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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（肠易激综合征的一种症状）的疗法