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Liver Int. Author manuscript; available in PMC 2016 April 08.
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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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Harbouring roughly 2-5 1011 bacteria per gram of faeces in humans, the intestinal tract
embodies an incredibly complex biological ecosystem (1). This microbiome' includes not
only bacteria, which may be symbiotic or pathologic but also the collective ensemble of
fungi, viruses and other microorganisms, their metabolites, degradative byproducts and
genomes, as suggested by the Greek root words bios (life) and oma (mass). The composition
of the human enteric microbiome is influenced by numerous factors including, but not
limited to, host genotype, diet, age, disease state and exposure to antibiotics. The
constituents of the microbiome, in addition to executing their respective biologically
constitutive processes, are known to interact with each other as well as with their host; these
interactions influence innumerable physiologic as well as pathophysiological immuno-
biological processes in a multitude of cell types and tissues (2).
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Receiving approximately 75% of its blood supply from the splanchnic circulation, the liver
is continuously exposed to a wide repertoire of molecules, be they beneficial or noxious,
from the intestinal microbiome. An ever-increasing body of literature has begun to shed light
on the role of this gut-liver axis' in the maintenance of health as well as in the pathogenesis
Correspondence; Dr Steven P. O'Hara, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First
Street, SW, Rochester, MN 55905, USA, Tel: +1 507 284 1006; Fax: +1 507 284 0762 ohara.steven@mayo.edu.
James H. Tabibian and Cyril Varghese are co-first authors.
Conflicts of interest: The authors do not have any disclosures to report.
Tabibian et al. Page 2
of fatty liver disease, autoimmune and idiopathic liver disease, hepatic fibrosis and
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hepatocarcinogenesis.
Herein we provide an overview, from both a clinical and molecular perspective, of the
interaction of the intestinal microbiome with host immunity and hepatic physiology as well
as its impact on the initiation, progression and clinical complications of hepatobiliary
disease.
Vital to this function are pattern-recognition receptors (PRRs), which are plasma membrane
and cytoplasmic proteins that sense and respond to pathogen-associated molecular patterns
(PAMPs). PRRs, which include toll-like receptors (TLRs) and nucleotide-binding
oligomerization domain receptors (NLRs), have been identified in numerous recruited and
resident hepatic cells including biliary epithelial, sinusoidal, endothelial, stellate, Kupffer
cells and hepatocytes (58).
Thirteen TLRs have been identified to date in mammals, 10 of which have been
characterized in humans (i.e. TLR1-10). These type 1 transmembrane proteins are located on
the plasma membrane or in the endosomal compartment (i.e. TLR3, TLR7 and TLR9) (9)
each recognizing distinct lipid, lipoprotein, protein and nucleic acid molecular patterns from
microbes such as bacteria, virus, parasites and fungi. TLRs initiate signalling cascades
through at least two pathways, MyD88-dependent and MyD88-independent pathways.
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Recognition of individual PAMPs induces distinct signalling pathways via hetero- and
homodimerization of TLRs, the recruitment of distinct adaptor proteins and activation of a
multitude of downstream signalling molecules (Fig. 1). TLR signalling in the liver is
activated when PAMPs are delivered to it, for example, via the portal venous circulation,
hepatic artery or ascension from the small intestine, and recognized by their respective
cognate TLRs (8). This leads to signal transduction culminating in nuclear translocation of
transcription factors and ultimately biosynthesis of interleukins, interferons and/or
chemokines, including but not limited to tumour necrosis factor (TNF-), interleukin (IL-1)
and various interferons (Fig. 1). Persistent TLR activation facilitates the clearance of PAMPs
but may also lead to secondary hepatobiliary injury (e.g. inflammation, fibrosis and cellular
senescence) depending on the nature of the insult/PAMP as well as host immunogenetic
factors (3, 10).
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molecules (e.g. ATP), and upon stimulus, can trigger autocatalytic cleavage of caspase-1
with subsequent bioactivation of interleukin 1p and IL18 (Fig. 1) (3, 11).
Additional innate immune PRRs present in the liver include the retinoic acid-inducible gene
1 (RIG-I)-like receptors (RLRs) and the C-type lectin receptor (CLR) family (6, 12). RLRs
(e.g. RIG-I, MDA5 and LGP2) are cytoplasmic proteins involved in viral recognition and the
induction of a type-1 interferon response, while CLRs comprise a large family of calcium-
dependent PRRs involved in fungal recognition and initiation of multiple innate immune
responses (12, 13).
Given the intricate nature of PRR signal transduction and its downstream effects, it is not
surprising that defects in these processes are associated with a variety of infectious,
autoimmune and metabolic disorders, including those of the hepatobiliary system (14).
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Multiple lines of evidence suggest that the microbiome may play a primary role in the
initiation of select liver diseases. Multiple mechanisms have been proposed regarding how
microbial and other intestinally derived molecules may incite hepatobiliary injury which
may lead to chronic disease. Below we mention a few examples of hepatobiliary disorders
wherein the intestinal microbiome may be a key etiologic trigger.
associated with intestinal dysbiosis (23). In addition, portal bacteraemia, bactero- bilia (24,
25) and 16s ribosomal ribonucleic acid (rRNA) in bile (26, 27) have all been described in
PSC. Moreover, PSC cholangiocytes accumulate lipopolysaccharide (LPS) in vivo (28) and
are hyper-responsive to LPS treatment in vitro (22, 29, 30). In addition, several genomic
associations have been established with loci implicated in host-microbiome interactions (e.g.
fuco-syltransferase 2, interleukin 2 receptor) in patients with PSC (3133). Intriguingly,
recent studies have shown that treatment with select oral antibiotics may offer several
therapeutic benefits in patients with PSC (10, 34, 35) Further evidence for an aetiologic role
of the intestinal microbiome is provided by animal model studies, wherein enteric microbial
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steatohepatitis (NASH), of which approximately a third will progress to cirrhosis (39, 40). It
is, therefore, not an overstatement that NAFLD (and in particularly NASH) represents a
major public health concern. Among the many aspects of NAFLD/NASH that have been
investigated to date, there are accumulating data that the intestinal microbiome is altered in
patients with this disease. For example, the abundance of the two major intestinal bacterial
phyla, Firmicutes and Bacteroidetes, is altered, with most studies revealing a relative
increase in the former (41). The altered micro- biome in NAFLD has an increased capacity
to harness energy from the host diet and can suppress fasting- induced adipocyte factor (i.e.
ANGPTL4), thereby increasing lipoprotein lipase activity and hepatocyte triglyceride
accumulation (42). In addition, high-fat diets lead to microbiome changes that increase
conversion of dietary choline into methylamines. Hence, plasma concentrations of
phosphatidylcholine are reduced, which in turn decreases the assembly and secretion of very
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acted upon enzymatically by intestinal bacteria, can also have direct (antimicrobial) effects
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NAFLD associated with increased circulating endotoxin levels but may be a condition in
which hepatic innate immune cells are (inordinately) primed for responding to circulating
endotoxin.
NAFLD, saturated LCFAs, both dietary and microbially generated, exhibit a protective effect
in alcoholic liver disease, likely through restoration of eubiosis and restoration of the
intestinal epithelial barrier.
and neoplasia (17, 44, 56). For example, deficiency in TLR4 signalling and antibiotic
treatment have both been shown to reduce hepatic fibrosis following experimental bile duct
ligation (57). With the above in mind, the impact of the microbiota in the modulation of
chronic liver disease may well be far-reaching and is a topic of ongoing and important
investigation (52).
congestion as a result of reduced portal venous flow. Prior studies have shown significant
over-representation of Streptococcaceae and underrepresentation of Lachnospiraceae in
patients with cirrhosis (58), although specific changes may depend on various host factors as
well as the type and severity of underlying disease (59).
Complications of cirrhosis are in some ways related to the intestinal microbiome. Increased
ammonia causing hepatic encephalopathy is because of both liver dysfunction and possible
overproduction of ammonia by a dysbiotic microbiome. Thus, it is no surprise that intestinal
decontamination with non-absorbable antibiotics, such as rifaximin, is an effective treatment
for subclinical hepatic encephalopathy (60). Spontaneous bacterial peritonitis, another
complication of cirrhosis, occurs as a result of migration of intestinal bacteria into the
peritoneal cavity, the risk of which increases with advancing cirrhosis because of a
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immune signalling was a key determinant of increased liver injury. In an even more recent
study, we observed significantly exacerbated serological and histological hepatobiliary
disease as well as increased cholangiocyte senescence in GF compared to conventionally
housed mdr2/ mice (62). Furthermore, we found that the commensal microbial metabolite
ursodeoxycholic acid (which was absent in GF mice) abrogates human cholangiocyte
senescence in an in vitro model of LPS- or H202-induced cellular senescence (62).
It is now recognized that both primary (hepatocyte- derived) and secondary (microbially
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modified) BAs function as signalling molecules. BAs regulate their own synthesis and
modulate key metabolic pathways and inflammation through activation of FXR
(preferentially through primary BAs) and the G protein-coupled BA receptor 1 [GPBAR1
(TGR5); preferentially through secondary BAs] (63, 64). While the composition of the BA
pool is modulated by microbial metabolism of primary (hepatocyte-derived) to secondary
BAs, the composition of the microbiome is modulated by BAs (65, 66). This delicate
balance of BA composition, microbial populations and the activation of FXR and TGR5 has
profound effects on metabolic, anti-inflammatory and hepatoprotective processes in the liver.
For this reason, FXR and TGR5 agonists continue to be explored as potential therapeutic
approaches for liver disease in both animal models (reviewed in 67) and in clinical trials
(reviewed in 68). The aforementioned and other accumulating findings provide proof of
concept regarding the protective role of the commensal microbiota and its metabolites in the
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pathobiology of hepatobiliary injury and disease. Future studies should aim to better
understand the structure and role of the commensal microbiota in hepatobiliary disease and
identify commensal microbial metabolites which may impart cyto- protective effects against
hepatobiliary injury. Insights from such studies are expected to generate new knowledge
regarding how to harness the therapeutic properties of the commensal microbiota for
translation into potential therapeutic applications.
Conclusion
The large biomass of microorganisms and molecules comprising the human intestinal
microbiome has constant interactions with the liver (conceptual schema presented in Fig. 2).
Collectively, these organisms have significant effects on the development, progression and
outcomes of hepatobiliary disease, the extent and nature of which remain areas of ongoing
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investigation and intrigue. In this brief review, we have provided a framework which
delineates current understanding of the role of the microbiome in health as well as various
stages of hepatobiliary disease. Although these relationships and multidirectional
interactions can be incredibly complex, with the advent of high-throughput techniques and
increasing reliance on a team science approach, the ability to rapidly, reliably and affordably
study these dynamics will continue to grow. These advances hold promise in elucidating
pathophysiological ramifications in hepatobiliary health and disease as well as identifying
novel therapeutic opportunities.
Acknowledgments
Financial support: This work was supported by National Institutes of Health Grants AI089713 (to S.P.O.),
DK57993 (to N.F.L), the Mayo Foundation, and the Mayo Clinic Center for Cell Signaling in Gastroenterology
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(P30DK084567).
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Abbreviations
BA bile acid
CLR C-type lectin receptor
FGF19 fibroblast growth factor 19
FXR farnesoid X receptor
GF germ free
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Key points
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The intestinal microbiome and the gut liver axis' are increasingly recognized in
the maintenance of hepatobiliary health as well as the pathogenesis of disease.
The liver plays an important role in innate immunity, defects in which are
associated with a variety of hepatobiliary disorders.
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
NFB activation and subsequent transcription of inflammatory cytokines (e.g. IL-1 and
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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) NFB activation and
caspase production, the latter of which (iv) activates precursor cytokines, e.g. IL- 1 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-.
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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,
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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
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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).