Invited Commentary for Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury

Abstract

In this issue, Tecos et al [ 1 Tecos ME Steinberger AE Guo J Rubin DC Davidson NO Warner BW Disruption of enterohepatic circulation of bile acids ameliorates small bowel resection associated hepatic injury. J Pediatr Surg. 2023; (in press) Google Scholar ] expand on their previous demonstration that parenteral nutrition (PN)-independent hepatoxicity in a murine small bowel resection (SBR) model is region dependent and may be mitigated by tauroursodeoxycholic acid (TUDCA) supplementation. Interestingly, these results contradict a previous report from their own group as to the impact of proximal vs. distal resection, seemingly due to the presence or absence of the ileocecal valve (ICV) and adjacent bowel, which differed between the two studies [ 2 Barron LK Gayer GP Roberts A Golden JM Aladegbami BG Guo J Erwin CR Warner BW Liver steatosis induced by small bowel resection is prevented by oral vancomycin. Surgery. 2016; 160: 1485-1495 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar ]. Dr. Warner’s group was the first to report liver injury in a PN-independent murine SBR model [ 3 Chiang JYL Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 2017 Jun; 1: 3-9 Crossref PubMed Scopus (140) Google Scholar ]. In this latest study, they reveal that proximal SBR results in greater oxidative stress in the liver as evidenced by elevated mRNA transcripts for tumor necrosis factor-α, nicotininamide adenine dinucleotide phosphate oxidase, and glutathione synthetase with a greater compensatory antioxidant response consisting of elevated lipocalin 2. Furthermore, distal SBR demonstrated decreased hepatic bile acid content, smaller total bile acid pool size, and significant changes in bile acid composition, such as a decrease in the most insoluble, toxic, and hydrophobic bile acids, as well as an increase in de novo bile acid synthesis of physiologic, less toxic, hydrophilic bile acids. Equally compelling, the hepatotoxicity and injurious bile acid profile observed in proximal SBR was mitigated by exogenous TUDCA supplementation. In addition to these intriguing observations, the authors propose a mechanism for this difference. Distal SBR results in disruption of enterohepatic bile acid recycling, leading to amplified production of more physiologic, less toxic, and more hydrophilic bile acids, resulting in less oxidative stress to the liver and ultimately decreased liver injury. While TUDCA had similar hepatoprotective effects to distal SBR, they were not identical, and thus, the authors suggest it may differ in mechanism of action. Regardless, this study expands on the identification of therapeutic targets for intestinal failure-associated liver disease.