Skin Microbiome Editing with Fermentation Initiator

使用发酵引发剂编辑皮肤微生物组

• 批准号: 9407254
• 负责人: CHUN-MING HUANG
• 金额: $ 22.5万
• 依托单位: SURFACE BIOADVANCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407254
• 关键词: Abscess; Acne; Acne Vulgaris; Aerobic; Anaerobic Bacteria; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Bacteria; Bacteriophages; Biological; Biopsy; Butyric Acids; California; Carbohydrates; Carbon; Charge; Clinic; Clinical; Clinical Trials Unit; Collaborations; DNA; Dermatologic; Dermatology; Development; Disadvantaged; Disease; Effectiveness; FDA approved; Fees; Fermentation; Generations; Glucose; Glycerol; Goals; Growth; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Homeostasis; Human; Human Microbiome; Immunosuppression; In Vitro; Individual; Inflammation; Inflammatory; Lactose; Lesion; Microbe; Nonesterified Fatty Acids; Operative Surgical Procedures; Pathogenicity; Patients; Pattern; Polyethylene Glycols; Probiotics; Propionibacterium acnes; Publications; Reporting; Research; Resistance; Role; Services; Site; Skin; Source; Staphylococcus epidermidis; Surface; Symbiosis; Techniques; Technology; Testing; Transdermal substance administration; Universities; Virulence Factors; Volatile Fatty Acids; bactericide; base; biomaterial compatibility; cytokine; design; experimental study; fighting; in vivo; killings; microbial; microbiome; microorganism; pathogen; receptor; skin microbiome

Abstract Acne dysbiosis is defined as microbial imbalance with the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. We have demonstrated that Staphylococcus epidermidis (S. epidermidis), a probiotic bacterium co-existed with P. acnes in an acne lesion, can exploit the carbohydrate fermentation to produce short-chain fatty acids (SCFAs) and rein in the over-growth of P. acnes. In collaboration with Surface Bioadvances Inc. in San Diego, we have developed polyethylene glycol dimethacrylate (PEG-DMA), α-Lactose monohydrate (ALM), and propargyl-PEG5-tetra-Ac-beta-D-glucose as selective fermentation initiators (SFIs) which can specifically intensify fermentation activity of S. epidermidis, but not P. acnes. In this proposal, we will synthesize various PEG-carbohydrate conjugates as SFIs and identify the most potent SFI for rebalancing the dysbiotic acne vulgaris. The effects of SFIs on the suppression of P. acnes growth and reduction of {P. acnes-induced inflammation} will be investigated. We have recently obtained acne biopsies in partnership 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 SFIs on suppression of P. acnes growth and reduction of pro-inflammatory cytokines will be tested by using ex vivo acne explants. Three Specific Aims are proposed to verify our hypothesis. In Specific Aim 1, we will compare the differential potencies of PEG macromers and their carbohydrate conjugates as SFIs for S. epidermidis, and investigate the broad-spectrum capability of SFI fermentation in growth inhibition of various clinical P. acnes strains. In Specific Aim 2, we will determine the efficacy of SFI fermentation for treatment of different inflammatory stages of acne vulgaris, {and examine the effect of SFI fermentation on the bacterial abundance in the acne microbiome.} In Specific Aim 3, we will {compare the anti-P. acnes potency of SFIs with SCFAs,} and explore the possible anti-comedogenic or toxic activities of SFIs. We envision that SFIs are able to specifically intensify the probiotic ability of S. epidermidis, produce SCFAs to “beat” out its competitor (P. acnes). {The use of SFI to initiate fermentation of probiotic S. epidermidis can avoid difficulty in determining how many SCFAs in a mixture can be formulated as anti-P. acnes agents.} When successful, the SFI will be {the first fermentation initiator that can edit/reshape dysbiotic microbiome without using live microorganisms such as live bacteria or bacteriophages.}

摘要 痤疮微生态失调是指痤疮丙酸杆菌过度生长导致的微生物失衡 (P.痤疮）在痤疮微生物组中。我们已经证明表皮葡萄球菌（S。表皮）， 一种益生菌与痤疮丙酸杆菌共存于痤疮病变中， 以产生短链脂肪酸（SCFA）并控制痤疮丙酸杆菌的过度生长。协同 Surface Bioadvances Inc.在圣地亚哥，我们开发了聚乙二醇二甲基丙烯酸酯（PEG-DMA）， α-乳糖一水合物（ALM）和炔丙基-PEG 5-四-Ac-β-D-葡萄糖作为选择性发酵 引发剂（SFIs）可以特异性地增强S.表皮丙酸杆菌，而非痤疮丙酸杆菌。在 在这个建议中，我们将合成各种PEG-碳水化合物缀合物作为SFI，并确定最有效的 SFI用于重新平衡失调的寻常痤疮。SFI对痤疮丙酸杆菌生长的抑制作用 并研究{痤疮丙酸杆菌诱导的炎症}的减少。我们最近得了痤疮 与蒂萨R.哈塔说， 位于加州圣地亚哥（UCSD）。这些痤疮活检已被用于建立离体痤疮外植体。 SFI抑制痤疮丙酸杆菌生长和减少促炎细胞因子的有效性 将通过使用离体痤疮外植体进行测试。 提出了三个具体目标来验证我们的假设。在具体目标1中，我们将比较 PEG大分子单体及其碳水化合物缀合物作为SFI对S.表皮，和 研究SFI发酵对各种临床痤疮丙酸杆菌生长抑制的广谱能力 菌株在具体目标2中，我们将确定SFI发酵用于治疗不同的 寻常痤疮的炎症阶段，{并检查SFI发酵对细菌丰度的影响 在痤疮微生物组中。在具体目标3中，我们将{比较SFI与SCFA的抗痤疮丙酸杆菌效力，} 并探索SFI可能的抗粉刺或毒性活性。 我们设想SFI能够特异性地增强S.表皮产生 SCFAs“击败”其竞争对手（痤疮丙酸杆菌）。{The使用SFI启动益生菌S的发酵。 epidermidis可以避免难以确定混合物中有多少SCFA可以配制成抗-P。 痤疮剂。}当成功时，SFI将是{可以编辑/重塑的第一个发酵引发剂 在不使用活的微生物如活的细菌或噬菌体的情况下，微生态失调的微生物组。