Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.

Fermented foods are consumed in several cultures worldwide and their health benefits are being increasingly reported. Fermented soybean products in Asia include soybean paste (doenjang), fermented soybeans (cheonggukjang), red pepper paste (gochujang, GCJ), and natto. These fermented foods are reportedly associated with health benefits, including the alleviation of colitis and improvement of immune function. In this study, we investigated the immune-enhancing effects of GCJs produced in four different regions of Korea (including a commercial brand) in cyclophosphamide-treated immunosuppressed rats. The GCJs-treated group showed prevention of weight loss, increased levels of butyric acid in the cecum, and increased weight of lymphoid organs such as the thymus and spleen. Whole blood and serum analysis revealed increased numbers of white blood cells, including granulocytes and lymphocytes, pro-inflammatory cytokines (IL-2, IL-12, IFN-γ, and TNF-α), and elevated immunoglobulin G levels. Additionally, splenocyte proliferation, splenic natural killer cell activity, and immune-related signal pathways (MAPK and NF-κB) were increased. Histological analysis revealed improved tissue structure in the GCJs group. In conclusion, these findings show that GCJs enhance immune function by promoting the growth of immune organs, increasing cytokine production, and activating immune-related signaling pathways. These results suggested the potential of traditional Korean GCJs as a dietary intervention to improve immune health.

Fermented soybean-based foods contain diverse bioactive compounds with recognized health benefits. Among them, doenjang is widely consumed in East Asia and has been associated with protective effects against several disorders, including immunosuppression. This study evaluated the immunoenhancing effects of doenjang sourced from four regions of Korea in cyclophosphamide (CP)-induced immunosuppressed rats. Four-week doenjang administration restored spleen weight and improved hematological parameters, including white blood cell, lymphocyte, neutrophil, and monocyte counts. Additionally, doenjang intake enhanced immune function, as evidenced by increased splenic natural killer cell activity, increased splenocyte proliferation under lipopolysaccharide- and concanavalin A-stimulated conditions, and higher levels of interleukin (IL)-2, IL-12, interferon-γ, and immunoglobulin G. Furthermore, the suppressed phosphorylation of mitogen-activated protein kinases/nuclear factor kappa B signaling was recovered, accompanied by improved splenic structure. Collectively, our findings demonstrate that the regional varieties of doenjang effectively mitigate CP-induced immune dysfunction, indicating their potential as functional dietary interventions.