The evolution from chronic liver disease (CLD) to the onset of advanced cirrhosis brings with it a catalogue of complications affecting multiple organ systems. Patients often develop acute-on-chronic liver failure with significant morbidity and mortality [1]. The current incidence of CLD is estimated at 844 million, associated with an annual mortality of> 2 million [2]. Cirrhosis per se is now the fifth commonest cause of death in the United Kingdom, killing on average 19 years younger than those with cancer or heart disease [3]. Without access to liver transplantation, the outlook is often bleak, and yet, in spite of this global health threat and increasing burden on finite resources, few studies have identified new therapeutic targets or opportunities for intervention. The gut-liver axis is the term referring to a spectrum of interdependent activity between the liver and the gastrointestinal tract, influencing metabolism, digestion, intestinal permeability, and barrier function, as well as microbial diversity and behavior. Of its myriad functions, the liver is also a hotbed of immunological activity, acting as both a physical and immunological barrier. Microbiota-host interactions play a pivotal role in health and disease [4] and the liver is the first to challenge gut-derived bacteria after they enter the systemic circulation forming a firewall against invading bacteria [5]. Qin et al.[6] first described the gut microbiome as a separate genomic entity behaving as an organ with a central role in endogenous metabolism, with downstream effects on nutritional status, and immune regulation. The gut-liver axis is widely implicated in the pathogenesis of CLD, with the development of salivary and gut dysbiosis and a reduction in bacterial diversity with replacement of the healthy gut commensals by potentially pathogenic species [7]. This is often accompanied by an increase in gut permeability and small bowel bacterial overgrowth which culminates in bacterial translocation, endotoxemia, and dysregulated immune activity [8]. This is a strong determinant of the development and progression of CLD, decompensating events and 30-day mortality [9]. Indeed, 75,245 microbial genes have been identified as different between patients with cirrhosis and healthy individuals [10], associated with increased intestinal permeability and taxa belonging to both pro-inflammatory and ammoniagenic phyla [9]. Dysbiosis has also been linked with cardiovascular and renal complications, worsening hepatic encephalopathy (HE), and both localized and systemic infections [11]. Furthermore, treatment with antibiotics worsens dysbiosis [12].

With regard to treatment strategies in patients with cirrhosis that target the gut microbiome either directly or indirectly, the best data have been derived from treating HE. Modest successes have been achieved in the symptomatic regression of HE with lactulose, probiotics, and the non-absorbable antibiotic rifaximin. This includes a reduction in circulating endotoxin and improved clinical outcomes with rifaximin; Lproof of principleL that modifying the gut microbiota in cirrhosis can modify clinical endpoints [11, 13]. However, these therapies have little overall impact on transplant-free long-term outcomes. Many patients with cirrhosis are also treated with proton pump inhibitors which have been shown to reduce the healthy commensal population and increase the number of bacteria originating from the buccal cavity [14]. The data on the impact of probiotic therapies in patients with cirrhosis have been largely disappointing and most looking only at HE. Most trials have been low quality and have shown no impact on mortality [12, 15]. The lack of probiotic efficacy may relate to its route of delivery with …