MetALD Liver Transcriptome Resides Closer to MASLD Than ALD: A Surrogate Analysis for Auto-Brewery Syndrome with MASLD

Auto-brewery syndrome (ABS) is an ultra-rare condition characterized by endogenous ethanol (EtOH) production via gut fermentation. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~30% of the adult population globally. Consequently, an estimated 30% of patients with ABS are likely to also present with MASLD. Our hypothesis is that patients with ABS+MASLD are at risk for a two-hit hepatic insult in the form of MASLD and EtOH exposure. Since liver transcriptomic datasets for ABS+MASLD do not exist we utilized metabolic dysfunction- and alcohol-related liver disease (MetALD) as a surrogate to delineate the potential liver transcriptome in ABS+MASLD. We curated public murine liver transcriptomic datasets for MASLD (high-fat diet, HFD), MetALD (HFD+EtOH), and alcohol-related liver disease (ALD; EtOH alone). Genes of interest were identified using pi-scores which combine the magnitude of change in gene expression and its statistical significance. Pairwise transcriptomic similarity across top pi-score-ranked upregulated, downregulated, and combined gene sets was quantified using the Jaccard Tanimoto Similarity Index (JTSI). Gene Ontology (GO) Biological Process (BP) overrepresentation analysis was conducted to identify underlying signal transduction pathways. The liver transcriptomic signature of MetALD resides significantly closer to MASLD than to ALD across all pi-score lists. Upregulated pi-score genes showed a JTSI of 0.1342 for MetALD-MASLD versus 0.0256 for MetALD-ALD (5.23-fold greater similarity for MASLD). Downregulated pi-score genes demonstrated a JTSI of 0.0830 for MetALD-MASLD versus 0.0086 for MetALD-ALD (9.68-fold greater similarity for MASLD). Overall combined distance revealed ALD to be 3.82-fold further from MetALD than MASLD. GOBP pathway enrichment revealed shared immune activation and profound metabolic collapse in sterol/cholesterol biosynthesis, fatty acid processing, and insulin signaling. In MetALD, and by extension, in ABS+MASLD, the liver transcriptome is dominated by HFD and metabolic stress rather than EtOH exposure. These data suggest that patients presenting with ABS+MASLD should focus on initiating dietary and metabolic corrections for the clinical management of their liver disease.