Development of therapeutic GABA-producing bacteria

治疗性 GABA 产生细菌的开发

基本信息

批准号：
10159244
负责人：
Jack Anthony Gilbert
金额：
$ 66.76万
依托单位：
HOLOBIOME, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159244
关键词：
Abdomen Adult Affect Anhedonia Animal Model Animals Antibiotic Resistance Antibiotic susceptibility Anxiety Bacteria Behavior Behavior assessment Biological Brain Cecum Cerebrum Characteristics Coculture Techniques Collaborations Communication Communities Consult Development Disease Disease model Dose Effectiveness Engraftment Enteral Exhibits Feces Gastrointestinal tract structure Genes Genome Germ-Free Goals Grooming Growth Health Human Immune Immune response In Vitro Individual Intervention Intervention Studies Intestines Irritable Bowel Syndrome Kinetics Marble Measures Mental Depression Modality Modeling Moods Neuraxis Neurosciences Neurotransmitters Oral Organism Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Physiological Population Probiotics Production Rattus Reflex action Rodent Rodent Model Safety Serum Source Specialist Stress Sucrose Symptoms Testing Therapeutic Toxin Treatment Efficacy Vagotomy Validation Visceral pain Withdrawal anxiety symptoms anxiety-like behavior colorectal distension depression model depressive symptoms drug development drug discovery efficacy testing forced swim test gabapentin gamma-Aminobutyric Acid gut bacteria gut microbiome gut-brain axis habituation improved in vivo interest learned behavior maternal separation metabolome microbial microbiome microbiome sequencing nervous system disorder neurodevelopment novel novel therapeutics prebiotics preference pregabalin receptor repetitive behavior resistance gene response safety study stem symptomatic improvement therapeutic candidate therapeutic development therapeutic evaluation transcriptome treatment group

项目摘要

The goal of this project is to develop therapeutics to treat visceral pain (a symptom of irritable bowel syndrome – IBS), depression or anxiety by delivering bacteria capable of altering host GABAergic activity. IBS affects between 10-20% of the U.S. population. Depression affects up to 9% of adults in the U.S. per year, with anxiety affecting an estimated 10-29% of people in their lifetime. There are limited drugs for IBS, and roughly 50% of patients with depression or anxiety do not respond to front-line drugs, highlighting the need to exploring new therapeutic modalities. One potential source of new therapeutics is the gut microbiome – the bacteria that reside in the gastrointestinal tract. These symbiotic organisms have been shown to be involved in numerous components of health and disease, including neurodevelopment, brain development, and mood. A key mechanism for communication along the gut-brain-axis is the modulation of neurotransmitters by gut bacteria. Of interest is the ability of the microbiome to produce levels of the neurotransmitter GABA. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system and low levels and/or GABAergic dysregulation are associated with numerous diseases, including IBS, depression, stress, and altered brain development. Gut bacteria have been shown to produce GABA, germ-free animals have reduced GABA levels, and microbiome intervention in humans can alter serum GABA levels, suggesting the microbiome contributes to host levels. Importantly, interventional studies in rodents with bacteria capable of producing GABA has showed efficacy in improving symptoms of anxiety, depression, and visceral pain, as well as modulating GABAergic activity in the brain, suggesting microbial derived GABA is important. However, these previous efforts have failed to identify abundant bacteria from the human gut capable of producing GABA at a physiologically relevant pH for the human GI tract (5.7-7.4), which are likely the organisms contributing most to host GABA levels and/or GABAergic activity. In our preliminary studies, we developed a screen to identify novel GABA producing bacteria, capable of producing GABA at a physiologically relevant pH, found some of these organisms express genes involved with GABA production in healthy people, and are reduced in individuals with depression and IBS. In Phase 1 of this proposal, the GABA-producing, safety, and development profiles of these strains will be examined. Strains shown to exhibit strong developmental potential around these criteria will then be introduced in candidate therapeutic consortia in a human gut simulator model to study engraftment and GABA production capabilities in a mock human community. Consortia showing strong results in the gut simulator will then be tested in a pilot rat study to assess their ability to increase levels of systemic GABA, alter the GABAergic response, and engraft. Successful modulation of GABA/GABAergic activity by GABA producing bacteria will provide proof of principle to explore therapeutic efficacy and mechanism validation in Phase 2 in animal models of visceral pain, depression, and anxiety.

该项目的目标是开发治疗内脏疼痛（肠易激综合症的症状）的疗法 – IBS），通过传递能够改变宿主 GABA 活性的细菌来影响 IBS，从而导致抑郁或焦虑。每年有 10-20% 的美国人患有抑郁症，其中 9% 的成年人患有抑郁症。据估计，焦虑症影响着 10-29% 的人一生。治疗 IBS 的药物有限，而且大致有限。 50% 的抑郁或焦虑患者对一线药物没有反应，凸显了探索的必要性新治疗方法的一个潜在来源是肠道微生物组——产生这种现象的细菌。这些共生生物存在于胃肠道中，已被证明与多种疾病有关。健康和疾病的组成部分，包括神经发育、大脑发育和情绪。沿着肠脑轴的通讯机制是肠道细菌对神经递质的调节。令人感兴趣的是微生物组产生神经递质 GABA 水平的能力是主要的。哺乳动物中枢神经系统中的抑制性神经递质，水平较低和/或 GABA 能失调与许多疾病有关，包括肠易激综合症、抑郁症、压力和大脑疾病肠道细菌已被证明可以产生 GABA，无菌动物的 GABA 水平会降低，人类微生物组干预可以改变血清 GABA 水平，表明微生物组有助于重要的是，对能够产生 GABA 的细菌进行的啮齿类动物干预研究已取得进展。在改善焦虑、抑郁和内脏疼痛症状以及调节大脑中的 GABA 活性表明微生物来源的 GABA 很重要。未能从人类肠道中鉴定出大量能够在一定时间内产生 GABA 的细菌。人类胃肠道的生理相关 pH 值 (5.7-7.4)，这可能是对在我们的初步研究中，我们开发了一种筛选方法来识别宿主 GABA 水平和/或 GABA 活性。新型 GABA 产生细菌能够在生理相关 pH 值下产生 GABA，发现了一些这些生物在健康人体内表达与 GABA 产生有关的基因，并且在患有抑郁症和肠易激综合症的个体在该提案的第一阶段中，GABA 的产生、安全性和将检查这些菌株的发育概况，显示其具有强大的发育潜力。然后围绕这些标准将被引入人类肠道模拟器模型的候选治疗联盟中研究模拟人类群落中的植入和 GABA 生产能力。肠道模拟器中的强劲结果将在试点大鼠研究中进行测试，以评估其提高水平的能力系统性 GABA，改变 GABA 能反应，并成功调节 GABA/GABA 能。产生 GABA 的细菌的活性将为探索治疗功效和内脏疼痛、抑郁和焦虑动物模型的第二阶段机制验证。