Background/Purpose: Several intestinal bacteria produce short-chain fatty acids (SCFA) by the fermentation of dietary fibers. SCFA in the intestine differentiate regulatory T (Treg) cells by stabilizing the expression of the master gene, Foxp3. We have reported that SCFA-producing bacteria increased significantly in patients with relapsing polychondritis (RP) (Arthritis Rheumatol. 2017; 69 Suppl 10: 2477–2478.). Here, adding to the metagenomic analysis with newly recruited samples, we evaluated T cell cytokine gene expression titers of peripheral blood mononuclear cells (PBMC) in RP patients and compared the data with those in normal individuals.

Methods: We explored fecal microbiota of 25 patients with RP and 27 normal individuals by sequencing of 16S rRNA gene. The effect size of each bacterium in the two groups were estimated by LEfSe software. We cultured PBMC of 22 RP patients and 11 normal individuals with and without mitogen stimulation and measured T cell cytokine gene expressions of the cells. We measured serum matrix metalloprotease protein (MMP3) concentrations, an RP-related biomarker, in RP patients using an Elisa assay kit.

Results: We found that annotated species numbers were significantly higher in the intestine of RP patients than those of normal individuals. In the RP gut microbiota, we observed several predominant species which were reported to associate with propionate production in human intestine. Propionate was reported to induce IL-10-producing Treg cells in the intestine and we measured IL-10 gene expressions in PBMC of RP patients and normal individuals. We found that IL-10 gene expressions were significantly higher in freshly isolated PBMC of RP patients than those of normal individuals (P < 0.0001). In contrast, 6 hours after the initiation of the PBMC culture, IL-10 gene expressions of RP patients were significantly lower than those of normal individuals, regardless of the presence and absence of the mitogen stimulation (P = 0.0011 and P < 0.0001, respectively). Serum MMP3 concentrations were significantly higher in RP patients than those in normal individuals and correlated well with IL-10 gene expression levels in freshly isolated PBMC of the RP patients (P < 0.0001).

Conclusion: We suggest that propionate continuously stimulates intestinal Treg cells and induce hypo-responsiveness of the cells to antigenic stimulation in RP patients. Treg skewed cells may play a role in the chondritis of RP patients through inappropriate chondrocyte secretion of MMP3.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulatory-t-cells-with-skewed-responses-and-propionate-producing-gut-bacteria-increased-simultaneously-in-patients-with-relapsing-polychondritis/