Dissociation between gut microbiota remodeling and early gut-liver injury in CLP-induced sepsis

Introduction: Sepsis is a life-threatening condition in which early host responses critically determine organ dysfunction, yet strategies targeting this critical window remain limited. We investigated whether pre-septic modulation of host metabolism and gut microbiota could mitigate early organ injury in severe polymicrobial sepsis. Methods: Male Sprague-Dawley rats were pretreated for 4 weeks and then subjected to cecal ligation and perforation (CLP). Outcomes were assessed within the first 24 h after sepsis induction, with survival monitored for 7 days. Gut microbiota composition was analyzed at the group level before and after CLP. Results: Early sepsis was characterized by adrenal catecholamine depletion, ileal villus shortening, colonic inflammatory activation, rapid gut microbiota restructuring, and hepatic oxidative stress with selective inflammatory transcriptional activation. Although pretreatments altered baseline gut microbiota composition and partially preserved commensal and short-chain fatty acid-associated taxa, they did not improve survival nor prevent early intestinal and hepatic injury. Early mortality occurred exclusively in meldonium-pretreated animals, indicating a potential trade-off of metabolic preconditioning under severe septic stress. Despite pretreatment-specific modulation of selected antioxidant enzymes, hepatic redox imbalance and stress-associated protein oxidation persisted during early sepsis. Discussion: Collectively, these observations indicate an apparent dissociation at the group level between gut microbiota remodeling and early gut-liver injury. The first 24 h after sepsis onset thus emerge as a period of limited pharmacological plasticity, underscoring the need for therapeutic strategies that directly target the robust, systemic, host-driven stress mechanisms predominating during this early phase in severe sepsis.