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

越来越多的证据表明，肠道来源的细菌毒素可能参与各种胃肠道和肝脏疾病，包括炎症性肠病（IBDs）和酒精性肝病（ALD）。在本研究中，我们研究了先天免疫系统在ALD和ibd中识别细菌毒素（即来自革兰氏阴性菌的内毒素（脂多糖，LPS））的作用。关于ALD的发病机制，我们研究了急性乙醇处理小鼠肝脏中toll样受体(TLR)-4及其下游信号分子的表达模式。正常肝组织中组成型检测到TLR-4 mRNA；然而，单次灌胃注射乙醇（5 g/kg BW）后6小时内，它下降了近90%，随后在24小时内逐渐上升到基础水平。急性乙醇注射后，白细胞介素- 1受体相关激酶（interleukin- 1 receptor associated kinase， IRAK）蛋白水平和活性明显升高。这些发现很可能解释了乙醇中毒时Kupffer细胞对LPS的耐受性和敏化机制。此外，我们评估了沙利度胺在大鼠酒精性肝炎实验模型中的作用。沙利度胺防止因肠源性内毒素而激活库普弗细胞，从而保护其免受酒精诱导的肝损伤。这种方法似乎对严重酒精性肝炎患者有用。此外，我们开发了一种新的免疫营养方法来治疗ibd，使用甘氨酸，一种非必需氨基酸。甘氨酸已被证明可以防止由细菌毒素引起的巨噬细胞和中性粒细胞的活化。因此，在本研究中，我们评估了膳食甘氨酸是否能预防大鼠化学诱导的实验性结肠炎。甘氨酸通过减少结肠组织中炎症细胞因子和趋化因子的诱导，预防TNBS和dss诱导的结肠炎，分别代表人类克罗恩病和溃疡性结肠炎。据推测，甘氨酸对ibd的治疗是有用的，其机制涉及调节肠道内的先天免疫系统

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