Abstract

Post-traumatic stress disorder(PTSD) is associated with cirrhosis in Veterans and therapeutic results are suboptimal. An altered gut-liver-brain axis exists in cirrhosis due to hepatic encephalopathy(HE), but the added impact of PTSD is unclear. Aim: Define linkages between gut microbiota and cognition in cirrhosis with/without PTSD. Cirrhotic Veterans (with/without prior HE) underwent cognitive testing (PHES, inhibitory control test,ICT and block design BDT), serum lipopolysaccharide-binding protein(LBP) and stool collection for 16SrRNA microbiota composition and predicted function analysis(PiCRUST). PTSD was diagnosed using DSM-V criteria. Correlation networks between microbiota and cognition were created. Patients with/without PTSD and with/without HE were compared. 93 combat-exposed male Veterans [(58 years, MELD 11, 34% HE, 31% Combat-PTSD (42 no HE/PTSD,19 PTSD-only,22 HE-only,10 PTSD+HE)] were included. PTSD patients had similar demographics, alcohol history, MELD but worse ICT/BDT, higher antidepressant use and LBP levels. Microbial diversity was lower in PTSD (2.1±0.5 vs 2.5±0.5,p=0.03) but unaffected by alcohol/antidepressant use. PTSD(p=0.02) and MELD(p<0.001) predicted diversity on regression. PTSD patients showed higher pathobionts (Enterococcus and Escherichia/Shigella) and lower autochthonous genera belonging to Lachnospiraceaeae and Ruminococcaceae regardless of HE. Enterococcus was correlated with poor cognition, while the opposite was true for autochthonous taxa regardless of PTSD/HE. Escherichia/Shigella were only linked with poor cognition in PTSD. Gut-brain axis-associated microbiota functionality was altered in PTSD. Conclusions: In male cirrhotic Veterans, combat-related PTSD is associated with cognitive impairment, lower microbial diversity, higher pathobionts and lower autochthonous taxa composition and altered gut-brain axis functionality. Cognition was differentially linked to gut microbiota, which could represent a new therapeutic target.