RATIONALE: Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients' needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. METHODS: We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at - 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH - such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) - to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. RESULTS: We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. CONCLUSIONS AND RECOMMENDATIONS IN THE FRAMEWORK OF 3PM: In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa - to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH's pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00381-5.

Centre of Biosciences Institute of Molecular Physiology and Genetics Slovak Academy of Sciences Bratislava Slovakia

Departamento de Gastroenterologia Escuela de Medicina Pontificia Universidad Catolica de Chile Santiago Chile

Department of Internal Medicine Charles University 1st Faculty of Medicine and Military University Hospital Prague Prague Czech Republic

Department of Mathematics Faculty of Natural Sciences Matej Bel University Banska Bystrica Slovakia

Department of Microbiology and Virology Faculty of Natural Sciences Comenius University Bratislava Bratislava Slovakia

Department of Radiology FD Roosevelt Faculty Hospital Banska Bystrica Slovakia

Division of Gastroenterology Department of Medicine Schulich School of Medicine Western University and London Health Sciences Centre London ON Canada

Faculty of Chemical and Food Technology Institute of Biochemistry and Microbiology Slovak University of Technology Bratislava Slovakia

Gastroenterology and Hepatology Subdivision 5Th Department of Internal Medicine Comenius University Faculty of Medicine University Hospital Bratislava Bratislava Slovakia

Geneton Ltd Bratislava Slovakia

HEGITO Department of Hepatology Gastroenterology and Liver Transplantation of F D Roosevelt University Hospital Banska Bystrica Slovakia

Institute of Gastrointestinal Oncology Military University Hospital Prague Prague Czech Republic

Jessenius Faculty of Medicine in Martin Gastroenterology Clinic JFM CU Comenius University in Bratislava Martin Slovakia

Predictive Preventive and Personalised Medicine University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

UniLabs S R O Pathology Prague Czech Republic

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