Oral Sheep Milk-Derived Exosome Therapeutics for Cadmium-Induced Inflammatory Bowel Disease

Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., <i>Bacteroides</i> and <i>Parabacteroides</i>) were increased in FMT mice. SM-Exo treatment increased beneficial bacteria, particularly <i>Lachnoclostridium</i>, and activated the Cyclic Adenosine Monophosphate (cAMP) pathway, upregulating genes like <i>Adcy1</i>, <i>Adcy3</i>, <i>CREB</i>, and <i>Sst</i>. These changes were linked to reduced Cd-induced cell death and alleviation of colonic inflammation. In conclusion, SM-Exo appears to be a promising treatment for Cd-induced colitis, likely through modulation of the gut microbiota and activation of the cAMP pathway.