Microbiota-derived succinic acid mediates attenuating effect of dietary tomato juice supplementation on steatohepatitis through enhancing intestinal barrier.

The hepatoprotective potential of tomato juice (TJ) has been reported in chronic liver models, and its potential prebiotic properties may be key to its preventative effects. However, the mechanistic role of the gut microbiota and its derived metabolites in ameliorating nonalcoholic steatohepatitis (NASH) via TJ remains unclear. In this study, we explored how TJ regulates gut microbiota and succinic acid (SA) to restore intestinal barrier function and thus suppress NASH progression. TJ supplementation effectively reduced serum lipid concentrations, alleviated endotoxin levels, and suppressed activation of the endotoxin-TLR4-NF-κB pathway in methionine-choline-deficient (MCD) diet-induced NASH mice. TJ restored the MCD diet-induced gut microbiota dysbiosis, increased the abundance of short-chain fatty acid and SA-producing bacteria (Bifidobacterium, Ileibacterium, Odoribacter, and Parasutterella) and enhanced the expression of intestinal barrier-associated proteins (E-cadherin, Claudin-1, MUC-2, and ZO-1). The hepatoprotective and enteroprotective effects of TJ were abolished in an antibiotic-treated mouse model, underscoring the pivotal role of the gut microbiota in the beneficial effects of TJ on NASH. Fecal metabolomics demonstrated that TJ significantly upregulated the tricarboxylic acid cycle, pyruvate metabolism, and butanoate metabolism pathways, increasing levels of butyric acid (BA) and SA-metabolites associated with reduced hepatic steatosis and intestinal damage. We further found that the physiological concentration of SA, rather than BA, could reduce pro-inflammatory cytokines (TNF-α and IL-6) levels and enhance mucin proteins and tight junction markers in the LPS-induced colon cell line LS174T. This study uncovers new mechanisms by which TJ prevents NASH, highlighting the potential of TJ and SA as effective dietary supplements for patients with chronic liver diseases.