Bidirectional mechanisms of brain-gut interaction in sepsis-associated encephalopathy and its clinical translation

Sepsis-associated encephalopathy (SAE) is the most common and deadly neurological issue linked to sepsis. While traditionally thought to result from brain-specific processes like blood-brain barrier disruption and microglial activation, the exact systemic infection pathways causing brain damage are not well understood. As the gut-brain axis (GBA) theory gains traction, research on SAE is shifting from a brain-focused to a systemic view. This article reviews the two-way interactions between the brain and gut in SAE. In the gut-to-brain pathway, sepsis-induced dysbiosis of the gut microbiota promotes neuroinflammation via immune, metabolic, neurological, and endocrine pathways. In the descending GBA pathway, brain injury further impairs intestinal barrier function and gut microbiota homeostasis via autonomic nervous system dysfunction, excessive hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, and the migration of brain-derived immune cells into the intestine, thereby forming a vicious cycle of synergistic dual-barrier destruction. Building on the existing mechanism, diagnostic and therapeutic strategies targeting the GBA are quickly moving towards clinical use. Intestinal molecules like fecal miRNA show promise as early SAE biomarkers. Treatments such as fecal microbiota transplantation and probiotics could restore gut health and reduce neuroinflammation. Additionally, targeted interventions like SCFA supplementation, tryptophan pathway modulation, and γδ T17/STING axis inhibition have shown neuroprotective effects in animal studies. Future integration of multi-omics and mechanism-based trials will enhance precise SAE diagnosis and treatment.