Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease

乳果糖 肝性脑病 微生物群 利福昔明 肝病 益生元 抗生素 胃肠病学 肠道菌群 炎症性肠病 慢性肝病 医学 生物 内科学 微生物学 肝硬化 疾病 免疫学 生物信息学 生物化学
作者
Matthew A. Odenwald,Huaiying Lin,Christopher Lehmann,Nicholas P. Dylla,Cody G. Cole,Jake D. Mostad,Téa Pappas,Ramanujam Ramaswamy,Angelica Moran,Alan L. Hutchison,M.R. Stutz,Mark Dela Cruz,Emerald Adler,Jaye Boissiere,Maryam Khalid,Jackelyn Cantoral,Fidel Haro,Rita A. Oliveira,Emily Waligurski,Thomas G. Cotter
出处
期刊:Nature microbiology [Nature Portfolio]
卷期号:8 (11): 2033-2049 被引量:30
标识
DOI:10.1038/s41564-023-01493-w
摘要

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease. A multi-omics approach reveals that bifidobacteria metabolize the prebiotic lactulose to produce acetate and deconjugate bile acids, which is associated with reduced densities of drug-resistant pathogens and decreased incidences of infection in patients with liver disease.
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