The Gut Microbiome and Short-Chain Fatty Acid Metabolites in Sepsis

Sepsis profoundly perturbs the intestinal microbiome and its metabolite output, yet the mechanisms by which these changes influence organ injury remain incompletely defined. In this review, we focus on short-chain fatty acids (SCFAs) as key mediators linking gut microbes to sepsis pathophysiology. We first summarize how sepsis and its treatments reshape gut communities, depleting SCFA-producing anaerobes and altering the gut metabolome. We then examine determinants of SCFA concentrations in the intestinal lumen and describe how gut-blood trafficking of these charged metabolites depends on epithelial transporters and tight-junction-regulated paracellular pathways. We highlight emerging data on how leak and pore pathways, including claudin-2-dependent pores, are upregulated in sepsis and may misdirect microbial products into the portal and systemic circulation. Finally, we synthesize experimental and human evidence for organ-specific effects of individual SCFAs: butyrate as a colonocyte fuel and barrier stabilizer, propionate as a modulator of lung immune tone, and acetate as a systemic immunometabolite that shapes inflammatory responses and sepsis outcomes. Across these sections, we outline therapeutic strategies that aim to preserve or restore SCFA-producing microbes, modify diet, target transport and permeability pathways, or deliver microbial metabolites directly. Together, these data position SCFAs and their trafficking as central to the gut-sepsis axis and as promising targets for future precision therapies.