Donkey Milk Exosomes Protect Against DSS-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota

Current treatments for Ulcerative colitis (UC) face significant challenges, including severe side effects, high relapse rates, individual variability in response, and inadequate repair of the intestinal barrier. These limitations highlight an urgent need for safer and more effective therapeutic strategies. Milk-derived exosomes (exo) have emerged as a promising natural option due to their inherent safety, ability to carry anti-inflammatory microRNAs (miRNAs) and proteins, and their established roles in regulating immunity, promoting epithelial repair, and modulating the gut microbiota.

Researchers isolated and characterized donkey milk exosomes, confirming typical exosomal markers (TSG101, CD63, CD9). These exosomes were then orally administered to mice with dextran sulfate sodium (DSS)-induced colitis. The study assessed several primary endpoints: changes in body weight, colon length, and disease activity index (DAI). Intestinal barrier integrity was evaluated by measuring tight junction proteins (Occludin, Claudin-1, ZO-1) via unspecified methods. Inflammatory responses were quantified by measuring pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and anti-inflammatory IL-10. Oxidative stress, neutrophil infiltration, miRNA content, and gut microbiota composition were also analyzed.

Oral administration of donkey milk exosomes to DSS-induced colitis mice significantly reduced body weight loss, colon shortening, and the disease activity index. Exosomes enhanced intestinal barrier function by upregulating tight junction proteins, including Occludin, Claudin-1, and ZO-1. They also significantly lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while increasing anti-inflammatory IL-10, and attenuated both oxidative stress and neutrophil infiltration. Mechanistically, the exosomes contained 1212 miRNAs, with eca-let-7g and eca-miR-148a being the most abundant. > eca-let-7g directly targeted the TLR4 3'UTR, leading to the inhibition of the NF-κB inflammatory pathway, while eca-miR-148a targeted the NLRP3 3'UTR, thereby suppressing the NLRP3-Caspase-1-IL-18 axis. Furthermore, exosome treatment reshaped the gut microbiota, reducing pathogenic Bacteroides and Desulfovibrio species and enriching beneficial bacteria like Akkermansia muciniphila and Turicibacter.