Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis

Abstract

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Among the numerous contributory factors, the gut microbiota and its metabolites are increasingly recognized as potential modulators of systemic inflammation, acting through multiple gut-organ axes. Within this network, macrophages serve as central integrators that transduce microbial signals into organ-specific inflammatory or reparative outcomes. Disease evolution is critically determined by immune-metabolic reprogramming of macrophages. This reprogramming comprises tricarboxylic acid cycle truncation, lipid remodeling, mitochondrial dysfunction, and inflammasome activation. These processes are closely intertwined with NFκB, cGAS-STING, TLR/MyD88, and aryl hydrocarbon receptor signaling. Gut-derived metabolites, particularly short-chain fatty acids and indole derivatives, shape macrophage functions in distal organs. These mechanisms predominantly operate during the acute phase of sepsis, driving early organ injury. In contrast, sepsis survivors often enter a distinct chronic phase, characterized by persistent immune dysregulation. Trained immunity, through metabolic-epigenetic rewiring, may underlie this long-term dysfunction in survivors. Preclinical promise has been demonstrated by host-directed therapies that target macrophage metabolism. Nevertheless, major challenges impede clinical translation. These include inadequate preclinical models, the absence of validated real-time biomarkers for immune-metabolic phenotyping, and marked heterogeneity among patients. This review positions macrophages as actionable sentinels in gut-organ crosstalk during acute sepsis, and further explores their role in chronic sequelae, underscoring the need for biomarker-guided stratification and precision immune-metabolic editing to overcome barriers in both settings.