Enteral Feeding With Omega-3 Polyunsaturated Fatty Acids Mitigates Liver Injury Following Massive Intestinal Resection.

BACKGROUND & AIMS: Intestinal failure-associated liver disease results from massive small bowel resection (SBR). We assessed the impact of isocaloric enteral omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) on intestinal function and liver injury following massive enterectomy.

METHODS

Male C57BL/6J mice underwent SBR or sham operation. Mice received either ω-3-enriched, ω-6-enriched, or a balanced saturated/monounsaturated/PUFA (control) diet postoperatively. At 10 weeks, body composition, metabolic profiles, intestinal adaptation, and liver injury were assessed. Targeted lipidomic profiling and bulk RNA sequencing of liver and intestine was completed. The role of Pparα activity was assessed in vivo by genetic deletion and pharmacologic activation.

RESULTS

ω-3-fed mice experienced improved weight recovery and more efficient energy metabolism following SBR. Compared with control mice, SBR mice fed either ω-3 or ω-6 diets showed reduced serum aspartate aminotransferase and alanine aminotransferase. Hepatic free fatty acid analysis reflected dietary intake. Hepatic steatosis and fibrosis was lowest in ω-3, intermediate in ω-6, and highest in control mice following SBR. Hepatic RNA sequencing found upregulation of fibrotic pathways in both the SBR control and SBR ω-6 with lipid metabolism upregulated in the SBR ω-3. Pparα was shown to be necessary for survival but not sufficient for hepatoprotection following SBR, which suggested that ω-3 fatty acids engage in Pparα-independent effects. RNA sequencing of the remnant ileum found ω-3 fatty acids promote upregulation of genes related to lipid metabolism and nutrient absorption consistent with a more proximal intestinal identity.

CONCLUSIONS

These data suggest that enteral feeding with ω-3 PUFAs improves intestinal functional adaptation and protects the liver injury after SBR while improving weight recovery and energy expenditure.