Short chain fatty acids: Master regulators of cutaneous immunity and potential candidates for therapeutic interventions

有证据表明，肠道共生微生物通过结肠中调节性T细胞（Treg）的扩张影响粘膜免疫系统。这是通过短链脂肪酸（SCFA）介导的，短链脂肪酸是纤维发酵过程中产生的细菌代谢产物，包括丁酸盐、丙酸盐和醋酸盐。我们假设共生皮肤细菌产生的SCFA也可能激活常驻皮肤Treg，其活性在某些炎症性皮肤病中减弱。局部应用丁酸钠对小鼠变应性接触性皮炎有抑制作用。这种效应与Treg的诱导/激活有关。在吡喹莫德诱导的牛皮癣样皮肤炎症小鼠模型中也观察到类似的有益作用。在本提案中，应研究其他SCFA如丙酸盐或醋酸盐是否具有类似的抗炎功能。SB似乎直接影响T细胞并将其转变为调节性表型。其潜在的分子机制有待阐明。此外，SB是否也影响抗原提呈细胞还有待研究。局部应用SB似乎也发挥全身抗炎作用。通过过继转移实验和转基因小鼠（DEREG， hca2敲除小鼠），阐明SB产生这种意想不到的效果的机制。为了阐明SB在人体系统中的作用，应在体内用SB治疗来自过敏性接触性皮炎反应和银屑病斑块的活检，并分析其原位变化。SB似乎可以逆转银屑病患者的Treg活性。应证实这些初步观察结果，并阐明其潜在机制。该项目将明确SCFA是否是利用Treg抗炎的合适化合物，并为未来的临床研究奠定基础，最终评估这些化合物的治疗潜力。

There is evidence that gut commensal microbes affect the mucosal immune system via expansion of regulatory T cells (Treg) in the colon. This is mediated via short-chain fatty acids (SCFA), bacterial metabolites generated during fiber fermentation, which include butyrate, propionate, and acetate. We postulated that SCFA produced by commensal skin bacteria may also activate resident skin Treg, the activity of which is diminished in certain inflammatory dermatoses. Sodium butyrate (SB) applied topically was found to suppress allergic contact dermatitis in mice. This effect was associated with the induction/activation of Treg. A similar beneficial effect of SB was observed in imiquimod-induced inflammation, an established murine model of psoriasis-like skin inflammation. In this proposal it shall be studied whether other SCFA like propionate or acetate exert similar anti-inflammatory features. SB appears to directly affect T cells and to shift them into a regulatory phenotype. The underlying molecular mechanisms shall be clarified. In addition, it shall be studied whether SB also affects antigen-presenting cells. Topically applied SB appears to exert also systemic anti-inflammatory effects. It shall be clarified by which mechanisms SB exerts this unexpected effect by utilizing adoptive transfer experiments and transgenic mice (DEREG, HCA2-knock-out mice). To elucidate the effects of SB in the human system, biopsies from allergic contact dermatitis reactions and psoriatic plaques shall be treated ex vivo with SB and the in situ changes shall be analyzed. SB appears to reverse the mitigated activity of Treg from psoriasis patients. These preliminary observations shall be confirmed and the underlying mechanisms shall be elucidated. Together this project shall clarify whether SCFA are suitable compounds to harness Treg for anti-inflammatory purposes and be the basis for future clinical studies, finally evaluating the therapeutic potential of these compounds.