Development of therapeutic GABA-producing bacteria

The goal of this project is to develop therapeutics to treat visceral paina symptom of irritable bowel syndromeIBSdepression or anxiety by delivering bacteria capable of altering host GABAergic activityIBS affects betweenof the U SpopulationDepression affects up toof adults in the U Sper yearwith anxiety affecting an estimatedof people in their lifetimeThere are limited drugs for IBSand roughlyof patients with depression or anxiety do not respond to front line drugshighlighting the need to exploring new therapeutic modalitiesOne potential source of new therapeutics is the gut microbiomethe bacteria that reside in the gastrointestinal tractThese symbiotic organisms have been shown to be involved in numerous components of health and diseaseincluding neurodevelopmentbrain developmentand moodA key mechanism for communication along the gut brain axis is the modulation of neurotransmitters by gut bacteriaOf interest is the ability of the microbiome to produce levels of the neurotransmitter GABAGABA is the major inhibitory neurotransmitter in the mammalian central nervous system and low levels and or GABAergic dysregulation are associated with numerous diseasesincluding IBSdepressionstressand altered brain developmentGut bacteria have been shown to produce GABAgerm free animals have reduced GABA levelsand microbiome intervention in humans can alter serum GABA levelssuggesting the microbiome contributes to host levelsImportantlyinterventional studies in rodents with bacteria capable of producing GABA has showed efficacy in improving symptoms of anxietydepressionand visceral painas well as modulating GABAergic activity in the brainsuggesting microbial derived GABA is importantHoweverthese 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 tractwhich are likely the organisms contributing most to host GABA levels and or GABAergic activityIn our preliminary studieswe developed a screen to identify novel GABA producing bacteriacapable of producing GABA at a physiologically relevant pHfound some of these organisms express genes involved with GABA production in healthy peopleand are reduced in individuals with depression and IBSIn Phaseof this proposalthe GABA producingsafetyand development profiles of these strains will be examinedStrains 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 communityConsortia 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 GABAalter the GABAergic responseand engraftSuccessful modulation of GABA GABAergic activity by GABA producing bacteria will provide proof of principle to explore therapeutic efficacy and mechanism validation in Phasein animal models of visceral paindepressionand anxiety The goal of this project is to develop new therapies for symptoms of irritable bowel syndromedepressionand anxietyBacteriaisolated from healthy humanswill be tested for the ability to safely treat these diseases in established animal modelswhich are predictive of effectiveness in humans