Innate immune response to gut-derived bacterial toxins in gastrointestinal andhepatic disorders

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Increasing lines of evidence have suggested a possible involvement of gut-derived bacterial toxins in various kinds of gastrointestinal and hepatic disorders including inflammatory bowel diseases (IBDs) and alcoholic liver disease (ALD). In the present study, we investigated the role of innate immune system that recognizes bacterial toxins [i.e., endotoxin (lipopolysaccharide, LPS) from Gram-negative bacteria] in ALD and IBDs.Regarding the pathogenesis of ALD, we investigated the expression pattern of Toll-like receptor (TLR)-4 and its downstream signaling molecules in the liver following acute ethanol treatment in mice. TLR-4 mRNA was detected constitutively in the normal liver tissue; however, it was decreased almost 90% within 6 hr after a single intragastric injection of ethanol (5 g/kg BW), followed by a gradual increase to the basal levels in 24 hr. In contrast, interleukin- 1 receptor associated kinase (IRAK) protein levels and its activity in Kupffer cells were increased 21 hr … More after acute ethanol injection. These findings most likely explain the mechanism of tolerance and sensitization of Kupffer cell to LPS in ethanol intoxication. Further, we evaluated the effect of thalidomide in an experimental model of alcoholic hepatitis in the rat. Thalidomide prevented activation of Kupffer cells due to gut-derived endotoxin , thereby protecting from alcohol-induced liver injury. This approach appears to be useful in patients of severe alcoholic hepatitis. In addition, we developed a new immuno-nutritional approach to IBDs using glycine, a non-essential amino acid. Glycine has been shown to prevent activation of macrophages and neutrophils due to bacterial toxins. In the present study, therefore, we evaluated whether dietary glycine prevents chemical-induced experimental colitis in the rats. Glycine prevented both TNBS- and DSS-induced colitis, which represent human Crohn's disease and ulcerative colitis, respectively, by decreasing induction of inflammatory cytokines and chemokines in the colonic tissue. It is postulated that glycine is useful for therapeutics of IBDs based on the mechanism that involves modulation of the innate immune system in the gut Less