From animal behavior to human perioperative neurocognitive disorders: translational boundaries of the gut-brain axis

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), delayed neurocognitive recovery (DNR), and postoperative neurocognitive disorder, are common after surgery in older adults, and the gut-brain axis has been proposed as a contributing pathway. Most mechanistic support rests on rodent behavioral assays, yet these endpoints and human clinical diagnoses are routinely treated as interchangeable. This critical narrative review examines that translational boundary. PND is used here as a clinically consequential test case for a broader behavioral-neuroscience problem: how animal behavioral phenotypes, microbiome-associated signals, and intervention effects should be translated into human diagnostic constructs. A structured search identified and appraised the principal evidence rather than an exhaustive synthesis; no formal risk-of-bias or certainty-of-evidence assessment was performed. Evidence was separated into human perioperative studies reporting a neurocognitive outcome with either a measured gut-brain exposure or a gut-directed intervention; those reporting gut-brain change without a cognitive outcome; perioperative preclinical evidence; and indirect non-perioperative evidence. The retrieved human perioperative evidence spans observational cohorts across gastric, orthopedic, spinal and cardiac surgery, multi-omic and metabolomic cohorts, and randomized perioperative probiotic trials reporting lower rates of study-defined cognitive outcomes. It nonetheless remains heterogeneous and largely single-center, with modest event numbers, inconsistent sampling and assessment, and limited external validation. Mechanistic support still comes mainly from perioperative rodent models using water maze, fear-conditioning, recognition-memory, and delirium-like readouts, which measure narrow, species-specific capacities and are not diagnostic equivalents of POD, DNR, or postoperative neurocognitive disorder. Microbiome-mediated causation is unproven, and cross-species endpoint alignment remains a central route to improved translation.