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.
Public Health Relevance Statement: The goal of this project is to develop new therapies for symptoms of irritable bowel syndrome, depression, and anxiety. Bacteria, isolated from healthy humans, will be tested for the ability to safely treat these diseases in established animal models, which are predictive of effectiveness in humans.
NIH Spending Category: Behavioral and Social Science; Brain Disorders; Chronic Pain; Complementary and Integrative Health; Depression; Mental Health; Mental Illness; Microbiome; Neurosciences; Pain Research
Project Terms: Abdomen; Adult; Affect; Anhedonia; Animal Model; Animals; Antibiotic Resistance; Antibiotic susceptibility; Anxiety; anxiety symptoms; anxiety-like behavior; Bacteria; Behavior; Behavior assessment; Biological; Brain; Cecum; Cerebrum; Characteristics; Coculture Techniques; Collaborations; colorectal distension; Communication; Communities; Consult; depression model; depressive symptoms; Development; Disease; Disease model; Dose; drug development; drug discovery; Effectiveness; efficacy testing; Engraftment; Enteral; Exhibits; Feces; forced swim test; gabapentin; gamma-Aminobutyric Acid; Gastrointestinal tract structure; Genes; Genome; Germ-Free; Goals; Grooming; Growth; gut bacteria; gut microbiome; gut-brain axis; habituation; Health; Human; Immune; Immune response; improved; In Vitro; in vivo; Individual; interest; Intervention; Intervention Studies; Intestines; Irritable Bowel Syndrome; Kinetics; learned behavior; Marble; maternal separation; Measures; Mental Depression; metabolome; microbial; microbiome; microbiome sequencing; Modality; Modeling; Moods; nervous system disorder; Neuraxis; neurodevelopment; Neurosciences; Neurotransmitters; novel; novel therapeutics; Oral; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Population; prebiotics; preference; pregabalin; Probiotics; Production; Rattus; receptor; Reflex action; repetitive behavior; resistance gene; response; Rodent; Rodent Model; Safety; safety study; Serum; Source; Specialist; stem; Stress; Sucrose; symptomatic improvement; Symptoms; Testing; Therapeutic; therapeutic candidate; therapeutic development; therapeutic evaluation; Toxin; transcriptome; Treatment Efficacy; treatment group; Vagotomy; Validation; Visceral pain; Withdrawal
