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Review
. 2016 Apr;36(4):480-7.
doi: 10.1111/liv.13009. Epub 2015 Dec 12.

The enteric microbiome in hepatobiliary health and disease

James H Tabibian  1 , Cyril Varghese  2 , Nicholas F LaRusso  3 , Steven P O'Hara  3
Affiliations
Review

The enteric microbiome in hepatobiliary health and disease

James H Tabibian et al. Liver Int. 2016 Apr.

Abstract

Increasing evidence points to the contribution of the intestinal microbiome as a potentially key determinant in the initiation and/or progression of hepatobiliary disease. While current understanding of this dynamic is incomplete, exciting insights are continually being made and more are expected given the developments in molecular and high-throughput omics techniques. In this brief review, we provide a practical and updated synopsis of the interaction of the intestinal microbiome with the liver and its downstream impact on the initiation, progression and complications of hepatobiliary disease.

Keywords: cholangiopathies; cirrhosis; liver diseases; microbiota; toll-like receptors.

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Conflict of interest statement

Conflicts of interest: The authors do not have any disclosures to report.

Figures

Fig. 1
Fig. 1
Schematic representation of TLR and NLR pathways driving pro-inflammatory state after exposure to extracellular and Intracellular microbial products. TLRs are localized either on the cell surface (TLR 2, 1,4, 6, 11) or within an endosome (TLR 3, 7, 9) of biliary epithelial, sinusoidal, endothelial, stellate, Kupffer cells and hepatocytes. TLR 2, 1 and 6 associate with each other and adaptor proteins, thereby initiating (i) MyD88 adaptor protein-dependent NFκB activation and subsequent transcription of inflammatory cytokines (e.g. IL-1β and IL-18). TLR3 and TLR4, when stimulated, also initiate (ii) the TRIF pathway, which activates downstream IRFs and subsequent transcription of type I interferons. NLRs such as NOD1/2, when stimulated by intracellularly incorporated signals (e.g. bacterial peptidoglycans), form inflamma- some complexes that lead to both (iii) NFκB activation and caspase production, the latter of which (iv) activates precursor cytokines, e.g. IL- 1 β and IL-18. IL, interleukin; IRF, interferon regulatory factor; NLR, NOD-like receptor; NOD, nucleotide-binding oligomerization domain; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β.
Fig. 2
Fig. 2
Conceptual schema of the gut microbiome-liver interaction in hepatobiliary disease. A healthy, highly diverse gut microbiome maintains liver health through the synthesis of metabolites involved in immune regulation, lipid and BA homoeostasis, and energy utilization (cytoprotective). The physiology and dysregulation of this gut-liver axis and its complex and dynamic interactions are the focus of intense investigation and hold promise for advancing management of chronic liver disease. Additionally, a growing body of basic, translational, and clinical evidence suggests that intestinal microbiome dysbiosis and microbially derived molecules (1) modify the microbial environment and may be involved in the progression of chronic hepatobiliary disease. Multiple mechanisms may be involved including the disease, host genotype, diet, age and exposure to antibiotics. In disease models and patients with advanced cirrhosis, there is (2) epithelial barrier defects (e.g. tight junction disruption). This results in increased intestinal permeability and enterohepatic circulation of injurious microbial molecules (cytodestructive, e.g. lipopolysaccharide). In the liver, these PAMPs (3) activate PRRs on multiple cell types including hepatocytes, biliary epithelia, endothelial, stellate and Kupffer cells. Activation of PRRs (4) induces the expression of pro-inflammatory mediators and promotes hepatobiliary injury (e.g. inflammation, fibrosis, apoptosis and senescence) and initiation of immune dysregulation (e.g. development of auto-immunity). Ultimately, these processes may result in the (5) induction, modulation or progression of chronic liver disease. BA, bile acid; NLR, NOD-like receptor; PAMPs, pathogen-associated molecular patterns; PtdC, phosphatidylcholine; TJ, tight junction; TLR, toll-like receptor. Figure modified from ref. (69).
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