Exosomal MicroRNA-181a Derived From Mesenchymal Stem Cells Improves Gut Microbiota Composition, Barrier Function, and Inflammatory Status in an Experimental Colitis Model

Abstract

Background: Mesenchymal stem cell (MSC)-derived exosomes (Exos) are recently proved to be a promising candidate for ulcerative colitis (UC), but the mechanism remains unclear. We investigated the effects of MSC-derived exosomal microRNA-181a (miR-181a) on gut microbiota, immune responses, and intestinal barrier function in UC.Methods: Human bone marrow MSC-derived Exos were extracted and identified via transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and Western blotting. Dextran sodium sulfate (DSS)-induced colitis model and lipopolysaccharide (LPS)-induced human colonic epithelial cell (HCOEPIC) model were established to determine the effect of MSC-Exos on gut microbiota, immune responses, and intestinal barrier function in vivo and in vitro. The relationship between miR-181a and UC was analyzed using the Gene Expression Omnibus (GEO) database. MSC-miR-181-inhibitor was used to reveal the role of exosomal miR-181a in DSS-induced colitis.Results: TEM and NTA results showed that Exos of a diameter of about 100 nm with the round and oval vesicle-like structure were successfully extracted. The expressions of the CD63, CD81, and TSG101 proteins were positive in these Exos. After MSC-Exo treatment, the colon length in colitis mice increased; colon inflammatory injury decreased; TNF-α, IL-6, IL-1β, IL-17, and IL-18 levels decreased; and Claudin-1, ZO-1, and IκB levels increased. In addition, the structure of the gut microbiota in DSS-induced colitis mice was changed by MSC-Exos. MSC-Exos showed antiapoptotic effects on LPS-induced HCOEPIC. The protective effects decreased significantly by treatment with MSC-Exos interfered with miR-181a inhibitor in vivo and in vitro.Conclusion: MSC-derived exosomal miR-181a could alleviate experimental colitis by promoting intestinal barrier function. It exerted anti-inflammatory function and affected the gut microbiota. This indicated that MSC exosomal miR-181a may exhibit potential as a disease-modifying drug for UC.

Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies

“…miRNAs are singlestranded non-coding RNA molecules of approximately 22 nucleotides in length that play important roles in regulating gene expression and biological function (79). In recent years, studies have shown that EV-derived miRNA expression is related to gut microbiota and intestinal barrier function (80)(81)(82). Mice deficient in IECs miRNA showed intestinal dysbiosis and exacerbation of colitis, which ameliorated after transplantation with fecal EV-derived miRNA from wild-type mice (80).…”

“…Another study found that EV-derived miRNAs of dietary ginger can induce IL-22 production to improve intestinal barrier function and thus ameliorate intestinal inflammation ( 83 ). A recent study showed that exosome miR-181a derived from MSCs alleviated colitis by improving gut microbiota imbalance and intestinal barrier function and reducing pro-inflammatory factor secretion ( 82 ). Taken together, the above results suggest that some EV-derived miRNAs in the intestinal tract may inhibit the progression of SLE by improving gut microbiota homeostasis and intestinal barrier function.…”

“…For instance, dietary ginger-derived miRNAs can induce IL-22 production to improve intestinal barrier function and thus ameliorate intestinal inflammation ( 83 ). Furthermore, MSC-derived exosome miR-181a can alleviate colitis by improving gut microbiota imbalance and intestinal barrier function and reducing pro-inflammatory factor secretion ( 82 ). Mice deficient in IECs miRNA showed intestinal dysbiosis and exacerbation of colitis, which ameliorated after transplantation with fecal EV-derived miRNA from wild-type mice ( 80 ).…”

“…In contrast, miRNA-181a of MSC-derived exosomes can attenuate intestinal inflammation in mouse models of colitis by improving the composition of gut microbiota and restoring barrier function. These studies suggest that MSCs or MSC-derived exosomes can improve gut microbiota dysbiosis and intestinal barrier function and ameliorate intestinal inflammation ( 82 ).…”

Therapeutic Applications of Extracellular Vesicles for Myocardial Repair

“…For example, overexpression of miR-125b targeting SIRT7 in bone marrow MSC-derived exosomes down-regulated the levels of Bax, caspase-3 apoptotic proteins and IL-1β, IL-6, TNF-α inflammatory factors, and up-regulated the expression of Bcl-2, in order to repair the myocardial injury of I/R-rats ( 73 ). In addition, miR-181a delivered by exosomes of MSCs may inhibit the inflammatory response through c-Fos and promote the polarization of Treg cells to protect myocardial injury caused by miRs ( 74 – 77 ). These results suggest that donor cell engineering allows for directed cargo loading of small nucleotides into EVs, providing an effective therapeutic strategy for ischemia-reperfusion injury.…”