한빛사논문
- 조회724
Vishal Patel1,2,9,#, Sunjae Lee3,10,#, Mark McPhail1,5, Kevin Da Silva7, Susie Guilly7, Ane Zamalloa2, Elizabeth Witherden3, Sidsel Støy4, Godhev Kumar Manakkat Vijay1, Nicolas Pons7, Nathalie Galleron7, Xaiohong Huang1, Selin Gencer5, Muireann Coen5, Thomas Henry Tranah1,2, Julia Alexis Wendon1,2, Kenneth Bruce6, Emmanuelle Le Chatelier7, Stanislav Dusko Ehrlich7, Lindsey Ann Edwards1, Saeed Shoaie3,8, Debbie Lindsay Shawcross1,2,*
1Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 125 Coldharbour Lane, London SE5 9NU, UK
2Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
3Centre for Host-Microbiome Interactions, Dental Institute, King’s College London, UK
4Aarhus University Hospital, Department of Hepatology and Gastroenterology, Aarhus, Denmark
5Imperial College London, Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, London, UK
6King’s College London, Institute of Pharmaceutical Science, 5th Floor Franklin-Wilkins Building, London, UK
7University Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, 78350, France
8Science for Life Laboratory, KTH - Royal Institute of Technology, 171 21, Stockholm, Sweden
9The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK
10School of Lif Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
#These authors contributed equally.
*Corresponding author
Abstract
Background
Rifaximin is efficacious in the prevention of recurrent hepatic encephalopathy (HE) but its mechanism of action remains unclear. We postulated that rifaximin reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE.
Design
A randomised placebo-controlled double-blind mechanistic study of rifaximin versus placebo was performed in cirrhotic patients with HE. Rifaximin-α 550mg (TARGAXAN) twice daily (n=19) or placebo (n=19) was administered for 90-days. Primary outcome: 50% reduction in neutrophil oxidative burst (OB) at 30-days. Secondary outcomes: Psychometric Hepatic Encephalopathy Scale (PHES), shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolome, blood bacterial DNA, neutrophil toll-like receptor (TLR)-2/4/9 and interleukin-8 expression, and plasma and faecal cytokine analysis.
Results
Patients were well-matched: median MELD [11 rifaximin-α versus 10 placebo]. Day 30 HE grade normalised on rifaximin-α but not placebo (p=0.014) with an improvement in PHES score; p=0.009. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day-30 (p=0.021) with a reduction in plasma tumour necrosis factor-α (TNF-α); p<0.001. Rifaximin-α suppressed oralisation of the gut, reducing the mucin-degrading sialidase-rich species Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α and IL-17E enriched intestinal microenvironment augmenting anti-bacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection [odds ratio 0.21(0.05-0.96)].
Conclusion
Rifaximin-treated patients were less likely to develop infection with resolution of overt and covert HE. Rifaximin-α reduced oralisation of the gut with mucin-degrading species attenuating systemic inflammation. These data link rifaximin-α as having a role in gut barrier repair as a mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis.
Lay Summary
This clinical trial examined the underlying mechanism of action of an antibiotic called rifaximin which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). It shows that rifaximin suppresses gut bacteria that translocate from the mouth to the intestine which causes the intestinal wall to become leaky by breaking down the protective mucus barrier. This resolves encephalopathy and reduces inflammation in the blood preventing the development of infection.
논문정보
- Research article
- 2021년 09월 (BRIC 등록일 2021-10-01)
- 국내+국외 연구진
- 의약학 > 인체시스템의학
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