O2134: Dietary Fat Composition Influences Liver Injury after Massive Intestinal Resection

Background: Resection-associated liver steatosis, injury, and ultimate fibrosis is a devastating complication after massive small bowel resection (SBR). The optimal enteral feeding formulation to enhance adaptation, preserve barrier function, and attenuate liver injury is unknown. We hypothesized that diets rich in pro-inflammatory omega (n)-6 polyunsaturated fatty acids (PUFAs) are associated with worsened liver injury after massive enterectomy compared to diets rich in anti-inflammatory n-3 PUFAs.

Methods: C57BL/6 mice underwent 75% proximal SBR or sham operation. Mice were fed with n-6 enriched (n=8 SBR, 6 sham), n-3 enriched (n=9 SBR, 6 sham), or control (n=8 SBR, 6 sham) liquid diet post-operatively. Custom diets were isocaloric, isonitrogenous, and equivalent in nutrient composition other than fatty acid profile. At 10 weeks, body composition was determined by MRI, and metabolic profile was assessed by indirect calorimetry. Liver injury was assessed by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations and by hepatic expression of fibrosis-associated genes, COL1A1 and ACTA2. Targeted hepatic lipidomic profiling was completed using liquid chromatography tandem mass spectrometry. ANOVA was used for statistical analyses. The Animal Studies Committee approved these studies (#20-0197).

Results: Mice fed with n-3 diet experienced less weight loss and improved weight gain following 75% SBR (p < 0.001, Figure 1A). Diet did not significantly impact body composition. The respiratory energy ratio did not differ significantly based on diet after 75% SBR. However, absolute oxygen consumption, carbon dioxide production, and energy expenditure was lowest among the n-3 cohort (Figure 1B). Surprisingly, SBR mice fed either n-3 or n-6 diets showed reduced liver injury compared to control diet as indicated by reduced serum AST and ALT and reduced expression of fibrosis-associated genes, COL1A1 and ACTA2 (Figure 1C-D). Liver lipidomic analysis of SBR mice showed unique free fatty acid profiles that reflected dietary intake. n-3 mice demonstrated increased eicosapentaenoic acid and docosahexanoic acid (both n-3 PUFAs); n-6 mice showed increased linoleic acid (an n-6 PUFA), and control mice demonstrated a predominance of oleic acid and palmitic acid (Figure 2A-B). Additionally, the total liver triacylglycerol (TAG) content was greatest in SBR control mice, intermediate in n-6 mice, and least in n-3 mice (p < 0.0001, Figure 2C).

Conclusion: Following 75% SBR, mice fed an n-3 enriched diet showed improved weight trajectory and metabolic profile compared to mice fed an n-6 enriched or control diets. Interestingly, both n-3 enriched and n-6 enriched diets correlated with reduced liver injury after 75% SBR, indicating that dietary fat composition influences liver injury after SBR, but the n-3: n-6 ratio is unlikely to be the specific driver. The relative scarcity of TAGs in livers of n-3 fed mice suggests these mice have improved processing of free fatty acids, and therefore they are not storing them in the liver.