Gut–Brain Axis and Nutrition in Sepsis-Associated Encephalopathy: A Narrative Review

Background: Sepsis-associated encephalopathy (SAE) is among the most frequent neurological complications of sepsis, contributing independently to mortality, prolonged mechanical ventilation and intensive care unit stay and long-term cognitive disability. The gut–brain axis has been proposed as a key mediator, through dysbiosis, intestinal barrier failure, bacterial translocation and neuroinflammation. This review synthesises the evidence on this axis in SAE and appraises whether nutritional and microbiome-directed strategies can be regarded as modulators of it, or should be framed as a testable hypothesis. Methods: A narrative review was conducted and reported according to the SANRA criteria. PubMed/MEDLINE, Scopus and Web of Science were searched from inception to September 2026 for preclinical and clinical studies on gut microbiota, intestinal permeability, neuroinflammation, blood–brain barrier dysfunction and nutritional or microbiome-directed strategies in sepsis. Results: Four communication pathways are described: neural (vagal), immune/humoral, metabolic (short-chain fatty acids, tryptophan-derived indoles, host kynurenines) and neuroendocrine. Evidence that nutritional or microbiome-directed interventions act on them is almost entirely preclinical and derives from rodent models of limited translational validity. Randomised trials of feeding route and dose, immunonutrients and probiotics were designed around mortality, infection and respiratory outcomes—endpoints of the gut–immune and gut–lung axes—and, apart from one negative cognitive follow-up in acute lung injury, none has reported SAE, delirium or cognition. This is an absence of evidence rather than heterogeneous evidence. Conversely, microbial composition and metabolites are emerging as candidate predictors of SAE and intensive care unit delirium. Conclusions: The gut–brain axis in SAE remains an unproven hypothesis. Nutrition should be regarded as a biologically plausible but untested modulator rather than an established therapy. Prospective studies with standardised neurological endpoints, and microbiota-based risk stratification, are required before any gut-directed intervention can be recommended for brain protection in sepsis.