Sustained Delivery of Microbes to Treat Ulcerative Colitis

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Abstract Intestinal inflammation encompasses a debilitating set of diseases, including Crohn's disease and ulcerative colitis which can result from dysregulated immune responses to resident microbiota. These diseases affect over 1.5 million people in the Unites States and currently approved treatment options include anti-inflammatory drugs and immune system suppressors. Unfortunately, these drugs do not address the mechanistic cause of inflammation and are focused on reducing symptoms. Previous work has shown that modulation of the microbiome towards a protective composition can be an effective strategy to prevent the induction of colitis. However, microbiome modulation via the delivery of living microbes remains a challenge. Accordingly, we will develop a new approach to control the location, duration, and concentration of delivered microbes to the gastrointestinal tract to improve microbiome modulation and thus efficacy in both prevention and treatment of colitis. There are two independent aims. In Aim 1, we will develop and optimize a formulation capable of controlling microbe concentration and contact time at the colon surface to modulate microbe adhesion, growth, and colonization. In this aim, we will determine how the spatiotemporal interactions of delivered microbes influences their colonization. In Aim 2, we will determine the role of spatiotemporal interactions between delivered microbes in the protection and treatment of experimental colitis. In this aim, we will first test how the delivery of a 23-member Lachnospiraceae consortium impacts protection against experimental ulcerative colitis. We will evaluate both: (i) non-formulated microbes delivered via various dosing regiments using standard oral gavage, and (ii) microbes formulated in polymer films that are capable achieving distinct delivery profiles, residence times, and local concentrations. Overall, we aim to develop new approaches that can control the delivery, adhesion, colonization, and efficacy of microbe therapeutics.