<![CDATA[Background: Metabolic dysfunction-associated steatohepatitis (MASH) is driven by breakdown of the gut-liver axis. Loss of short-chain fatty acid (SCFA)-producing commensals weakens mucosal tight junctions and allows portal translocation of lipopolysaccharide (LPS), which activates hepatic Kupffer cells and promotes fibrosis. The Indonesian Jamu formulations Beras Kencur (Kaempferia galanga and Oryza sativa) and Kunyit Asam (Curcuma longa and Tamarindus indica) act at this mucosal interface. Objective: To delineate the multi-target systems pharmacology of Jamu phytomolecules across the gut-liver axis. Methods: Fecal shotgun metagenomes (BioProject PRJNA737472; N = 180: 60 healthy controls, 60 non-alcoholic fatty liver and 60 MASH) were profiled with MetaPhlAn 4 and HUMAnN 3. Community flux balance analysis of a four-species commensal consortium was performed in AGORA2 using COBRApy, and molecular docking was run in AutoDock Vina 1.2.0 against tight junction, innate immune and nuclear receptor targets. Results: Faecalibacterium prausnitzii (−77.4%) and Akkermansia muciniphila (−83.5%) were depleted in MASH (both p < 0.001), together with the SCFA biosynthetic genes but (−58.4%), pct (−46.2%) and ackA (−38.7%). Jamu supplementation restored acetate cross-feeding and raised community butyrate secretion by 84.6% (0.422 to 0.779 mmol/gDW/h). Ethyl p-methoxycinnamate bound the Toll-like receptor 4/myeloid differentiation factor 2 complex (ΔG = −8.84 kcal/mol; inhibition constant, Ki = 0.33 µM), curcumin bound Occludin (ΔG = −8.92 kcal/mol) and demethoxycurcumin bound zonula occludens-1 (ΔG = −8.45 kcal/mol). Barrier reinforcement reduced modeled portal LPS influx by 68%. Conclusion: Beras Kencur and Kunyit Asam restore commensal SCFA cross-feeding, reinforce the mucosal barrier and attenuate endotoxin-driven hepatic inflammation in MASH.]]>
