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Elucidating the role of short chain fatty acids in gut microbiome dynamics and host response in rheumatoid arthritis

Award Number: K23AR086980
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Elucidating the role of short chain fatty acids in gut microbiome dynamics and host response in rheumatoid arthritis - PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder affecting ~1% of the worldwide population (~2 million adults in the US alone). It is characterized by chronic synovitis that, when left untreated, can result in irreversible joint destruction and deformity, leading to increased morbidity and mortality. Methotrexate (MTX), a widely used disease-modifying antirheumatic drug (DMARD), is the anchor drug for most patients who are recently diagnosed with RA. However, up to 50% of RA patients do not respond adequately to MTX monotherapy and require escalation to other DMARDs and/or biologic targeted medications. The molecular mechanisms involved in MTX response are incompletely understood, but multiple factors are known to contribute, including host genetics and environmental factors. Our preliminary studies have shown that the gut microbiome can serve as a predictor of future MTX response, in part by interindividual variation of microbial composition contributing to differential metabolism of MTX. Additionally, we have shown that the microbially produced short-chain fatty acid, butyrate, modulates microbiota composition and correlates with MTX response. Based on our preliminary studies, our objectives for the K23 proposal are: 1) to identify gut microbial signatures and host signatures that are modulated by butyrate in new onset RA (NORA) and 2) to evaluate the effects of butyrate on microbial MTX metabolism. In Aim 1, we will identify modifiable gut microbial and host immune features that differentiate NORA patients taking butyrate and MTX vs. MTX alone in an established study cohort using shotgun metagenomic and advanced flow cytometry and proteomic techniques. We hypothesize that butyrate supplementation will demonstrate unique microbe-microbe interactions and metabolic pathways not found in patients taking MTX alone. Additionally, butyrate will induce a regulatory immune response in RA patients. In Aim 2, we will investigate the effect of butyrate supplementation on MTX metabolism in the gut focusing on in vivo and ex vivo metabolism. We expect butyrate to either directly or indirectly inhibit microbial MTX metabolism. Also, we will use an in silico approach to validate butyrate’s effects in clinical responders. The PI of this study has prior experience in translational research and publications in the microbiome field and is supported by a dedicated interdisciplinary team of mentors, collaborators and contributors with unique expertise in rheumatology, immunology, bioinformatics, next-generation sequencing technologies and metabolomics. The research and analytic experiences gained from this project, together with the comprehensive training and didactic plan (including hands-on instruction in the laboratories of her mentors and collaborators), will allow the PI to develop the foundation and add necessary skills for becoming an independent translational investigator. Branching out from the proposed project, she will have a unique perspective and robust tools to study how microbial and dietary modifications can achieve effective and personalized therapies in rheumatic conditions which will constitute the basis of a future R01 grant.


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 = $184,896 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/10/2026	NEW	$184,896
														Subtotal = $184,896

Grand Total All Awards = $184,896

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Elucidating the role of short chain fatty acids in gut microbiome dynamics and host response in rheumatoid arthritis

Award Number: K23AR086980

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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