皮肤菌群代谢产物丙酸对瘙痒的调控及其在特应性皮炎中的作用研究

瘙痒是特应性皮炎(AD)的基本特征，AD瘙痒机制的研究多集中于炎症致痒机制，发现IL-4、IL-31等是瘙痒的重要介质。近期瘙痒的负向调控机制开始引起关注，但仍尚知甚少。我们前期发现AD患者皮肤菌群脂肪酸代谢降低，其代谢产物丙酸的水平低于正常人，并发现丙酸显著抑制小鼠慢性瘙痒、抑制IL-4介导的背根神经节(DRG)神经元的活化。基于以往发现丙酸对神经的广泛作用，且外周感觉神经元表达丙酸受体GPR41，我们提出假说认为丙酸直接作用于痒觉神经元，通过抑制瘙痒通道活化、神经元递质合成而调控瘙痒，参与AD炎症控制。本项目拟深入研究丙酸对小鼠非炎症瘙痒模型的作用，挖掘丙酸对DRG神经元活化作用的分子机制，明确丙酸对致痒通路的调控及其机制，探索丙酸通过调控瘙痒在AD炎症中的作用。本研究首次从皮肤菌群-神经免疫的角度探索AD瘙痒的负向调控机制，有望建立通过直接抑制痒觉神经元活化来治疗AD瘙痒的新策略。

Pruritus is an important character of atopic dermatitis (AD), and the mechanistic studies of it are mainly focused on inflammation, such as IL-4 and IL-31 which are proven to be major mediators. The negative regulations on pruritus are getting more interests recently, but there are still very little progresses. Our group found that the levels of fatty acid metabolisms of skin microbiota were decreased in AD patients, especially propionic. Propionic could inhibit chronic pruritus in mouse model significantly, as well as ameliorate IL-4 induced dorsal root ganglion (DRG) neurons activation. Based on previous reported the extensive effects of propionic on neurons, and the fact that receptor of propionic such as GPR41 is expressed on neurons, we put forward to a hypothesis that propionic can act on itchy neurons directly, inhibit pruritus channel activation and neurotransmitters synthesis, those of the mechanisms regulate pruritus and control the skin inflammation of AD. This project is aimed to study the following aspects: ①effects of propionic on non-inflammation pruritus mouse model; ②molecular mechanisms of DRG activation by propionic; ③regulatory mechanisms of propionic on the common itching pathways; ④effects of propionic on AD inflammation through regulating pruritus. According to our knowledge, this project is the first study on the negative regulations of pruritus from the view of skin microbiota-neuroimmune interaction. Through the research, we hope to build a fully new treatment strategy for pruritus of AD by inhibiting itchy neurons activation directly.