Background/Purpose: The gut microbiome and its metabolites are dysregulated in rheumatoid arthritis. Short chain fatty acids (SCFAs), microbial fermentation byproducts of certain gut microbes, induce regulatory T cells (Treg) that exhibit anti-inflammatory properties. Unsurprisingly, SCFA are found at reduced levels in both murine models of RA and patients. The SCFA butyrate has been shown to increase levels of gut and circulating Treg and ameliorate inflammatory arthritis in murine models. Additionally, we previously noted that SCFA supplementation in WT mice led to significant perturbations in gut bacterial composition with a significant increase in SCFA-producing commensals. Similarly, others have shown that a high-fiber diet increases circulating levels of SCFAs and decreases pro-arthritogenic cytokines (Durholz et al. Nutrients. 2020). We therefore hypothesized that butyrate supplementation may promote favorable gut microbial changes and increase tolerogenic adaptive immune response in RA patients.

Methods: We designed an ongoing, prospective, proof-of-principle study to determine the effects of butyrate supplementation in new-onset RA (NORA) patients. First, we evaluated the effects of butyrate supplementation in healthy subjects (n=7; 1 gm 3 times daily for 14 days). Next, we evaluated the effects of butyrate on new-onset RA (n=5; 1 gm 3 times daily for 30 days) compared to methotrexate (n=20). Clinical history and joint exam were performed at baseline and follow up. Peripheral blood and fecal samples were collected at baseline and follow up for flow cytometric analysis of Treg and 16s rRNA sequencing, respectively. Wilcoxon signed-rank test was used to compare differences in Treg before and after butyrate administration.

Results: Although butyrate supplementation in healthy subjects did not lead to significant community changes by 7 days, it did lead to a significant increase in the percentage of circulating CD4⁺CD25⁺FoxP3⁺ Treg (p=0.02) followed by a significant increase in highly activated CD39⁺ Treg by 14 days (p < 0.0001). Gut bacterial alpha diversity (Shannon index) was significantly lower in NORA patients compared to healthy subjects at baseline (p=0.04; wilcox-test). After butyrate supplementation, NORA alpha diversity increased to levels approaching those of healthy subjects, with a modest increase in abundance of both Firmicutes and Bacteroidetes. LDA Effect Size analysis recapitulated previous studies where healthy subjects had greater abundance of SCFA producing commensals compared to NORA.

Conclusion: In both health and new-onset RA, butyrate supplementation is associated with changes in human gut microbiota composition and in peripheral Treg abundance and markers of Treg activation. In preliminary analyses of this ongoing prospective study, butyrate increased gut microbial diversity in NORA, suggesting that gut microbial composition may shift towards a healthier level of diversity. As seen in murine models, butyrate also increased Treg in healthy subjects. We hypothesize that, in patients, butyrate will induce modifications in gut microbial communities that favor a regulatory adaptive immune response that may ultimately lead to better clinical response.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-short-chain-fatty-acid-supplementation-in-modulation-of-gut-microbiome-and-t-regulatory-cells-in-health-and-new-onset-rheumatoid-arthritis/