New therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A‐I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis.

Daily injections of 5A peptide, a synthetic bihelical apoA‐I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v^‐1) dextran sodium sulfate (DSS) in drinking water or healthy controls.

Daily treatment with 5A peptide potently restricted DSS‐induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNFα and IL‐6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein‐1 and the monocyte expression of adhesion‐mediating molecule CD11b were down‐regulated, pro‐inflammatory CD11b⁺/Ly6c^high monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide‐treated animals as determined by intravital macrophage‐related peptide‐8/14‐directed fluorescence‐mediated tomography and post‐mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM‐1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNFα‐stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS‐induced inflammation was noted in apoA‐I^−/− mice.

The 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA‐I mimetics as a potential treatment approach for IBD.