Orally-delivered microbial extracellular vesicle induces anti-inflammatory activity in mice

Abstract

Abstract The small intestinal axis is a network of anatomical and functional connections linking the small intestine with the rest of the body. It senses external signals in the gut lumen and translates them into systemic immune effects. We have previously shown that an oral microbial drug candidate induces anti-inflammatory activity in preclinical models of inflammation by acting directly on host cells without colonization of the gut or modulation of the microbiome. We now extend these observations to EDP2939, a bacterial extracellular vesicle (EV), that has potent anti-inflammatory activity in preclinical models. EVs are non-replicating bacterial membrane vesicles with approximately 1/1000th the volume of the parent cell. EDP2939 was orally delivered and gut-restricted in distribution, it acts by modulation of innate and adaptive immunity within the small intestine to attenuate systemic inflammatory responses. We observed significantly decreased ear swelling and inflammation in a delayed-type hypersensitivity model, showing that EDP2939 modulates systemic inflammatory responses. Activity of EDP2939 is dependent upon both TLR2 signaling and the presence of local immune cells. In vitro results show TLR2 agonism and induction of anti-inflammatory cytokine responses in immune cells by EVs. This is the first report of striking anti-inflammatory effects of an orally delivered microbial extracellular vesicle. EDP2939 induces broad-based resolution of inflammation across multiple pathways via a novel mechanism of systemic pharmacology without systemic exposure. EVs are particularly effective at engaging host cells in the gut to modulate distal inflammation. These data point to oral EVs as a new class of immunotherapeutic drugs.