Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California.
Department of Surgery, Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California.
Am J Physiol Gastrointest Liver Physiol. 2020 Aug 1;319(2):G212-G226. doi: 10.1152/ajpgi.00119.2020. Epub 2020 Jun 29.
Short bowel syndrome (SBS) is associated with changes in the intestinal microbiome and marked local and systemic inflammation. There is also a late complication of SBS, intestinal failure associated liver disease (IFALD) in which hepatic steatosis progresses to cirrhosis. Most patients with SBS arrive at massive intestinal resection after a contaminating intraabdominal catastrophe and have a history of exposure to broad-spectrum antibiotics. We therefore investigated whether the administration of broad-spectrum antibiotics in conjunction with SBS in zebrafish (ZF) would replicate these systemic effects observed in humans to identify potentially druggable targets to aid in the management of SBS and resulting IFALD. In zebrafish with SBS, broad-spectrum antibiotics altered the microbiome, decreased inflammation, and reduced the development of hepatic steatosis. After two weeks of broad-spectrum antibiotics, these fish exhibited decreased alpha diversity, with less variation in microbial community composition between SBS and sham fish. Additionally, administration of broad-spectrum antibiotics was associated with decreased expression of intestinal toll-like receptor 4 (4), increased expression of the intestinal gene encoding the Farnesoid X receptor ( decreased expression of downstream hepatic , and decreased development of hepatic steatosis. SBS in zebrafish reproducibly results in increased epithelial surface area as occurs in human patients who demonstrate intestinal adaptation, but antibiotic administration in zebrafish with SBS reduced these gains with increased cell death in the intervillus pocket that contains stem/progenitor cells. These alternate states in SBS zebrafish might direct the development of future human therapies. In a zebrafish model that replicates a common clinical scenario, systemic effects of the administration of broad-spectrum antibiotics in a zebrafish model of SBS identified two alternate states that led to the establishment of fat accumulation in the liver or its absence. Broad-spectrum antibiotics given to zebrafish with SBS over 2 wk altered the intestinal microbiome, decreased intestinal and hepatic inflammation, and decreased hepatic steatosis.
短肠综合征（SBS）与肠道微生物组的变化以及明显的局部和全身炎症有关。SBS 还有一个晚期并发症，即肠衰竭相关肝病（IFALD），其中肝脂肪变性进展为肝硬化。大多数 SBS 患者在经历了污染性的腹腔灾难后进行了大量的肠切除术，并且有广谱抗生素暴露史。因此，我们研究了在斑马鱼（ZF）中给予广谱抗生素是否会复制人类中观察到的这些全身效应，以确定潜在的可治疗靶点，以帮助管理 SBS 和由此产生的 IFALD。在 SBS 的斑马鱼中，广谱抗生素改变了微生物组，减少了炎症，并减少了肝脂肪变性的发展。在两周的广谱抗生素治疗后，这些鱼的α多样性下降，SBS 和假手术鱼之间的微生物群落组成变化较小。此外，广谱抗生素的给药与肠道 toll 样受体 4（4）的表达降低、肠道编码法尼醇 X 受体的基因表达增加、下游肝脏的表达降低和肝脂肪变性的发展减少有关。SBS 在斑马鱼中可重复性地导致上皮表面积增加，就像在表现出肠道适应的人类患者中一样，但在 SBS 的斑马鱼中给予抗生素会增加含干细胞/祖细胞的绒毛间袋中的细胞死亡，从而减少这些收益。SBS 斑马鱼中的这些替代状态可能指导未来人类治疗的发展。在一种复制常见临床情况的斑马鱼模型中，在 SBS 的斑马鱼模型中给予广谱抗生素的系统效应确定了两种替代状态，导致肝脏中脂肪积累的建立或不存在。在 SBS 的斑马鱼中给予广谱抗生素超过 2 周会改变肠道微生物组，减少肠道和肝脏炎症，并减少肝脂肪变性。
