Sepsis Reimagined: The Immunometabolic and Microbiome Frontiers of Sepsis

Abstract

Sepsis is a life-threatening syndrome arising from a dysregulated host response to infection, culminating in organ dysfunction, circulatory collapse, and persistently high global mortality. Conventional management, including timely antibiotics, fluid resuscitation, and vasopressor support, targets infection control and hemodynamics but does not adequately address the deeper immune, metabolic, and microbiome disturbances that fundamentally drive sepsis progression. Growing evidence highlights the central roles of innate immune dysregulation, endothelial injury, mitochondrial dysfunction, and neuroimmune crosstalk in triggering multi-organ failure. The gut microbiome has emerged as a key regulator of host immunity, metabolism, and epithelial integrity. Its metabolites, especially short-chain fatty acids, promote immune homeostasis, while sepsis-induced dysbiosis exacerbates inflammation, increases gut permeability, and fuels systemic deterioration. Parallel research shows that immunometabolic reprogramming determines whether patients develop overwhelming hyperinflammation or profound immunoparalysis, emphasizing the need for precision-based therapeutic strategies. Emerging interventions, including mitochondria-targeted antioxidants, metabolic modulators, probiotics, synbiotics, fecal microbiota transplantation, postbiotics, and selective immunotherapies, demonstrate significant promise in preclinical studies. However, translation into consistent clinical benefit remains limited, underscoring the complexity of sepsis pathobiology. Integrating these mechanistic insights with clinical practice may support the development of personalized, immunometabolic, and microbiome-directed therapeutic approaches that complement conventional care. Such strategies aim to restore host homeostasis, improve organ recovery, and ultimately reduce sepsis-related morbidity and mortality.