Maalumi, O.; Ben Moshe, Z.; Blank, O.; Barkan-Michaeli, R.; Yona, A.; Sharabi, K.

The gut microbiota produces metabolites that circulate to host tissues and are increasingly linked to metabolic health, yet the mechanisms by which individual microbial products regulate liver glucose metabolism remain poorly defined. Here, we identify the tryptophan-derived microbial metabolite indole-3-propionic acid (IPA) as a direct modulator of hepatic glucose production. In primary hepatocytes, a focused screen of indole metabolites revealed that several indole-containing compounds suppress glucagon-stimulated glucose output, with IPA emerging as a physiologically relevant candidate. IPA selectively reduced glucose production from mitochondrial-dependent gluconeogenic substrates while largely preserving glycerol-supported glucose production, suggesting that it does not simply shut down gluconeogenesis but instead alters how hepatocytes use metabolic fuels. Mechanistic analyses showed that IPA redirects lactate-derived carbon away from glucose production and reshapes mitochondrial metabolism, including redox balance, ATP availability, and urea cycle-linked metabolic activity. These effects occurred without detectable disruption of proximal insulin or glucagon signaling, supporting a model in which IPA acts primarily through intracellular metabolic remodeling. In mice, endogenous IPA levels varied with nutritional state, and short-term IPA administration improved fasting glycemia and glucose handling in Western diet-fed animals. Finally, microbiome-depleted mice colonized with IPA-producing Clostridium sporogenes displayed increased circulating IPA and improved glucose tolerance compared with mice colonized with an IPA-deficient mutant C. Sporogenes strain. Together, these findings identify IPA as a microbial metabolite that directly connects gut tryptophan metabolism to hepatic mitochondrial function and systemic glucose regulation, highlighting a mechanistic gut-liver pathway with potential therapeutic relevance to metabolic disease.