Development of a therapeutic bacterial consortium for constipation

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The goal of the proposed project is to develop a probiotic for the treatment of constipation, comprised of 2-3 anti- inflammatory strains of human gut-derived bacteria that enhance host serotonin (5-hydroxytryptamine, 5-HT) production and signaling. By addressing multiple targets associated with the etiology and symptoms of constipation (5-HT signaling and inflammation), we expect the result of this project to have broad utility. Constipation affects up to 20% of the general population, with rates even higher in the elderly, and comes in many forms ranging in severity. The most severe form, slow transit constipation (STC), affects ~15 to 30% of constipated patients. Less severe, but still representing a significant societal burden, are irritable bowel syndrome with constipation (IBS-C) and age-associated constipation. Constipation is also a major side effect of opioid medications, and is comorbid with neurological diseases including Parkinsonian syndromes. The etiology is multifarious, often involving a dysfunctional enteric nervous system, poor diet, and inflammation, but in many cases it is still poorly understood. Current treatment options are generally poor and include dietary modifications, pharmacological interventions, and—for severe forms like STC—surgery. As such, novel treatment options are needed, preferably those that can engage multiple therapeutic targets. One source of new therapeutics is the gut microbiome: the bacteria that reside in the gastrointestinal tract. These symbiotic organisms are involved in numerous components of health and disease, including development and maintenance of the immune and enteric nervous systems. Recently, it has been shown by a member of Holobiome’s team that the gut microbiome is a major regulator of host enteric 5-HT signaling: Germ free mice have a 50% reduction in serum 5-HT and have constipation, both of which can be corrected via recolonization with a normal microbiome or a human- derived consortium. It has also been shown that constipation in humans can be transferred into animals via fecal microbiome transplant; a phenotype that is driven via disrupted enteric 5-HT signaling and inflammation. This suggests a clear intervention strategy: deliver anti-inflammatory, 5-HT-modulating bacteria to the gut. In our preliminary studies we screened a proprietary panel of over 100 non-pathogenic species of human gut bacteria for the ability to modulate 5-HT in a cell culture model. We identified 17 bacterial strains with the capability to modulate 5-HT signaling via four mechanisms. In this Phase 1 application we seek to further test these strains as candidates for a 5-HT modulating and anti-inflammatory consortium. To do this, strains will first be profiled for safety and manufacturability in vitro and in silico. Strains meeting these criteria will be assembled into candidate consortia of 2-3 strains, which will be further optimized to impact 5-HT release and inflammation. These will be advanced for testing in mouse models of constipation to assess efficacy, safety, and engraftment. The most promising consortium will be further tested in PK/PD and dosing studies supported in a Phase 2 program.