Development of therapeutic GABA-producing bacteria - 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.
