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

Abstract

BACKGROUND\nRifaximin 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.\n\n\nDESIGN\nA 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.\n\n\nPRIMARY OUTCOME\n50% reduction in neutrophil oxidative burst (OB) at 30-days.\n\n\nSECONDARY OUTCOMES\nPsychometric 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.\n\n\nRESULTS\nPatients 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)].\n\n\nCONCLUSION\nRifaximin-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.\n\n\nLAY SUMMARY\nThis 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.\n\n\nCLINICAL TRIAL NUMBER\nClinicalTrials.gov NCT02019784.