Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

ABSTRACT

It is well known that caloric restriction leads to an increased longevity by forestalling age-related diseases. Dietary restriction of methionine also renders similar benefits. In this review, we report studies on the effect of methionine restriction on epithelial barrier function in a renal epithelial LLC-PK1 cell, a rodent gastrointestinal model and a clinical trial using Crohn’s patients. In LLC-PK1 cell culture, a reduction of culture medium methionine by 80% resulted in altered tight junctional claudin composition with improved epithelial barrier function as exemplified by increased transepithelial electrical resistance and decreased paracellular leak to 14C-D-mannitol. In addition to small but significant reductions in plasma and intracellular colonocyte methionine levels, dietary methionine restriction tightens intestinal epithelium and reduces mannitol permeability in rat colonic, but not ileal tissue. Crohn’s patients on methionine-restricted diet reported improved symptoms as demonstrated by a reduced CDAI index, but this diet was not able to significantly reduce the plasma methionine level in patients recruited. An increased urinary lactulose/mannitol ratio was also the result of the regimen in Crohn’s patients, suggesting an increased, rather than decreased ileal leakage. Overall, our results showed that reduction in dietary intake of methionine is promising in improving at least some epithelial barriers and this may be through altering tight junctional protein compositions. Methionine restriction might result in contrasting effects depending on the tissue type and possible disease conditions, thus wider range of studies are required.