Gut microbiota–host co-metabolism in sepsis and critical illness: source, compartment, immune state, and host defense

Critical illness can profoundly disturb the intestinal microbiota–metabolite–host immune axis through the combined effects of shock, hypoxia, altered nutritional intake, antimicrobial exposure, organ dysfunction, and impaired epithelial barrier integrity. These changes can reshape microbial metabolic capacity, host co-metabolism, and systemic metabolite exposure, while the host may simultaneously exhibit overlapping features of hyperinflammation, immune tolerance, lymphocyte dysfunction, impaired antimicrobial defense, and tissue repair. Metabolites generated through microbial metabolism or shared microbial–host pathways may therefore contribute to immune reprogramming, although their effects are highly context dependent and cannot be regarded as uniformly beneficial or detrimental. This narrative review examines short-chain fatty acids, tryptophan-derived indoles, secondary bile acids, succinate, lactate, trimethylamine N-oxide, polyamines, and aromatic metabolites, with particular attention to source attribution, anatomical compartment, host co-metabolism, receptor signaling, and their potential influence on antimicrobial immunity. These metabolites may act through G-protein-coupled receptors, AhR, PXR, FXR, TGR5, VDR, HIF-1α, inflammasome pathways, mitochondrial signaling, and epigenetic mechanisms to modulate macrophages, neutrophils, dendritic cells, innate lymphoid cells, T lymphocytes, epithelial barriers, and endothelial responses. The direction and magnitude of these effects are likely to vary according to timing, concentration, anatomical compartment, immune-cell state, pathogen burden, and renal or hepatic clearance. Within this framework, attenuation of inflammatory signaling may help limit early collateral tissue injury, yet the same response could become disadvantageous when antimicrobial competence is already impaired. Similarly, succinate and lactate may reflect or contribute to distinct inflammatory, regulatory, or reparative programs depending on whether they arise from microbial or host metabolism and whether they act within intracellular or extracellular compartments. Human studies in critically ill populations have linked dysbiosis and metabolomic alterations with secondary infection, prolonged organ support, and mortality; however, most have not been able to resolve microbial source attribution or establish causal mediation. Future work would therefore benefit from integrating longitudinal microbiome, metabolome, immune-function, and organ-clearance measurements with source-resolved approaches, including isotope tracing, as well as state-specific and trajectory-informed clinical endpoints. Microbiome-directed interventions may be most appropriately investigated as context-dependent modulators of host defense rather than as broadly anti-inflammatory strategies.