Therapeutic Potential and Translational Challenges for Bacterial Extracellular Vesicles in Inflammatory Bowel Disease

Despite the availability of numerous new immune-directed therapeutics, the major constituents of inflammatory bowel disease (IBD)-ulcerative colitis (UC) and Crohn's disease (CD)-continue to afflict millions worldwide, resulting in significant morbidity and long-term health risks. IBD results from a triad of immune, environmental (eg, gut microbiome), and genetic (including epigenetic) mechanisms, and therefore has been subject to a wide variety of therapeutic strategies. Among these, the administration of probiotics, particularly Gram-positive lactic acid bacteria (LAB), targeting both immune and environmental factors, has shown promising potential for efficacy in selected populations in early clinical trials. However, knowledge gaps and inconsistent efficacy currently prevent recommendations for the use of probiotics in larger IBD patient populations. The inconsistent efficacy of probiotics is likely due to variable cell viability and potency after administration, further exacerbated by IBD patient heterogeneity. Thus, an alternative to live probiotics for IBD has emerged in the form of bacterial extracellular vesicles (BEVs)-cell-secreted nanovesicles containing abundant bioactive cargo that, like live probiotics, can regulate immune and environmental factors but with fewer viability limitations and safety concerns. In this review, we summarize the work done to date establishing the potential of BEVs to provide the therapeutic benefits in IBD and discuss the hurdles BEVs must overcome to achieve clinical translation. We also consider future directions for BEV therapeutics, especially treatment potential for necrotizing enterocolitis (NEC), which shares similarities in pathophysiology with IBD.