Deficiency of Short-Chain Fatty Acids in Acne Vulgaris

寻常痤疮缺乏短链脂肪酸

基本信息

批准号：
9316161
负责人：
CHUN-MING HUANG
金额：
$ 20.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-07 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316161
关键词：
Abscess Acne Acne Vulgaris Adjuvant Adjuvant Therapy Adverse effects Anaerobic Bacteria Anti-Inflammatory Agents Anti-inflammatory Antibiotic Therapy Antibiotics Attenuated Bacteria Bacterial Infections Bacterial Interference Bacterial Model Biological Biopsy Butyrates Butyric Acids California Carbohydrates Cells Cellulitis Clinical Trials Unit Collaborations Combined Antibiotics Dermatologic Dermatology Dose Ecosystem Effectiveness Fermentation Fruit Generations Germ-Free Glycerol Growth Health Histone Deacetylase Histone Deacetylase Inhibitor Homeostasis Human Human Microbiome Immunization Immunosuppression In Vitro Infection Inflammation Inflammatory Intestines Lactose Lesion Lipopolysaccharides Meningitis Microbe Modeling Mus Operative Surgical Procedures Osteomyelitis Patients Probiotics Prodrugs Production Propionibacterium acnes Publications Pus Reporting Resistance Role Skin Staphylococcus epidermidis Starch Succinic Acids TNF gene Time United States Environmental Protection Agency United States Food and Drug Administration Universities Vaccines Volatile Fatty Acids antimicrobial bactericide clinical development commensal microbes cytokine fighting gastrointestinal system killings microbiome microorganism neutrophil novel strategies pathogen preclinical development skin microbiome sugar ward

项目摘要

Abstract Results in our publication demonstrate for the first time that Staphylococcus epidermidis (S. epidermidis), a commensal bacterium of the human skin, functions as a probiotic bacterium that employs carbohydrate fermentation to restrain the over-growth of Propionibacterium acnes, a skin opportunistic bacterium associated with acne vulgaris. To intensify the ability of S. epidermidis to beat out its competitor (P. acnes), the α-lactose monohydrate (ALM), a selective fermentation initiator, has been used to exclusively trigger the fermentation of S. epidermidis. Short-chain fatty acids (SCFAs) produced by ALM fermentation of S. epidermidis effectively suppress the growth of P. acnes in vitro and in mice. We thus hypothesize that SCFAs within acne lesions are key components to rein in the overgrown P. acnes. The deficiency of SCFAs in human skin may promote the progression of acne vulgaris. SCFAs will act as adjuvants in the post-antibiotic adjuvant therapy for treatment of acne vulgaris. The post-antibiotic adjuvant therapy will reduce the required dose and side-effects of antibiotics. We have recently obtained acne biopsies in collaboration with Dr. Tissa R. Hata, a Director of the Dermatology Clinical Trials Unit at University of California, San Diego (UCSD). These acne biopsies have been used to establish ex vivo acne explants. The effectiveness of SCFA or the SCFA/antibiotic combination on suppression of P. acnes growth and reduction of pro-inflammatory cytokines will be evaluated by using ex vivo acne explants. Furthermore, we will explore the action mechanism of SCFAs on reduction of inflammatory acne vulgaris via inhibition of histone deacetylase (HDAC). Three Specific Aims are proposed to validate our hypothesis. In Specific Aim 1, we will obtain the P. acnes-selective SCFAs, and examine the role of the inhibition of HDAC by SCFAs in the reduction of P. acnes-induced inflammation. In Specific Aim 2, we will explore the essential roles of SCFAs in the inhibition of P. acnes growth using SCFA-deficient/germ-free mice, and quantify the concentrations of SCFAs in human ex vivo acne explants derived from different stages of acne vulgaris. In Specific Aim 3, we will {use the human ex vivo acne explants to evaluate the post-antibiotic adjuvant therapy using the combination of antibiotic and SCFA or ALM, and detect the possible anti-comedogenic and toxic activities of SCFAs.} We here introduce a new concept that probiotic bacteria within acne lesions express carbohydrate fermentation and produce the SCFAs to rebalance the acne dysbiosis. If successfully, SCFAs naturally produced by commensal bacteria in the human microbiome can be used as antibiotic adjuvants for treatment of various human infections.

抽象的我们出版物中的结果首次证明表皮葡萄球菌 (S. epidermidis) epidermidis）是一种人类皮肤的共生细菌，具有益生菌的功能，利用碳水化合物抑制痤疮丙酸杆菌的过度生长，痤疮丙酸杆菌是一种皮肤机会性细菌增强表皮葡萄球菌击败其竞争对手的能力。（痤疮丙酸杆菌），α-乳糖一水合物 (ALM)，一种选择性发酵引发剂，已被用于专门触发 ALM 产生的短链脂肪酸 (SCFA) 的发酵。我们因此研究发现痤疮病变内的 SCFA 是控制过度生长的痤疮丙酸杆菌的关键成分。人体皮肤中 SCFA 的缺乏可能会促进寻常痤疮的进展。 SCFA 将在治疗寻常痤疮的抗生素后辅助治疗中充当佐剂。抗生素后辅助治疗将减少抗生素的所需剂量和副作用。最近与皮肤科主任 Tissa R. Hata 博士合作进行了痤疮活检加州大学圣地亚哥分校 (UCSD) 的临床试验单位已使用这些痤疮活组织检查。建立离体痤疮外植体或 SCFA/抗生素组合对痤疮的有效性。将通过使用前评估对痤疮丙酸杆菌生长的抑制和促炎细胞因子的减少此外，我们将探讨 SCFA 减少痤疮外植体的作用机制。通过抑制组蛋白脱乙酰酶 (HDAC) 来治疗炎症性寻常痤疮。提出了三个具体目标来验证我们的假设。在具体目标 1 中，我们将获得：痤疮丙酸杆菌选择性 SCFA，并检查 SCFA 抑制 HDAC 在减少痤疮丙酸杆菌中的作用。在具体目标 2 中，我们将探讨 SCFA 在痤疮引起的炎症中的重要作用。使用缺乏 SCFA/无菌小鼠抑制痤疮丙酸杆菌生长，并量化痤疮丙酸杆菌的浓度在特定目标 3 中，来自寻常痤疮不同阶段的人体外痤疮外植体中的短链脂肪酸 (SCFA)。我们将{使用人类离体痤疮外植体来评估抗生素后辅助治疗抗生素与 SCFA 或 ALM 的组合，并检测可能的抗粉刺和毒性活性 SCFA。} 我们在这里介绍一个新概念，痤疮皮损内的益生菌表达碳水化合物如果成功的话，SCFA 自然会由人类微生物组中的共生细菌产生的可用作抗生素佐剂治疗各种人类感染。