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.

抽象的 结果首次证明了葡萄球菌表皮（S. 表皮），一种人类皮肤的共生细菌，起着益生菌的作用 碳水化合物发酵以限制痤疮丙酸杆菌的过度生长，这是皮肤机会主义的 与痤疮的细菌相关。增强S. epidermidis击败竞争对手的能力 （P.痤疮），选择性发酵引发剂的α-乳糖一水合物（ALM）已用于 仅触发表皮链球菌的发酵。 ALM产生的短链脂肪酸（SCFA） 表皮链球菌的发酵有效地抑制了体外和小鼠痤疮假单胞菌的生长。我们这样 假设痤疮病变中的SCFA是控制肥大的P.痤疮的关键组成部分。这 人类皮肤中SCFA的缺乏可能会促进痤疮粉刺的进展。 SCFA将充当抗生素调节后治疗痤疮的调节剂。 抗生素调节后的疗法将减少抗生素所需的剂量和副作用。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）的临床试验部门。这些痤疮活检已习惯 建立离体痤疮外植体。 SCFA或SCFA/抗生素组合的有效性 抑制痤疮疟原虫生长和促炎细胞因子的降低将通过EX进行评估 体内痤疮外植体。此外，我们将探讨SCFA在还原方面的作用机制 通过抑制组蛋白脱乙酰基酶（HDAC），炎症性痤疮张开。 提出了三个具体目标来验证我们的假设。在特定目标1中，我们将获得 P. acnes选择性SCFA，并检查SCFA抑制HDAC在P.还原中的作用。 痤疮引起的炎症。在特定目标2中，我们将探讨SCFA在 使用SCFA缺乏/无菌小鼠抑制痤疮疟原虫生长，并量化 人体外痤疮外植体中的SCFA来自痤疮的不同阶段。在特定的目标3中 我们将使用人体外痤疮外植体来评估抗生素调节疗法 抗生素和SCFA或ALM的组合，检测可能的抗肌和有毒活性 scfas。} 我们在这里介绍了一个新概念，即痤疮病变中的益生菌细菌表达碳水化合物 发酵并产生SCFA，以重新平衡痤疮营养不良。如果成功的话，SCFA自然而然 人类微生物组中的共生细菌可以用作抗生素调节剂的 治疗各种人类感染。