Engineering Commensal Clostridia for Therapeutic Microbiome Interventions

Commensal gut bacteria contribute a large set of genes and their products to their host, influencing a variety of functions such as metabolism and defence from pathogens. Recent research has associated disruption of the homeostatic relationship between the human host and the gut microbiota with a variety of morbidities, ranging from inflammatory bowel diseases to metabolic and even neurological disorders. There is, therefore, enormous interest to explore the potential use of host microbes as therapeutic interventions for many human diseases. Probiotic bacteria have been used for many years to alleviate conditions linked to gastrointestinal (GI) distress and pathology, and more recently faecal microbiota transplant for treatment of antibiotic-associated diarrhoea and recurrent C. difficile associated disease has further highlighted the potential for gut microbiome-based interventions. While such approaches using wildtype strains show clinical efficacy relating to the natural properties of these strains, the possibility to genetically engineer these gut bacteria to optimise specific functional traits opens up an even greater opportunity. CHAIN Biotechnology Ltd is genetically engineering a member of Clostridia, which due to its beneficial properties, including production of the SCFA butyrate, and its sporulating nature has long been used as an effective probiotic to treat GI dysfunction. CHAIN’s platform strain can be engineered to produce a variety of therapeutic products, including metabolites, anti-inflammatory and anti-bacterial molecules. Being administered in spore form, the engineered strains have advantages over other therapeutics relating to ease of delivery, manufacture, storage and shelf-life. Here, we report on progress made with the development of the platform strain and its derivatives engineered to produce therapeutics for treatment of inflammatory bowel disease, antibacterial treatment, and in mucosal vaccination strategies for viral and bacterial infections.