Posttraumatic stress disorder is associated with altered gut microbiota that modulates cognitive performance in veterans with cirrhosis.

Posttraumatic 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. The aim of this study was to 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 test (BDT)], serum lipopolysaccharide-binding protein (LBP) and stool collection for 16S rRNA 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. Ninety-three combat-exposed male veterans [ (58 yr, 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, and higher antidepressant use and LBP levels. Microbial diversity was lower in PTSD (2.1 ± 0.5 vs. 2.5 ± 0.5, = 0.03) but unaffected by alcohol/antidepressant use. PTSD ( = 0.02) and MELD ( < 0.001) predicted diversity on regression. PTSD patients showed higher pathobionts ( and ) and lower autochthonous genera belonging to Lachnospiraceaeae and Ruminococcaceae regardless of HE. was correlated with poor cognition, while the opposite was true for autochthonous taxa regardless of PTSD/HE. was only linked with poor cognition in PTSD patients. Gut-brain axis-associated microbiota functionality was altered in PTSD. 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 compared with non-PTSD combat-exposed patients. Cognition was differentially linked to gut microbiota, which could represent a new therapeutic target. Posttraumatic stress disorder (PTSD) in veterans with cirrhosis was associated with poor cognitive performance. This was associated with lower gut microbial diversity in PTSD with higher pathobionts belonging to and and lower beneficial taxa belonging to Lachnospiraceaeae and Ruminococcaceae, with functional alterations despite accounting for prior hepatic encephalopathy, psychoactive drug use, or model for end-stage liver disease score. Given the suboptimal response to current therapies for PTSD, targeting the gut microbiota could benefit the altered gut-brain axis in these patients.