Review Article

The Gut Microbiome as a Therapeutic Target in the Pathogenesis and Treatment of Chronic Liver Disease

C. A. Woodhouse; V. C. Patel; A. Singanayagam; D. L. Shawcross

Disclosures

Aliment Pharmacol Ther. 2018;47(2):192-202. 

In This Article

Abstract and Introduction

Abstract

Background Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target.

Aim To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver.

Methods We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website.

Results Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation.

Conclusions Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of "healthy" bacteria may ameliorate the dysbiosis and alter prognosis.

Introduction

Our understanding of the gut microbiome in health and disease has increased significantly in recent years. The use of nonculture-dependent techniques, such as 16s rRNA sequencing and more recently metagenomic analysis, has been key in these advances, allowing sequencing of whole populations of microbiota in a short period of time. The advent of these techniques has allowed researchers to examine the impact of the microbiome on a host of different conditions. As the liver receives the majority of its blood supply directly from the microbiota laden gut, via the portal vein, inherently the host microbiome and the liver become intimately linked. This article will examine in detail the role of the gut microbiota in the pathogenesis and progression of chronic liver disease and tease out how modulation of the gut microbiome might offer novel therapeutic targets.

There is a wealth of data to link conditions such as non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD) and primary sclerosing cholangitis (PSC) with an altered and potentially "dysfunctional" gut microbiome. The term gut "dysbiosis" has been coined to encapsulate the perturbations in the structure of the complex commensal communities, which can lead to deficient priming of the host immune system leading to a predisposition to develop immune-mediated diseases. Interestingly, emerging evidence suggests that rather than 1 or 2 dominant organisms being responsible for host health, the composition of the entire microbial community contributes to a balanced immune response. The host has also developed a number of mechanisms to counteract changes in the gut microbial community structure. This has broad implications on the development of future therapies that goes beyond the introduction of a single organism to induce health such as introducing a probiotic agent to the diet. It ultimately means that we must identify mechanisms that reconstitute a healthy complex microbiome after dysbiosis has occurred, a process that could be referred to as "rebiosis," which will be fundamental to treating chronic liver disease especially those conditions which may be directly or indirectly immune mediated. 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 chronic liver disease, an evolving therapy referred to as faecal microbiota transplantation (FMT).

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....