treatment should be conceptualized as positively modulating the composite patient, comprised of both host cells and the GUT microbiome, this aim will also explore a novel, clinically relevant CO-treatment strategy combining antibiotics with scfa-NPS. In summary, this work will 1) establish a mechanistic framework for the clinical development of GUT-targeted nanomedicines, and 2) advance a paradigm-shifting approach to treating MS centered on restoring GUT-CNS axis homeostasis. Given that there is currently no cure for MS and current treatments are associated with significant side effects, this work aims to forward the next generation of MS therapeutics by harnessing the therapeutic potential of targeting the GUT. In line with the mission of the national institute of allergy and infectious diseases, the principal investigator will contribute fundamental knowledge about the role of the GUT-CNS axis in MS pathogenesis and be prepared to conduct independent research upon completion of the proposed research and training.