Kevin Lopez B.S.1, Nizam Karim B.S.1 1The University of Texas Medical Branch (UTMB) John Sealy School of Medicine, Galveston, TX

Background • Post-operative cognitive dysfunction (POCD) is a detrimental neurocognitive disorder that occurs after surgery with anesthesia where a substantial change in a patient’s baseline cognitive ability leads to difficulty completing activities of daily living, socializing, maintaining a job, and is associated with an increased risk of death.1 • POCD can affect anyone, but patients over 60 years old are at increased risk, lasting from weeks to over a year in some cases.1 • Currently, no treatment exists, and research is very limited. Recently, the Gut-Brain-Axis has been implicated in the pathogenesis of POCD. • This systematic review aims to summarize recent animal studies and controlled human trials focusing on mechanisms of pathogenesis and/or therapeutic targets for POCD relating to gut microbiome dysbiosis and its role in cognition and neuroinflammation.

Methods • Systematic review conducted in PubMed database over 5-year period, 2019-2024, using relevant search/MeSH terms. • Review designed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. SYRCLE's risk of bias tool and revised Cochrane risk of bias tool (Rob 2) were used.

Results • 2 articles demonstrate healthy donor fecal matter transplantation (FMT) to POCD-animals ameliorates POCD-like symptoms. • 3 articles demonstrate that POCD-donor FMT to healthy germ-free animals induces dysbiosis and POCD-like symptoms. • 1 article demonstrated perioperative probiotic administration in humans as effective to reduce incidence of POCD in elderly patients undergoing non-cardiac surgery.

Potential Mechanisms of POCD Dysregulated Signaling pathways inducing POCD Symptoms: ERK/Nrf2, ACCS2/HDAC, BTG2/Bax, TLR4/NF-kB, Keap1/Nrf2 “Toxicity”: Increased molecule/compound inducing POCD Symptoms: Trimethylamine N-oxide (TMAO), NLRP3 inflammasome, Palmitic acid, Valeric acid, IL17A/IL17RA, intestinal exosomes “Deficiency”: Decreased molecule/compound inducing POCD Symptoms: C1BR, SIRT1, tight junction protein, methionine sulfoxide reductase (MsrA) “Protective”: Increased molecule/compound ameliorating POCD Symptoms: CB1R, SIRT1, and miR-146a (via BTG2/Bax axis)

Novel Therapeutics Ameliorating POCD Symptoms Short chain fatty acid (SCFA) (via ACCS2/HDAC2 axis), Sodium butyrate (NaB), indole propionic acid, propionic acid, 4 octyl itaconate (via ERK/Nrf2 axis), exogenous dietary restriction (via TLR4/MyD88/NF-kB axis), Sulforaphane (via Keap/Nrf2 axis), and exosome inhibitor GW4869, PLX5622, probiotics, exercise, Cefazolin, Ibuprofen, prebiotic xylooligosaccharides (XOS)

Discussion Interestingly, it was determined that anesthesia may induce microbiome dysbiosis independently from surgery. This suggests that anesthesia plus surgery may induce dysbiosis in an additive manner in addition to other predisposing factors such as age and anesthesia dose, type, route of administration, and duration of use, comorbidities, pre-existing cognitive dysfunction or other psychiatric conditions.

Future Directions Further translational research evaluating perioperative administration of novel therapeutic agents, such as those in this search, could provide promising results. Further evaluation of changes in the Gut-Brain-Axis could uncover a deeper understanding of the pathogenesis of POCD.

References 1. Brodier, E., & Cibelli, M. (2020). Postoperative cognitive dysfunction in clinical practice. BJA Education, 21(2), 75–82. https://doi.org/10.1016/j.bjae.2020.10.004