Triple-Functional Probiotics with Intracellularly Synthesized Selenium Nanoparticles for Colitis Therapy by Regulating the Macrophage Phenotype and Modulating Gut Microbiota

The dysregulated macrophage phenotype, as the main cause of colitis, not only enhanced oxidative stress to exacerbate inflammatory responses but was closely related with gut microbial dysbiosis. It was needed to simultaneously address the three issues for the effective treatment of colitis, but it was not satisfied. Here, we developed "three-birds-one-stone" probiotics, named Se@EcN-C₂/A₂, for colitis treatment. <i>Escherichia coli</i> Nissle 1917 (EcN), a clinically approved probiotic, was used to intracellularly synthesize selenium (Se) nanoparticles by biomineralization, giving Se@EcN. Coating glycol chitosan and sodium alginate on the surface of Se@EcN (Se@EcN-C₂/A₂) endowed probiotics with high resistance to the harsh gastrointestinal tract environment and strong adhesion and targeting ability to the inflamed site of the colon to facilitate the uptake by M1 macrophages. Se@EcN-C₂/A₂ was metabolized to SeCys₂ and MetSeCys to be involved in the synthesis of GPX2 and TXNRD1, which led to reaction oxygen species clearance to inhibit Toll-like receptor and nuclear factor κB signaling pathways to suppress inflammatory response and polarize M1 macrophages to M2 phenotypes by activating PI3K/AKT signaling pathways. In DSS-induced colitis mice, Se@EcN-C₂/A₂ exerted satisfactory therapeutic and prophylactic effects, including scavenging oxidative stress and regulating macrophage phenotypes to suppress inflammatory response and restore gut barrier functions. Moreover, the living probiotic EcN in the colon effectively regulated microbial dysbiosis by decreasing the abundance of <i>Escherichia</i>-<i>Shigella</i> and increasing the abundance of <i>Lactobacillus</i> and <i>Bifidobacterium</i>.