Deficiency of Short-Chain Fatty Acids in Acne Vulgaris

寻常痤疮缺乏短链脂肪酸

• 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
• 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

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.

摘要 我们发表的结果首次证明了表皮葡萄球菌(S. 表皮)，一种人类皮肤的共生细菌，其功能是一种益生菌，它利用 碳水化合物发酵抑制皮肤机会型痤疮丙酸杆菌的过度生长 与寻常痤疮有关的细菌。为了增强表皮葡萄球菌击败竞争对手的能力 α-乳糖一水合物是一种选择性发酵引发剂，已被用于 独家触发表皮葡萄球菌的发酵。ALM产生的短链脂肪酸(SCFA) 表皮葡萄球菌发酵能有效抑制痤疮假单胞菌在体外和小鼠体内的生长。因此，我们 假设痤疮皮损中的单链脂肪酸是控制过度生长的痤疮假单胞菌的关键成分。这个 人体皮肤中SCFAs的缺乏可能促进寻常痤疮的进展。 单链脂肪酸将在抗生素后辅助治疗寻常型痤疮中发挥辅助作用。 抗生素后辅助治疗将减少抗生素的所需剂量和副作用。我们有 最近与皮肤科主任Tissa R.Hata博士合作获得了痤疮活检 加州大学圣地亚哥分校(UCSD)临床试验部门。这些痤疮活检已经被用来 建立体外痤疮外植体。SCFA与SCFA/抗生素联合应用的疗效观察 对痤疮假单胞菌生长的抑制和促炎细胞因子的减少将通过EX进行评估 活体痤疮外植体。此外，我们还将探讨SCFA在减少环境污染方面的作用机制。 组蛋白脱乙酰酶(HDAC)抑制引起的炎症性寻常痤疮。 为了验证我们的假设，本文提出了三个具体目标。在具体目标1中，我们将获得 并检测SCFAs对HDAC的抑制作用，以及SCFAs对P.acnes的抑制作用。 粉刺引起的炎症。在具体目标2中，我们将探讨SCFA在以下方面的基本作用 利用SCFA缺陷/无菌小鼠抑制痤疮假单胞菌的生长，并量化 人不同时期寻常痤疮外植体中的单链脂肪酸。在具体目标3中， 我们将{使用人类体外痤疮外植体来评估抗生素后的辅助治疗，使用 抗生素与SCFA或ALM的组合，并检测可能的抗粉刺和毒性活性 超临界脂肪酸。 我们在这里引入了一个新的概念，即痤疮皮损内的益生菌表达碳水化合物。 发酵并产生单链脂肪酸，以重新平衡痤疮的生态失调。如果成功，SCFA自然会 由人体微生物群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。