Patel, Vishal C., Lee, Sunjae, McPhail, Mark J. W., Da Silva, Kevin, Guilly, Susie, Zamalloa, Ane, Witherden, Elizabeth, Stoy, Sidsel, Vijay, Godhev Kumar Manakkat, Pons, Nicolas, Galleron, Nathalie, Huang, Xaiohong, Gencer, Selin, Coen, Muireann, Tranah, Thomas Henry, Wendon, Julia Alexis, Bruce, Kenneth D., Le Chatelier, Emmanuelle, Ehrlich, Stanislav Dusko, Edwards, Lindsey Ann, Shoaie, Saeed, Shawcross, Debbie Lindsay, Patel, Vishal C., Lee, Sunjae, McPhail, Mark J. W., Da Silva, Kevin, Guilly, Susie, Zamalloa, Ane, Witherden, Elizabeth, Stoy, Sidsel, Vijay, Godhev Kumar Manakkat, Pons, Nicolas, Galleron, Nathalie, Huang, Xaiohong, Gencer, Selin, Coen, Muireann, Tranah, Thomas Henry, Wendon, Julia Alexis, Bruce, Kenneth D., Le Chatelier, Emmanuelle, Ehrlich, Stanislav Dusko, Edwards, Lindsey Ann, Shoaie, Saeed, and Shawcross, Debbie Lindsay
Background & Aims: Rifaximin-alpha is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-alpha 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-alpha (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-alpha vs. 10 placebo). Rifaximin-alpha 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-alpha. Rifaximin-alpha reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-alpha (TNF-alpha) (p <0.001). Rifaximin-a suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-alpha promoted a TNF-alpha-and interleukin17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-alpha were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). Conclusion: Rifaximin-alpha led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflamm, QC 20220304