Gut–Liver Axis Modulation with IgG-Enriched Oral Immunotherapy in Severe Alcohol-Associated Hepatitis

Background: There are currently no FDA-approved treatments for severe alcohol-associated hepatitis. Bovine Colostrum, a natural product rich in immunoglobulins and lactoferrin, has been shown to neutralize endotoxins and repair the leaky intestinal mucosal barrier. We aimed to evaluate the efficacy and safety of bovine Colostrum in treating severe alcohol-associated hepatitis. Methods: This phase 3, parallel-group, double-blind, randomized (1:1), placebo-controlled trial was conducted across five academic hospitals in India. Patients with probable severe alcohol-associated hepatitis were enrolled. Randomization was performed centrally using the Trans European Network for Clinical Trials Services. Participants received either 20 g of freeze-dried Colostrum or a placebo (pasteurized bovine milk powder) three times daily for 4 weeks. Treatment allocation was masked from patients, investigators, and statisticians. The primary outcome was 90-day survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov ID NCT02473341(Completed). Findings: Between 2017 and 2023, 174 patients were enrolled: 89 in the colostrum group and 85 in the placebo group. Survival at 90 days was significantly higher in the colostrum group, at 89ꞏ9% (80/89) [MELD score - 30ꞏ2 (27ꞏ9, 33ꞏ4)], compared to 57ꞏ6% (49/85) in the placebo group [MELD - 31ꞏ5 (27ꞏ9, 34ꞏ2)] (p<0ꞏ0001), with a hazard ratio of 0ꞏ18 (95% CI: 0ꞏ09-0ꞏ38, p<0ꞏ001). Secondary outcomes: survival at 30 days was significantly higher (p<0ꞏ0001), with notable reductions in serum endotoxin levels [1ꞏ4 (0ꞏ9, 1ꞏ7)] vs. [-0ꞏ2 (-0ꞏ5, 1ꞏ0)] (p<0ꞏ001), TNF-α levels [6ꞏ0 (3ꞏ0, 11ꞏ0) vs. -6ꞏ0 (-10ꞏ0, 9ꞏ0)] (p=0ꞏ01), and fewer sepsis episodes at one month in the colostrum group (60) compared to the Placebo (75) (p=0ꞏ01). Serious adverse events were mild, occurring at similar rates in both groups. Interpretation: Bovine Colostrum significantly improved 90-day survival among patients with very severe alcohol-associated hepatitis, possibly by restoring gut barrier function, reducing endotoxemia, hepatic inflammation, and Sepsis.背景：目前尚无美国食品药品监督管理局（Food and Drug Administration, FDA）批准的重症酒精相关性肝炎治疗方案。牛初乳（Bovine Colostrum）是一种富含免疫球蛋白与乳铁蛋白的天然产物，研究证实其可中和内毒素并修复受损的肠黏膜屏障。本研究旨在评估牛初乳治疗重症酒精相关性肝炎的有效性与安全性。方法：本研究为一项3期、平行组、双盲、1:1随机安慰剂对照试验，在印度5家教学医院开展。纳入疑似重症酒精相关性肝炎患者，通过欧洲临床试验服务网络（Trans European Network for Clinical Trials Services）集中完成随机分组。受试者每日三次分别接受20g冻干牛初乳或安慰剂（巴氏灭菌牛乳粉），持续治疗4周。研究对受试者、研究者及统计人员设盲。主要结局为意向治疗人群的90天生存率。本试验已在ClinicalTrials.gov注册，注册号为NCT02473341（已完成）。结果：2017年至2023年间，共纳入174例患者，其中牛初乳组89例，安慰剂组85例。牛初乳组90天生存率显著更高，为89.9%（80/89），终末期肝病模型（Model for End-Stage Liver Disease, MELD）评分为30.2（27.9, 33.4）；安慰剂组90天生存率为57.6%（49/85），MELD评分为31.5（27.9, 34.2），组间差异具有统计学意义（p<0.0001），风险比为0.18（95%置信区间：0.09-0.38，p<0.001）。次要结局方面：牛初乳组30天生存率显著升高（p<0.0001）；血清内毒素水平[1.4（0.9, 1.7）vs. -0.2（-0.5, 1.0），p<0.001]、肿瘤坏死因子-α（Tumor Necrosis Factor-α, TNF-α）水平[6.0（3.0, 11.0）vs. -6.0（-10.0, 9.0），p=0.01]较基线显著降低；牛初乳组1个月内脓毒症发作次数（60次）少于安慰剂组（75次，p=0.01）。两组严重不良事件均为轻度，发生率无显著差异。解读：牛初乳可显著改善极重型酒精相关性肝炎患者的90天生存率，其潜在机制可能为恢复肠道屏障功能、减轻内毒素血症、肝脏炎症及脓毒症发生风险。