Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.
Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.
复制标题
壁溶酶变溶菌素对内源性细菌细胞壁聚合物的降解可防止实验性肠道细菌过度生长的遗传易感大鼠的肝胆损伤。
DOI：
10.1172/jci115996
复制
发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Sartor,RB
中科院分区：
文献类型：
--
作者：
Lichtman,SN;Okoruwa,EE;Keku,J;Schwab,JH;Sartor,RB
空肠自充盈盲袢伴随后的小肠细菌过度生长（SBBO）诱导遗传易感性刘易斯大鼠的肝胆损伤。病变包括门脉炎症、胆管增生和破坏。为了确定SBBO诱导的肝胆损伤的发病机制，我们通过使用几种具有不同活性机制的药物治疗SBBO诱导的刘易斯大鼠。缓冲液处理，熊去氧胆酸，泼尼松，甲氨蝶呤，环孢素A未能防止SBBO诱导的损伤，表现为血浆天冬氨酸转氨酶（AST）升高和组织学评分升高。然而，肝损伤可通过变溶菌素预防，变溶菌素是一种胞壁溶解酶，其唯一已知的活性是分裂肽聚糖-多糖（PG-PS）的β 1-4 N-乙酰胞壁酰-N-乙酰葡糖胺键，PG-PS是一种具有强效炎症和免疫调节特性的细菌细胞壁聚合物。与缓冲液处理的大鼠（分别为228 +/-146 U/L，P < 0.05，8.2 +/-1.9，P < 0.001）相比，在手术形成盲袢的当天开始变溶菌素治疗并持续8周显著降低了AST（101 +/-37 U/L）和肝组织学评分（2.2 +/-2.7）。在肝损伤的早期阶段（手术后16-21天）开始变溶菌素治疗，11只大鼠中7只的AST从142 +/- 80 U/L降低至103 +/- 24 U/L，而11只缓冲液治疗的大鼠中9只的AST从108 +/- 52 U/L升高至247 +/- 142 U/L，P < 0.05。变溶菌素不改变环内的细菌总数，消除拟杆菌属，具有体外抗菌作用或减少粘膜PG-PS转运。然而，变溶菌素治疗防止了血浆抗PG抗体和肿瘤坏死因子-α（TNF α）水平的升高，这发生在SBBO缓冲液处理的大鼠中，并降低了PG-PS体外刺激的分离枯否细胞中TNF α的产生。基于这种高度特异性的胞壁溶解酶的预防和治疗活性，我们得出结论，来自内源性肠道细菌的PG-PS的全身摄取有助于SBBO在敏感大鼠品系中诱导的肝胆损伤。
Jejunal self-filling blind loops with subsequent small bowel bacterial overgrowth (SBBO) induce hepatobiliary injury in genetically susceptible Lewis rats. Lesions consist of portal tract inflammation, bile duct proliferation, and destruction. To determine the pathogenesis of SBBO-induced hepatobiliary injury, we treated Lewis rats with SBBO by using several agents with different mechanisms of activity. Buffer treatment, ursodeoxycholic acid, prednisone, methotrexate, and cyclosporin A failed to prevent SBBO-induced injury as demonstrated by increased plasma aspartate aminotransferase (AST) and elevated histology scores. However, hepatic injury was prevented by mutanolysin, a muralytic enzyme whose only known activity is to split the beta 1-4 N-acetylmuramyl-N-acetylglucosamine linkage of peptidoglycan-polysaccharide (PG-PS), a bacterial cell wall polymer with potent inflammatory and immunoregulatory properties. Mutanolysin therapy started on the day blind loops were surgically created and continued for 8 wk significantly diminished AST (101 +/- 37 U/liter) and liver histology scores (2.2 +/- 2.7) compared to buffer-treated rats (228 +/- 146 U/liter, P < 0.05, 8.2 +/- 1.9, P < 0.001 respectively). Mutanolysin treatment started during the early phase of hepatic injury, 16-21 d after surgery, decreased AST in 7 of 11 rats from 142 +/- 80 to 103 +/- 24 U/liter contrasted to increased AST in 9 of 11 buffer-treated rats from 108 +/- 52 to 247 +/- 142 U/liter, P < 0.05. Mutanolysin did not change total bacterial numbers within the loop, eliminate Bacteroides sp., have in vitro antibiotic effects, or diminish mucosal PG-PS transport. However, mutanolysin treatment prevented elevation of plasma anti-PG antibodies and tumor necrosis factor-alpha (TNF alpha) levels which occurred in buffer treated rats with SBBO and decreased TNF alpha production in isolated Kupffer cells stimulated in vitro with PG-PS. Based on the preventive and therapeutic activity of this highly specific muralytic enzyme, we conclude that systemic uptake of PG-PS derived from endogenous enteric bacteria contributes to hepatobiliary injury induced by SBBO in susceptible rat strains.