Department of Pathology at Saint Louis University School of Medicine, SSM Cardinal Glennon Hospital, 1465 South Grand Blvd., St. Louis, MO 63104, USA.
Department of Pediatrics at Saint Louis University School of Medicine, SSM Cardinal Glennon Hospital, 1465 South Grand Blvd., St. Louis, MO 63104, USA.
Nutrients. 2020 May 20;12(5):1493. doi: 10.3390/nu12051493.
Total parenteral nutrition (TPN) provides all nutritional needs intravenously. Although lifesaving, enthusiasm is significantly tempered due to side effects of liver and gut injury, as well as lack of mechanistic understanding into drivers of TPN injury. We hypothesized that the state of luminal nutritional deprivation with TPN drives alterations in gut-systemic signaling, contributing to injury, and tested this hypothesis using our ambulatory TPN model.
A total of 16 one-week-old piglets were allocated randomly to TPN ( = 8) or enteral nutrition (EN, = 8) for 3 weeks. Liver, gut, and serum were analyzed. All tests were two-sided, with a significance level of 0.05.
TPN resulted in significant hyperbilirubinemia and cholestatic liver injury, = 0.034. Hepatic inflammation (cluster of differentiation 3 (CD3) immunohistochemistry) was higher with TPN ( = 0.021). No significant differences in alanine aminotransferase (ALT) or bile ductular proliferation were noted. TPN resulted in reduction of muscularis mucosa thickness and marked gut atrophy. Median and interquartile range for gut mass was 0.46 (0.30-0.58) g/cm in EN, and 0.19 (0.11-0.29) g/cm in TPN ( = 0.024). Key gut-systemic signaling regulators, liver farnesoid X receptor (FXR; = 0.021), liver constitutive androstane receptor (CAR; = 0.014), gut FXR ( = 0.028), G-coupled bile acid receptor (TGR5) ( = 0.003), epidermal growth factor (EGF; = 0.016), organic anion transporter (OAT; = 0.028), Mitogen-activated protein kinases-1 (MAPK1) ( = 0.037), and sodium uptake transporter sodium glucose-linked transporter (SGLT-1; = 0.010) were significantly downregulated in TPN animals, whereas liver cholesterol 7 alpha-hydroxylase (CyP7A1) was substantially higher with TPN ( = 0.011).
We report significant alterations in key hepatobiliary receptors driving gut-systemic signaling in a TPN piglet model. This presents a major advancement to our understanding of TPN-associated injury and suggests opportunities for strategic targeting of the gut-systemic axis, specifically, FXR, TGR5, and EGF in developing ameliorative strategies.
全肠外营养（TPN）通过静脉途径提供所有营养需求。尽管它可以救命，但由于肝脏和肠道损伤的副作用，以及对 TPN 损伤驱动因素缺乏机制上的理解，人们对其的使用热情大大降低。我们假设 TPN 导致的肠道内腔营养剥夺状态会改变肠道-全身信号，导致损伤，并使用我们的可移动 TPN 模型来验证这一假设。
总共 16 只一周大的小猪被随机分配到 TPN（n=8）或肠内营养（EN，n=8）组，进行 3 周的治疗。分析肝脏、肠道和血清。所有测试均为双侧检验，显著性水平为 0.05。
TPN 导致明显的高胆红素血症和胆汁淤积性肝损伤，P=0.034。TPN 组的肝炎症（CD3 免疫组化）更高，P=0.021。丙氨酸氨基转移酶（ALT）或胆管增生无显著差异。TPN 导致黏膜肌层厚度减少和明显的肠道萎缩。EN 组肠道质量中位数和四分位距为 0.46（0.30-0.58）g/cm，TPN 组为 0.19（0.11-0.29）g/cm，P=0.024。关键的肠道-全身信号调节因子，肝脏法尼醇 X 受体（FXR；P=0.021）、肝脏组成型雄烷受体（CAR；P=0.014）、肠道 FXR（P=0.028）、G 蛋白偶联胆汁酸受体（TGR5；P=0.003）、表皮生长因子（EGF；P=0.016）、有机阴离子转运蛋白（OAT；P=0.028）、丝裂原激活蛋白激酶 1（MAPK1；P=0.037）和钠葡萄糖共转运蛋白 1（SGLT-1；P=0.010）在 TPN 动物中显著下调，而肝脏胆固醇 7α-羟化酶（CyP7A1）在 TPN 中明显升高，P=0.011。
我们报告了 TPN 仔猪模型中关键肝胆受体的显著改变，这些改变驱动着肠道-全身信号。这是我们对 TPN 相关损伤理解的重大进展，并为靶向肠道-全身轴的策略提供了机会，特别是 FXR、TGR5 和 EGF，以开发改善策略。
