Is treating the gut microbiome the key to achieving better outcomes in cirrhosis?

KEYWORDS:

• Cirrhosis
• hepatic encephalopathy
• gut microbiome
• immune dysfunction
• gut dysbiosis
• faecal microbiota transplantation

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; ‘proof of principle’ 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 a recent study showing that the majority of commercial probiotics are inactivated in the stomach [16]. Consequently, there has been a growing interest in fecal microbial transplantation (FMT), an already established therapy in treating recurrent Clostridium difficile infection [17], as a potential solution to reversing gut dysbiosis and its downstream complications in cirrhosis. A pilot safety study [18] was recently published assessing the impact of FMT compared to no treatment in patients with recurrent HE by rational selection of a single donor. FMT-treated subjects, but not controls, were pre-treated for 5 days with broad-spectrum antibiotics, and FMT was instilled by retention enema. FMT improved cognitive function. One question that this study raised was if cirrhosis is characterized by salivary dysbiosis and small bowel bacterial overgrowth, why would administering FMT by enema achieve ‘rebiosis’ and could the benefit observed here relate more to the administration of broad-spectrum antibiotics prior to the FMT? Theoretically, FMT may also influence the disease trajectory and may have the capacity to alter disease pathophysiology by reducing hepatic inflammation and fibrosis. A recent murine study, for example, demonstrated that FMT can alleviate steatohepatitis with a reduction in hepatic pro-inflammatory cytokines and endotoxemia [19]. These preliminary data have paved the way to a number of clinical trials currently recruiting exploring frozen and encapsulated FMT formulations in the context of acute alcoholic hepatitis, advanced cirrhosis, chronic hepatitis B, and HE administered by both the upper and lower gastrointestinal routes.

The ultimate therapy may thus involve transplanting what might be perceived as a healthy gut microbiome from a non-obese healthy donor to a patient with CLD. The question then arises as to what constitutes a ‘healthy’ microbiome, and are there individuals who have a more ‘liver-friendly’ microbiome than others? This will not only have implications on the choice of donor but may also allow us to screen those individuals who might be perceived to be at a greater risk of developing CLD. Overall, this will amount to personalizing microbiota interventions and understanding what the determinants will be that govern bacterial engraftment [20]. This becomes even more complicated when we consider that an individual’s microbiome can be influenced by many external factors including diet (particularly high fibre, high fat, and high fructose diets), and medications such as antibiotics.

Amidst the global rising tide of CLD, there is a vital need for improved mechanistic understanding of the interplay between the gut microbiome and innate intestinal immunity as a driver in the development and progression of CLD. This will yield novel targets for therapeutic intervention that will bolster antibacterial host defences and normalize dysfunctional microbiota–host interactions in patients with cirrhosis, in the hope that this will improve transplant-free outcomes.

Declaration of interest

D L Shawcross has received honoraria from Norgine Pharmaceuticals for consultancy, advisory board membership and paid lectures, Falk Pharma for paid lectures and Shionogi for consultancy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by funds from King’s College London.