O2130: An Engineered Medium-Chain Fatty Acid Analogue Protects Against Lipopolysaccharide-Induced Liver Injury in a Murine Model of Intestinal Failure-Associated Liver Disease

Background: Pediatric patients may develop short bowel syndrome as a result of surgical resections. Parenteral nutrition (PN)-dependent patients with short bowel syndrome are at risk of developing life-threatening complications, including intestinal failure-associated liver disease (IFALD) and central line-associated bloodstream infections (CLABSIs). IFALD pathophysiology involves a “two-hit” injury resulting from hepatosteatosis and bacterial endotoxin-driven inflammation. Large and small animal models have demonstrated the hepatoprotective and anti-inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 would protect against lipopolysaccharide (LPS) toxin-induced liver injury in an established murine model of PN-induced hepatosteatosis.

Methods: Eight-week-old C57BL/6J wild-type mice received PN-equivalent intake over a 19-day period, including oral fat-free, high-carbohydrate PN solution ad lib and intravenous injection of a soybean oil-based lipid emulsion (Intralipid, 4g fat/kg/d) or isovolumetric saline control q.o.d. Mice received SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) via oral gavage daily on days 15-18. Intraperitoneal LPS (15 mg/kg) or isovolumetric saline vehicle was administered 6 hours before sacrifice on day 19. Chow-fed control groups were treated and euthanized in parallel. The primary outcome was assessment of liver injury via serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Levels of LPS-induced production of pro-inflammatory cytokines, IL-6 and TNF-alpha, were additionally assayed.

Results: LPS-challenged mice had elevated serum levels of ALT and AST compared to saline-treated controls in all groups. In animals who underwent a “two-hit” injury of IFALD and endotoxin challenge, SEFA-6179 pre-treatment normalized liver enzymes compared to vehicle controls (Figure 1A, B). This effect was observed for both saline- and Intralipid-treated PN groups. Chow-fed mice treated with SEFA-6179 had lower AST levels compared to vehicle controls (Figure 1C). Among endotoxin-challenged IFALD mice, SEFA-6179 pre-treatment reduced IL-6 levels in serum (Figure 2A) and TNF-alpha in liver lysate (Figure 2B).

Conclusion: Pre-treatment with SEFA-6179 normalized liver enzymes and reduced downstream pro-inflammatory cytokines, IL-6 and TNF-alpha, compared to vehicle in a “two-hit” murine model of PN-induced hepatosteatosis and LPS-induced inflammation. These findings have clinical implications for short bowel syndrome or otherwise PN-dependent patients who are at risk of both chronic hepatosteatosis and CLABSIs. Based in part on this work, SEFA-6179 is now in a Phase 2 clinical trial in patients with IFALD.