This dataset examines the proteomic mechanisms by which synthetic mucin polymers (Shear-Labile Interaction Polymers, SLIPs) restore intestinal barrier integrity and modulate inflammation in chronic and acute colitis models. In the Agr2 KO model of chronic mucus deficiency, colon and spleen proteomes were analyzed following SLIP treatment to assess molecular recovery of mucosal and systemic homeostasis. In the DSS-induced model of acute epithelial injury, distal colon proteomes were compared between SLIP-treated and untreated mice during the recovery phase. Quantitative LC–MS/MS analyses revealed that SLIPs attenuate NF-κB and interferon-driven immune cascades, restore mitochondrial and redox pathways, and promote epithelial differentiation and mucus-associated repair. Together, these datasets define the molecular outcomes of artificial mucin therapy in distinct forms of gut barrier dysfunction.