Orally surface engineered probiotic system for ulcerative colitis therapy via modulating gut microbiota and immune homeostasis

Abstract

Oral probiotics have emerged as a promising therapeutical strategy for effectively managing ulcerative colitis (UC) in the world. The existing researches successfully preserve probiotic viability in the upper gastrointestinal tract, but they fall short in achieving precise release profile and effective colonization of probiotics at the site of colitis in colon as well as the understanding of therapeutic mechanism with suboptimal efficacy. This constraint poses a significant barrier to rational design and effective development of oral probiotic system. Here, we fabricate an orally layered-by-layered probiotic (Escherichia coli Nissle 1917, EcN) system (so-called CML@EcN) based on carboxymethyl modified lignin (CML) which can significantly protect EcN in gastric and small intestinal microenvironment and efficiently control release EcN in colon. Interestingly, the release and proliferation process of EcN in the colon are detected and can be modeled as a plug-flow mode. We derive a mathematical expression that highly matches the experimental results, providing a theoretical basis for quantitatively calculation of the release process. Furthermore, CML@EcN significantly alleviates symptoms in dextran sulfate sodium (DSS)-induced UC mice by modulating the multiple organ immune disorder and gut microbiota (GM)/metabolites profile as well as reconstructing the colon barrier. Importantly, we explore the mechanism of immune homeostasis regulation via metabolism from GM. Moreover, the CML armour is excreted and would not influence the process. This work not only reports a novel oral therapeutic for UC treatment with high efficacy as well as the exploration of mechanism between GM and immune homeostasis, but also provides a general approach to engineer probiotics for oral administration.