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Decreased Fecal Microbial Metabolite Enterolactone is a Novel Inflammatory and Oxidative Stress Related Biomarker of Alcoholic Liver Disease
Puneet Puri* 1, Faridoddin Mirshahi 1, Mohammad S. Siddiqui 1, Sherry Boyett 1, Carol C. Sargeant 1, Andrew Joyce 2, Velimir A. Luketic 1, Arun J. Sanyal 1
1Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, 2Venebio Inc, Richmond, Virginia
Alcoholic liver disease (ALD) results in significant morbidity and mortality with limited treatment options. Inflammatory and oxidative stress pathways contribute significantly in the pathogenesis of ALD. However, there are no well-established markers to distinguish ALD from similar appearing nonalcoholic fatty liver disease (NAFLD) and healthy controls (HC). We hypothesized that ALD has unique inflammatory and oxidative stress signature.
AIMS: To define fecal metabolome of microbial origin in HC, NAFLD and ALD subjects and (2) Biomarker that distinctly separates ALD from NAFLD and HC. Methods: After informed consent, HC, NAFLD and ALD subjects were recruited. The pertinent clinical data were obtained and fecal samples collected. These were processed and high throughput mass spectrometry was performed. Multivariate regression analysis including partial least square discriminant analysis, variable importance projection scores and biomarker discovery analysis using area under the receiver operating curve (AUROC) was performed. Results: Total of 50 age and gender matched subjects (17 healthy controls, 15 NAFLD and 18 ALD) were recruited. Fecal metabolomic analysis revealed significant changes in various metabolites which were significantly lower in ALD subjects (all p<0.05) including enterolactone, L-urobilin, deoxycholate, lithocholate and dehydrolithocholate. The enterolactone was significantly lower in ALD compared to HC (p<0.0001) and the AUROC was 0.95 to distinguish the two groups. The diglycerol/enterolactone ratio was 4.3 fold higher in ALD compared to healthy controls (p<0.00005) driven by decreased enterolactone levels. Interestingly, diglycerol/enterolactone ratio cut off of 2.01 distinguishes ALD from healthy controls with 100% sensitivity and 94% specificity, with AUROC 0.99 and a positive likelihood ratio of 18.0. CONCLUSION: Enterolactone is a lignan formed by enterobacteria from precursors in plant foods. Due to its phenolic structure, it can act as an antioxidant via direct scavenging of hydroxyl radical. Moreover, phenolic compounds can have indirect antioxidative effects through induction of heme oxygenase-1 (HO-1), which has anti-inflammatory functions. Thus decreased enterolactone is a distinct biomarker of ALD.
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