Liver steatosis induced by small bowel resection is prevented by oral vancomycin

Abstract

Background Intestinal failure-associated liver disease (IFALD) causes significant mortality in patients with short bowel syndrome (SBS). Steatosis, a major component of IFALD has been shown to persist even after weaning from parenteral nutrition. We sought to determine whether steatosis occurs in our murine model of SBS, and more importantly, whether steatosis was affected by manipulation of the intestinal microbiome. Methods Male C57BL6 mice underwent 50% small bowel resection (SBR) and orogastric gavage with vancomycin or vehicle for 10 weeks. DNA was extracted from stool samples then sequenced using 16s rRNA. Liver lipid content was analyzed. Bile acids were measured in liver and stool. Results Compared with unoperated mice, SBR resulted in significant changes in the fecal microbiome and was associated with > 25-fold increase in steatosis. Oral vancomycin profoundly altered the gut microbiome and was associated with a 15-fold reduction in hepatic lipid content after resection. There was a 17-fold reduction in fecal secondary bile acids after vancomycin treatment. Conclusion Massive SBR in mice is associated with development of steatosis, and prevented by oral vancomycin. These findings implicate a critical role for gut bacteria in IFALD pathogenesis and illuminate a novel surgical model for future investigation into this important morbidity.

Toll-like receptor 4 is critical for the development of resection-associated hepatic steatosis

“…In addition to the role for Gram-negative bacteria, LPS, and TLR4, we have recently reported that treatment with oral vancomycin also prevented the hepatic steatosis associated with SBR in our murine model(9). Vancomycin is not absorbed from the gastrointestinal tract and kills Gram-positive bacteria, which have been described to bloom in the gut of mice after SBR(35) and patients(21, 36) with short gut syndrome.…”

“…(9) Most murine models of NAFLD employ two basic approaches: genetic or nutritional. (10, 11) Our recently published model is most similar to the high fat diet models with the striking difference that after SBR mice have more severe steatosis sooner (10 weeks) with less fat (35%) in their diet.…”

“…(10, 11) Our recently published model is most similar to the high fat diet models with the striking difference that after SBR mice have more severe steatosis sooner (10 weeks) with less fat (35%) in their diet. (9, 12) Given the many similarities between the models, the purpose of this study is to elucidate the role of TLR4 in resection-associated hepatic steatosis.…”

Surgical Anatomy Does Not Affect the Progression of Intestinal Failure–Associated Liver Disease in Neonatal Piglets

“…In a cross‐sectional study of patients with pediatric‐onset intestinal failure, either weaned from or continuing to receive PN, liver fibrosis was observed to be more advanced in patients without an ICV, and lack of the ICV was determined to be the strongest predictor of fibrosis . Yet despite observations that the provision of PN and remnant anatomy in SBS may increase the risk of IFALD, studies of IFALD mechanisms often use gut‐resected, enterally fed animal models with the ileum and ICV in situ –. Evidence is beginning to emerge on the differential effects of surgical anatomy on the development of IFALD, but much is yet to be learned.…”

Intestinal resection-associated metabolic syndrome

“…Similar to MeS, data demonstrate that perturbations in glucose homeostasis are linked to non-alcoholic fatty liver disease (NAFLD)[7]. In addition to changes in body composition, previous studies from our lab have found that mice develop hepatic steatosis 10 weeks after small bowel resection [8]. Given our findings of altered body composition and development of steatosis resembling models of MeS and NAFLD, the purpose of this study was to test the hypothesis that massive intestinal resection results in perturbed glucose homeostasis due to a systemic proinflammatory response.…”