Journal
JOURNAL OF HEPATOLOGY
Volume 76, Issue 2, Pages 332-342Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2021.09.010
Keywords
Hepatic encephalopathy; rifaximin-alpha; cirrhosis; systemic inflammation; gut microbiome; salivary microbiome
Categories
Funding
- Norgine Pharmaceuticals UK Limited
- Engineering and Physical Sciences Research Council (EPSRC) [EP/S001301/1]
- Science for Life Laboratory
- Swedish National Infrastructure for Computing at SNIC through Uppsala Multidisciplinary Centre for Advanced Computational Science (UPPMAX) [SNIC 2018/3-434, SNIC 2020/6-153, ANR-11-DPBS-0001]
- Meta-GenoPolis grant [ANR-11-DPBS-0001]
- Medical Research Council (MRC) Centre for Transplantation, King's College London, UK - MRC grant [MR/J006742/1]
- National Institute for Health Research (NIHR) -Wellcome King's Clinical Research Facility
- NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- King's College London
- Global University Project (GUP) , GIST Research Institute (GRI) IIBR
- GIST
- Bio-Synergy Research Project of the Ministry of Science, ICT through the National Research Foundation, Korea [2021M3A9C4000991]
- Bio & Medical Technology Development Program of the Ministry of Science, ICT through the National Research Foundation, Korea [2021M3A9G8022959]
- Basic Science Research Program of the Ministry of Science, ICT through the National Research Foundation, Korea [2021R1C1C1006336]
- National Research Foundation of Korea [2021M3A9G8022959, 2021R1C1C1006336, 2021M3A9C4000991] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
Rifaximin-alpha can alleviate hepatic encephalopathy and reduce the likelihood of infection by reducing systemic inflammation and promoting gut barrier repair.
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 inflammation. Rifaximin-alpha plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available