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Inflammatory bowel diseases (IBD) are immune-mediated chronic diseases that are characterized by an overreaction of the intestinal immune system to the intestinal microbiota. VSL♯3, a mixture of 8 different lactic acid bacteria, is a clinically relevant probiotic compound in the context of IBD, but the bacterial structures and molecular mechanisms underlying the observed protective effects are largely unknown. The intestinal epithelium plays a very important role in the maintenance of the intestinal homeostasis, as the intestinal epithelial cells (IEC) are capable of sensing, processing, and reacting upon signals from the luminal microbiota and the intestinal immune system. This immune regulatory function of the IEC is lost in IBD owing to dysregulated activation of the IEC. Thus, the aim of this study was to reveal protective mechanisms of VSL♯3 on IEC function.In vitro, VSL♯3 was found to selectively inhibit activation-induced secretion of the T-cell chemokine interferon-inducible protein (IP)-10 in IEC. Cell wall-associated proteins of VSL♯3-derived Lactobacillus casei (L. casei) were identified to be the active anti-inflammatory component of VSL♯3. Mechanistically, L. casei did not impair initial IP-10 protein production, but induced posttranslational degradation of IP-10 in IEC. Feeding studies in tumor necrosis factor (TNF)ΔARE/+ mice, a mouse model for experimental ileitis, revealed that neither VSL♯3 nor L. casei is capable of reducing ileal inflammation. Even preweaning feeding of VSL♯3 did not prevent the development of severe ileitis in TNFΔARE/+ mice. In contrast, VSL♯3 feeding studies in IL-10-/- mice, a model for experimental colitis, revealed that VSL♯3 has local, intestinal compartment-specific protective effects on the development of inflammation. Reduced histopathologic inflammation in the cecum of IL-10-/- mice after VSL♯3 treatment was found to correlate with reduced levels of IP-10 protein in primary cecal epithelial cells.These results suggest that the inhibitory effect of VSL♯3-derived L. casei on IP-10 secretion in IEC is an important probiotic mechanism that contributes to the anti-inflammatory effects of VSL♯3 in specific subsets of patients with IBD. An important future aim is the identification of the active probiotic protein, which could serve as a basis for the development of new efficient therapies in the context of IBD.