Granulocyte Macrophage‐Colony‐stimulating Factor Autoantibodies and Increased Intestinal Permeability in Crohn Disease

Abstract

Alterations in intestinal permeability have been implicated in the pathogenesis of Crohn disease (CD). We have reported that granulocyte macrophage-colony-stimulating factor (GM-CSF) is required for mucosal barrier function in mice, and elevated neutralizing GM-CSF autoantibodies (Ab) are associated with stricturing ileal disease and surgery in patients with CD. We hypothesized that children with CD with elevated GM-CSF Ab would exhibit increased intestinal permeability. Subjects were divided into 3 groups: 15 with CD and high GM-CSF Ab (≥ 1.6 μg/mL, GM-CSF Ab Hi), 12 with CD and low GM-CSF Ab (<1.6 μg/mL, GM-CSF Ab Lo), and 15 healthy controls. Subjects ingested a lactulose:mannitol (L:M) solution, and urinary excretion of LM was measured by high-performance liquid chromatography. Serum GM-CSF Ab, endotoxin core Ab (EndoCAb), and lipopolysaccharide-binding protein (LBP), and fecal S100A12 were determined by enzyme-linked immunosorbent assay. The CD groups did not vary by age, sex, disease location, or activity. Neither systemic (serum LBP) nor mucosal (fecal S100A12) inflammation differed between the CD groups. Intestinal permeability as measured by the urine L:M ratio and endotoxin exposure as measured by serum EndoCAb were increased in the GM-CSF Ab Hi group compared to the GM-CSF Ab Lo group and controls. Patients with CD with elevated GM-CSF Ab exhibit an increase in bowel permeability relative to patients with CD with lower levels of GM-CSF Ab in the absence of differences in systemic or intestinal inflammation. Therapies that target the mucosal barrier may be of particular benefit in this subgroup of patients with CD.