Skladany Lubomir, Kubanek Natalia, Adamcova Selcanova Svetlana, Zilincanova Daniela, Havaj Daniel, Sulejova Karolina, Soltys Katarina, Messingerova Lucia, Lichvar Michal, Laffers Lukas, Zilincan Michal, Honsova Eva, Liptak Peter, Banovcin Peter, Bures Jan, Koller Tomas, Golubnitschaja Olga, Arab Juan-Pablo
HEGITO - Department of Hepatology, Gastroenterology and Liver Transplantation of F. D., Roosevelt University Hospital, Banska Bystrica, Slovakia.
Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovakia.
EPMA J. 2024 Oct 31;15(4):677-692. doi: 10.1007/s13167-024-00381-5. eCollection 2024 Dec.
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.
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.
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 ( = 0.0204) and non-significantly improved 90-day mortality ( = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, ( = 0.031; = 0.014; = 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) for the clinical research and practice, (ii) related to personalized/precise treatment allocation including evidence-based (ii) , as well as (iii) 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.
The online version contains supplementary material available at 10.1007/s13167-024-00381-5.
严重酒精性肝炎（SAH）是酒精性肝病（ALD）谱系中最危急、急性的炎症表型，其30天和90天死亡率很高。几十年来，皮质类固醇（CS）是唯一被批准的药物治疗方法，但其带来的生存益处非常有限。在此背景下，该领域迫切需要创新，以满足患者需求并改善个体预后。粪便微生物群移植（FMT）已成为一种新的潜在治疗选择。在本研究中，我们旨在解决精准医学（3PM）的关键领域，以评估（i）FMT对SAH患者死亡率的影响（超越CS的作用），（ii）识别与有待改善的预后相关的因素，（iii）预测治疗无效，（iv）预防与死亡率增加相关的次优个体预后，以及（v）个性化治疗分配。
我们对2018年1月至2022年8月期间对CS无反应（NR）或不符合CS治疗条件（NE）的成年SAH患者进行了一项前瞻性研究（NCT04758806）。干预措施包括五次100毫升的FMT，由来自无关健康供体的30克粪便制备，并在-80°C下冷冻，每天通过上消化道（GI）给药。我们评估了FMT对30天和90天死亡率的影响，并与通过倾向评分匹配选择并接受标准治疗的对照组进行比较；对照组来自肝脏科住院患者的RH7登记处（NCT04767945）。我们还根据SAH既定和潜在的预后因素——如终末期肝病模型（MELD）、马德雷判别函数（MDF）、慢加急性肝衰竭（ACLF）、肝脏脆弱指数（LFI）、肝静脉-门静脉压力梯度（HVPG）和酒精性肝炎组织学评分（AHHS）——仔细研究了FMT的结果，以查看3PM方法是否为它们在预测治疗反应、预防次优个体预后和个性化患者管理方面赋予了新的维度。
我们按意向性分析纳入了44例SAH（NR或NE）患者；我们按方案分析了33例患者的相关因素（另外11例因接受少于5次FMT而被排除），并通过倾向评分匹配分别分析了31例患者的相应个体预后。平均年龄为49.6岁，11例患者（33.3%）为女性。MELD评分中位数为29，27例患者（81.8%）有任何程度的ACLF。FMT改善了30天死亡率（P = 0.0204），90天死亡率虽未显著改善但也有一定改善（P = 0.4386）。单因素分析确定MELD≥30、MDF≥90和ACLF分级>1是30天死亡率的显著预测因素（P = 0.031；P = 0.014；P = 0.034）。生存与基线LFI、HVPG或AHHS无关。
在SAH最难治疗的亚组患者（即NR/NE）中，FMT改善了30天死亡率。与获益相关的因素包括MELD≤30、MDF≤90和ACLF<2。这些结果支持了肠道微生物群作为精准医学研究背景下治疗靶点的潜力，反之亦然——将精准医学方法用作微生物群研究便捷的统一模板。这些结果对以下创新概念有直接影响：（i）用于临床研究和实践，（ii）与个性化/精准治疗分配相关，包括基于证据的（ii），以及（iii）SAH患者个体预后不良的（iii）。此外，我们的结果补充了现有证据，有可能沿着SAH的发病机制途径开展新的研究，如对酒精毒性的不同个体易感性、宿主特异性线粒体功能和全身炎症，以及肠道菌群失调在其中的作用。
在线版本包含可在10.1007/s13167-024-00381-5获取的补充材料。
