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

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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.