Lauren K Barron1, James W Bao1, Bola G Aladegbami1, Jason J Colasanti1, Jun Guo1, Christopher R Erwin1, Brad W Warner2. 1. Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; St. Louis Children's Hospital, St. Louis, MO, USA. 2. Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; St. Louis Children's Hospital, St. Louis, MO, USA. Electronic address: Brad.Warner@wustl.edu.
Abstract
BACKGROUND: A significant number of children with short bowel syndrome experience intestinal failure-associated liver disease. We recently demonstrated accelerated hepatic steatosis after 50% small bowel resection (SBR) in mice. Since SBR is associated with alterations in the gut microbiome, the purpose of this study was to determine whether TLR4 signaling is critical to the development of resection-associated hepatic steatosis. METHODS: Male C57BL6 (control) and TLR4-knockout (KO) mice underwent 50% proximal SBR. Liver sections were analyzed to obtain the percent lipid content, and Ileal sections were assessed for morphological adaptation. Intestinal TLR4 mRNA expression was measured at 7days and 10weeks. RESULTS: Compared to controls, TLR4 KO mice demonstrated similar weight gain and morphological adaptation after SBR. Hepatic steatosis was decreased 32-fold in the absence of TLR4. Intestinal TLR4 mRNA expression was significantly elevated 7days after SBR. We also found that TLR4 expression in the intestine was 20-fold higher in whole bowel sections compared with isolated enterocytes. CONCLUSIONS: TLR4 signaling is critical for the development of resection-associated steatosis, but not involved in intestinal adaptation after massive SBR. Further studies are needed to delineate the mechanism for TLR4 signaling in the genesis of resection-associated liver injury. LEVEL OF EVIDENCE: Animal study, not clinical.
BACKGROUND: A significant number of children with short bowel syndrome experience intestinal failure-associated liver disease. We recently demonstrated accelerated hepatic steatosis after 50% small bowel resection (SBR) in mice. Since SBR is associated with alterations in the gut microbiome, the purpose of this study was to determine whether TLR4 signaling is critical to the development of resection-associated hepatic steatosis. METHODS: Male C57BL6 (control) and TLR4-knockout (KO) mice underwent 50% proximal SBR. Liver sections were analyzed to obtain the percent lipid content, and Ileal sections were assessed for morphological adaptation. Intestinal TLR4 mRNA expression was measured at 7days and 10weeks. RESULTS: Compared to controls, TLR4 KO mice demonstrated similar weight gain and morphological adaptation after SBR. Hepatic steatosis was decreased 32-fold in the absence of TLR4. Intestinal TLR4 mRNA expression was significantly elevated 7days after SBR. We also found that TLR4 expression in the intestine was 20-fold higher in whole bowel sections compared with isolated enterocytes. CONCLUSIONS:TLR4 signaling is critical for the development of resection-associated steatosis, but not involved in intestinal adaptation after massive SBR. Further studies are needed to delineate the mechanism for TLR4 signaling in the genesis of resection-associated liver injury. LEVEL OF EVIDENCE: Animal study, not clinical.
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