The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF-kappaB translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF-kappaB activation in these macrophages.

Butyrate inhibits VCAM-1 mediated leukocyte adhesion to human endothelial cells. This inhibition may contribute to the anti-inflammatory effects of butyrate in patients with distal ulcerative colitis.

Butyrate, a short-chain fatty acid, is generated by anaerobic fermentation within the colon. Clinical trials suggest that short-chain fatty acids ameliorate inflammation in ulcerative colitis. Nuclear factor (NF) kappaB, an inducible transcription factor that is activated in inflamed colonic tissue, is sequestered to the cytoplasm by its inhibitory IkappaB proteins. The anti-inflammatory effects of butyrate are associated with an inhibition of NF-kappaB nuclear translocation. To investigate the mechanism of NF-kappaB inhibition we examined the effects of butyrate on IkappaBalpha. Human adenocarcinoma cells (SW480, SW620, and HeLa229) were treated with butyrate for up to 48 h followed by tumor necrosis factor (TNF) alpha stimulation. NF-kappaB was detected by immunofluorescence staining with an antibody against its p65 subunit. Levels of IkappBalpha and phosphorylated IkappaBalpha were determined by western blot. Stimulation with TNFalpha resulted in rapid phosphorylation and degradation of IkappaBalpha followed by NF-kappaB nuclear translocation. Butyrate pretreatment successfully inhibited NF-kappaB activation. Pretreatment of adenocarcinoma cells with butyrate is associated with inhibition of TNFalpha-mediated phosphorylation and degradation of IkappaBalpha and effective blocking of NF-kappaB nuclear translocation. The anti-inflammatory effects of butyrate may at least in part be mediated by an inhibition of IkappaBalpha mediated activation of NF-kappaB.

Nuclear factor-kappa B (NF-kappaB) is a critical transcription factor for the inducible expression of multiple genes involved in inflammation. NF-kappaB is sequestered in the cytoplasm by inhibitory IkappaB proteins. Extracellular stimuli, notably interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) activate NF-kappaB nuclear translocation via IkappaB phosphorylation and degradation. Since previous reports suggest that the short chain fatty acid butyrate has antiinflammatory properties, the effects of butyrate on NF-kappaB nuclear translocation in human epithelial cells (HeLa229) were tested. In cells pretreated with butyrate, a time- and dose-dependent inhibition of IL-1beta-mediated NF-kappaB nuclear translocation was observed. However, IkappaB alpha phosphorylation and degradation occurred rapidly in both butyrate pretreated and nonpretreated cells, respectively. These data indicate that inhibition of IL-1beta-induced NF-kappaB activation by butyrate does not require an intact IkappaB alpha protein.