Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial

作者：Vishal Patel, Sunjae Lee, Mark J.W. McPhail, Kévin Da Silva, Susie Guilly, Ane Zamalloa, Elizabeth A. Witherden, Sidsel Hyldgaard Støy, Godhev K. Manakkat Vijay, Nicolas Pons, Nathalie Galleron, Xaiohong Huang, Selin Gencer, Muireann Coen, Thomas Henry Tranah, Julia Alexis Wendon, Kenneth D. Bruce, Emmanuelle Le Chatelier, S. Dusko Ehrlich, Lindsey Ann Edwards, Saeed Shoaie, Debbie Lindsay Shawcross · 发表于：Journal of Hepatology · 年份：2021 · DOI：10.1016/j.jhep.2021.09.010 · 被引用次数：230 · 研究领域：Liver Disease and Transplantation、Organ Transplantation Techniques and Outcomes、Clinical Nutrition and Gastroenterology

BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella....