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Targeting the Gut-CNS Axis via Distal Gut-Delivered Short-Chain Fatty Acids to Treat CNS Autoimmunity

Award Number: F31AI194931
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/28/2026
PERIOD OF PERFORMANCE END DATE: 11/27/2027

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Targeting the Gut-CNS Axis via Distal Gut-Delivered Short-Chain Fatty Acids to Treat CNS Autoimmunity - PROJECT SUMMARY/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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $45,521 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	1	5/28/2026	NEW	$45,521
														Subtotal = $45,521

Grand Total All Awards = $45,521

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Targeting the Gut-CNS Axis via Distal Gut-Delivered Short-Chain Fatty Acids to Treat CNS Autoimmunity

Award Number: F31AI194931

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/28/2026

PERIOD OF PERFORMANCE END DATE: 11/27/2027

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