Efficacy Of Bovine Colostrum In The Treatment Of Severe Alcohol-Associated Hepatitis: A Randomized Controlled Trial

INTRODUCTION

Background and Rationale Severe alcoholic hepatitis (AH) imposes a significant global burden, markedly contributing to liver-related illness and death. The worldwide impact is driven by increasing alcohol consumption and the lack of effective treatments for severe cases. Chronic alcohol intake disrupts normal gut microbiome balance, leading to dysbiosis. This imbalance involves an increase in harmful bacteria and a decrease in beneficial ones, affecting overall gut health. Alcohol also damages the intestinal barrier, making it more permeable. This increased permeability allows bacteria and their harmful byproducts, such as lipopolysaccharides (LPS), to leak into the bloodstream. The leaked bacteria and LPS (pathogen-associated molecular patterns-PAMPs) reach the liver via the portal vein. In the liver, LPS activates toll-like receptor 4 (TLR4) on immune cells, triggering a pro-inflammatory response and hepatocyte necrosis. These PAMPs also contribute to systemic endotoxemia and septicaemia. Despite optimal medical therapy, often including prednisolone, severe alcohol-associated hepatitis has a 28-day mortality rate of 30-40%. The gut-liver axis has emerged as a promising target for treatment in sAH. Interventions such as antibiotics, nonabsorbable disaccharides, probiotics, and fecal microbiota transplantation have shown variable benefits in modulating intestinal permeability and microbial imbalance in cirrhosis. However, none are currently standard treatments for sAH. Furthermore, corticosteroids, while somewhat improving short-term survival, do not address the gut-driven inflammatory cascade and may increase the risk of infections. Bovine colostrum, the first milk produced after birth, is naturally rich in immunoglobulin G (IgG), lactoferrin, antimicrobial peptides, and short-chain fatty acids. Preclinical studies show that oral bovine colostrum can neutralize lipopolysaccharides, promote epithelial regeneration transforming the leaky gut into a healthy mucosal barrier, and modify the intestinal microbiota. These properties are highly relevant to reducing the pathogenic factors of sAH. Therefore, we conducted a multicenter, double-blind, placebo-controlled Phase 3 trial to determine whether adding oral IgG-enriched bovine colostrum to standard medical treatment could enhance survival and liver function in patients with sAH. Our hypothesis was that targeting the gut-liver axis with a safe, enterally delivered biologic would decrease systemic and hepatic inflammation, mitigate hepatocyte necrosis, lower infection rates, and improve clinical outcomes.

Natural History of Severe Alcohol-Associated Hepatitis in the West:

In the STOPAH study, 60% - 67% patients were males; baseline Maddrey's Discriminant Function was 61.9 + 25.7 and the Model For End-Stage Liver Disease was 20.7 + 5.5 in the Placebo arm. Out of the total 418 deaths, 168(40%) occurred before day 29, 28% occurred between days 28 and 90 , 32% occurred between day 91 and 1 year.

Background cirrhosis was in 86.2-93.7% patients with Severe Alcohol Associated Hepatitis treated with prednisone who had undergone liver biopsies