Development of a therapeutic bacterial consortium for constipation

便秘治疗细菌联盟的开发

• 批准号: 10254559
• 负责人: Philip Peter Strandwitz
• 金额: $ 29.96万
• 依托单位: HOLOBIOME, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-06 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254559
• 关键词: Address; Affect; Age; Agonist; Animals; Anti-Inflammatory Agents; Antibiotic susceptibility; Antibiotics; Bacteria; Biological Assay; Blood specimen; Body Weight; Cecum; Cell Culture Techniques; Cells; Clinical; Constipation; Development; Diet; Diet Modification; Disease; Dose; Dyes; Eating; Effectiveness; Elderly; Engraftment; Enteral; Enteric Nervous System; Etiology; Exhibits; Exposure to; Feces; Fiber; Freeze Drying; Freezing; Future; Gastrointestinal tract structure; Gene Expression; General Population; Germ-Free; Goals; Growth; Health; Human; Immune; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Intestinal Mucosa; Intestines; Inulin; Irritable Bowel Syndrome; Lactobacillus casei rhamnosus; Liquid substance; Maintenance; Measures; Modality; Modeling; Morphine; Morphology; Mus; Neurobiology; Operative Surgical Procedures; Opioid; Oral; Organism; Organoids; Output; Parkinsonian Disorders; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phase; Phenotype; Population; Predisposition; Probiotics; Production; Recovery; Safety; Serotonin; Serotonin Agonists; Serotonin Receptors 5-HT4; Serum; Severities; Signal Transduction; Source; Symptoms; Technology; Testing; Therapeutic; Tissues; Toxin; Tryptamines; Unhealthy Diet; arm; associated symptom; base; cell motility; comorbidity; cytokine; effective therapy; experience; fecal transplantation; feeding; food surveillance; genome sequencing; gut bacteria; gut microbiome; in silico; in vivo Model; liquid chromatography mass spectrometry; manufacturability; meetings; member; metagenomic sequencing; microbiome; microbiome sequencing; microorganism; mouse model; nervous system disorder; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; prebiotics; prescription opioid; programs; screening; side effect; stem; subcutaneous; synergism; therapeutic candidate; therapeutic target; treatment arm

The goal of the proposed project is to develop a probiotic for the treatment of constipation, comprised of 2-3 anti- inflammatory strains of human gut-derived bacteria that enhance host serotonin (5-hydroxytryptamine, 5-HT) production and signaling. By addressing multiple targets associated with the etiology and symptoms of constipation (5-HT signaling and inflammation), we expect the result of this project to have broad utility. Constipation affects up to 20% of the general population, with rates even higher in the elderly, and comes in many forms ranging in severity. The most severe form, slow transit constipation (STC), affects ~15 to 30% of constipated patients. Less severe, but still representing a significant societal burden, are irritable bowel syndrome with constipation (IBS-C) and age-associated constipation. Constipation is also a major side effect of opioid medications, and is comorbid with neurological diseases including Parkinsonian syndromes. The etiology is multifarious, often involving a dysfunctional enteric nervous system, poor diet, and inflammation, but in many cases it is still poorly understood. Current treatment options are generally poor and include dietary modifications, pharmacological interventions, and—for severe forms like STC—surgery. As such, novel treatment options are needed, preferably those that can engage multiple therapeutic targets. One source of new therapeutics is the gut microbiome: the bacteria that reside in the gastrointestinal tract. These symbiotic organisms are involved in numerous components of health and disease, including development and maintenance of the immune and enteric nervous systems. Recently, it has been shown by a member of Holobiome’s team that the gut microbiome is a major regulator of host enteric 5-HT signaling: Germ free mice have a 50% reduction in serum 5-HT and have constipation, both of which can be corrected via recolonization with a normal microbiome or a human- derived consortium. It has also been shown that constipation in humans can be transferred into animals via fecal microbiome transplant; a phenotype that is driven via disrupted enteric 5-HT signaling and inflammation. This suggests a clear intervention strategy: deliver anti-inflammatory, 5-HT-modulating bacteria to the gut. In our preliminary studies we screened a proprietary panel of over 100 non-pathogenic species of human gut bacteria for the ability to modulate 5-HT in a cell culture model. We identified 17 bacterial strains with the capability to modulate 5-HT signaling via four mechanisms. In this Phase 1 application we seek to further test these strains as candidates for a 5-HT modulating and anti-inflammatory consortium. To do this, strains will first be profiled for safety and manufacturability in vitro and in silico. Strains meeting these criteria will be assembled into candidate consortia of 2-3 strains, which will be further optimized to impact 5-HT release and inflammation. These will be advanced for testing in mouse models of constipation to assess efficacy, safety, and engraftment. The most promising consortium will be further tested in PK/PD and dosing studies supported in a Phase 2 program.

拟议项目的目标是开发一种用于治疗便秘的益生菌，由2-3种抗-3 增强宿主5-羟色胺(5-羟色胺，5-羟色胺)的人肠道来源细菌的炎性菌株 生产和信号传递。通过解决与致病原因和症状相关的多个目标 便秘(5-羟色胺信号和炎症)，我们期待这个项目的结果具有广泛的实用价值。 便秘影响了高达20%的总人口，老年人的便秘发生率更高，而且 许多形式的严重程度不一。最严重的形式是慢传输型便秘(STC)，影响大约15%到30%的人 便秘患者。肠易激症状不那么严重，但仍是一个重大的社会负担。 便秘综合征(IBS-C)和年龄相关性便秘。便秘也是一种主要的副作用。 阿片类药物，并与包括帕金森综合征在内的神经系统疾病并存。病因学 是多种多样的，通常涉及肠道神经系统功能障碍，不良饮食和炎症，但在许多 人们对此仍知之甚少。目前的治疗选择通常很差，包括改变饮食， 药物干预，以及--对于像STC这样的严重形式--手术。因此，新的治疗选择是 需要的，最好是那些可以吸引多个治疗靶点的。新疗法的一个来源是 肠道微生物群：驻留在胃肠道中的细菌。这些共生生物参与了 健康和疾病的许多组成部分，包括发展和维持免疫和 肠道神经系统。最近，Holobiome团队的一名成员表明，肠道微生物群 是宿主肠道5-羟色胺信号的主要调节因子：无菌小鼠血清5-羟色胺降低50%， 便秘，这两种疾病都可以通过正常微生物群的再繁殖或人类- 派生财团。研究还表明，人类的便秘可以通过粪便传染给动物。 微生物组移植；一种由肠道5-羟色胺信号中断和炎症驱动的表型。这 建议一个明确的干预策略：将抗炎的5-羟色胺调节细菌输送到肠道。在我们的 初步研究我们筛选了100多种非致病的人类肠道细菌的专有小组。 在细胞培养模型中调节5-羟色胺的能力。我们鉴定了17株细菌，它们能够 通过四种机制调控5-羟色胺信号转导。在这个第一阶段的应用中，我们寻求进一步测试这些菌株 作为5-羟色胺调节和抗炎联盟的候选人。要做到这一点，首先要对菌株进行分析 在体外和硅胶中的安全性和可制造性。符合这些标准的菌株将被组装成候选菌株 由2-3个菌株组成的联合体，将进一步优化以影响5-羟色胺的释放和炎症。这些将是 用于小鼠便秘模型的测试，以评估有效性、安全性和植入性。最多的 有希望的财团将在PK/PD和第二阶段计划支持的剂量研究中进行进一步测试。