ABSTRACT: Objective:Washed microbiota transplantation may modulate the gut-liver-brain axis in hepatic encephalopathy (HE). Evidence in overt HE (OHE) remains limited, and previous trials have enrolled patients in remission rather than during an active episode. Methods:In this prospective, non-randomized pilot study, adults with cirrhosis and active OHE received an adjunctive protocol plus standard of care (SOC), or SOC alone, according to patient preference. The protocol comprised three inseparable components, namely polyethylene glycol (PEG) bowel lavage, colonic transendoscopic enteral tubing (TET) placed without sedation, and three consecutive daily infusions of washed microbiota suspension. Both groups received lactulose plus rifaximin. Nineteen protocol-treated and 19 concurrently enrolled SOC-alone patients were followed for 6 months. The primary endpoints were feasibility and safety. The primary clinical endpoint was the 10-day OHE resolution rate, defined as a West Haven grade of 0 or 1. Ten protocol-treated patients provided paired fecal samples for 16S rRNA gene sequencing and untargeted metabolomics, referenced against five healthy donors. Results:All 19 patients completed bowel preparation, tube placement, and all three infusions. No tube was dislodged, no aspiration occurred during nasogastric bowel preparation in the six patients with West Haven grade 3, and no serious adverse event was recorded; mild self-limiting adverse events occurred in 3 of 19. OHE resolution at day 10 was achieved by 16 of 19 protocol-treated patients (84.2%) and 9 of 19 SOC-alone patients (47.4%) (P = 0.038). Treatment failure, defined as no resolution at day 10 or recurrence within 6 months, occurred in 5 of 19 (26.3%) and 16 of 19 (84.2%) patients respectively (P < 0.001). Between-group differences were confined to blood ammonia, psychometric performance, and prealbumin, while Child-Pugh score, MELD, fibrosis indices, and the liver panel evolved in parallel. In the 10 patients with paired samples, all of whom were responders, fecal microbial and metabolic profiles showed partial remodeling toward the donor reference without donor-like engraftment. Conclusion:The protocol was fully deliverable and safe in active OHE. Because assignment was preference-based and the protocol group additionally received PEG lavage, which is itself effective in OHE, the clinical and biological differences cannot be attributed to microbiota transplantation, and randomized evaluation is required.
