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Table of contents
1. The gut microbiota and the liver: implications for clinical practice................................................................ 1
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Document 1 of 1

The gut microbiota and the liver: implications for clinical practice
Author: Quigley, Eamonn M; Monsour, Howard P
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Abstract: While a central role for the microbiota in the precipitation of infectious and non-infectious
complications of liver disease has been long established, evidence for a more fundamental role in the etiology
of several liver diseases continues to accumulate. However, though progress is rapidly occurring in this area,
the definitive delineation of the precise relevance of changes in the microbiota to various forms and stages of
liver disease is still far from complete. While high quality clinical evidence supports the use of antibiotic therapy,
in the management of hepatic encephalopathy, spontaneous bacterial peritonitis and other infectious
complications, how these interventions impact on the microbiota and microbiota-host interactions has not been
clearly defined. Although probiotics and even, perhaps, fecal transplantation hold promise in the management of
liver disease, and the potential impact of probiotics is supported by a considerable amount of laboratory data,
high-quality clinical evidence is scanty.
Full text: By virtue of its anatomical location and its blood supply, the liver is uniquely positioned to confront and
interact with those microbes, microbial components, and products of microbe-gut interactions that may have
traversed the gut barrier and gained access to the blood stream. Given that 75% of the portal venous blood flow
comes from the mesenteric venous system [1], the potential for gut -derived products to impact on the liver can
be immediately appreciated. Furthermore, by virtue of its immunological repertoire and multiple metabolic roles,
the liver is primed to respond to such encounters on behalf of the entire organism. However, should the ability of
the liver to respond be overwhelmed or bypassed, or the response become inappropriate or exaggerated,
disease may result.
The microbiota: the basics
The current explosion in research in the area of the microbiota, its components, and functions can be largely
attributed to rapid and ever evolving developments in technology. Rapid, high-throughput sequencing systems
now allow the identification of all of the microbial constituents of a given environment, such as the human
gastrointestinal tract, while approaches such as metagenomics and metabolomics permit the assignation of
functional characteristics to these very same microbes [2]. The microbiome is one of the 'hottest'areas in
biomedical research at present and much has been already learned of the critical role of our commensal flora in
health. Not only is the microbiome essential in protecting us against pathogens, in 'educating'our immune
system and promoting the maturation and ongoing integrity of the gut barrier, the intestinal neuromuscular
apparatus and even the vascular supply to the gastrointestinal tract, but also it is now appreciated that it plays a
major metabolic role [3,4]. This latter function has become the focus of considerable attention in studies of the
pathogenesis of obesity, metabolic syndrome and, of course, its liver manifestation: non-alcoholic fatty liver
disease (NAFLD) [5-7]. The potential of the microbiome, through its local interactions with the host or through
the elaboration and release of biologically active substances, to impact on organ functions distant from the gut
is exemplified by the concept of the microbiome-gut-brain axis [8]. According to this construct, the microbiome
can influence brain development, function and morphology; a concept that is far from new to the hepatologist
who has long cared for patients with hepatic encephalopathy (HE). Indeed, Chassaing and colleagues have
recently extended this concept directly to the liver through their description of the microbiota-liver axis [7].
The human microbiome contains between 1013 and 1014 organisms; more cells than in the human body and
more than 100 times more genes than in the human genome. While considerable variability exists between
individuals, two phyla, Firmicutes and Bacteroidetes, normally dominate in the human gut. As the complexity of
the human microbiome is revealed so too is the potential impact of a number of environmental factors on the
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composition and function of the microbiome. Indeed, such factors, largely ignored in prior studies, must be
considered in the assessment of apparent changes in the microbiome in any disease state. Two of these factors
have been well documented and are of particular relevance to any consideration of the role of the microbiome,
or its modulation, in liver disease: diet and antibiotics. In both the short- and long-term, diet is a major regulator
of the microbiome [9-11] but has rarely been controlled for in studies comparing the composition of the
microbiome in health and a given disease state. Antibiotics, virtually ubiquitous in modern medical practice and
frequently prescribed to patients with liver disease now appear to have a greater and more sustained impact on
the microbiome than was previously thought [12-14]. These effects may be especially relevant at the extremes
of life [13,14] given, on the one hand, the demonstrated association between the microbiota and health status in
the elderly [15] and, on the other, the potential for long-term effects arising from microbiome disruption in early
life [16]. The latter study illustrated the ability of antibiotic exposure to mice in early life to contribute, through
effects on the microbiome, to the development of obesity in later life [16]; in other studies antibiotic therapy has
been shown to improve glucose tolerance in both the ob/ob mouse and mice in whom obesity had been induced
by dietary measures [17]. Alcohol per se , and apart from changes that may be associated with alcohol-related
liver disease, can also modify the microbiome [18].
Other metabolic functions of the microbiota are also of fundamental importance to the pathogenesis of liver
disease. Thus, not only are certain bacteria critical to the deconjugation of bile salts in the gut lumen but the
microbiota also can influence bile acid synthesis through effects on the farnesoid X receptor (FXR) in the ileum
[19].
The gut microbiome &the liver
It has long been speculated that the microbiota could play a role in diseases and disorders far removed from the
gut. This concept led to the theory of 'autointoxication', which was widely promulgated in the 19th century and
led, unfortunately, to colectomy being recommended for the treatment of a variety of disorders on the
assumption that removal of the colon together with its offending bacterial populations would lead to cure. Not
surprisingly, the notion that the microbiota could play a role in systemic illness fell into disrepute and was not
resurrected until well into the past century when the relationship between gut bacteria, their metabolic products
and hepatic coma was first recognized [20]. Subsequently, coma in cirrhosis was linked to an overgrowth of
coliforms in the small intestine [21] and the primacy of the role of bacteria settled once and for all and when
those treated with antibiotics showed resolution of HE [22]. More recently, intestinal coliforms have been
incriminated in the pathophysiology of portal hypertension and as causative organisms in such infectious
complications of chronic liver disease as spontaneous bacterial peritonitis (SBP) and systemic sepsis. The
critical role of the liver in protecting against sepsis is illustrated by its role, in health, in clearing those trace
amounts of bacterial endotoxins, produced by Gram-negative intestinal bacteria, that cross the intestinal
mucosa and gain access to the portal blood. Those many factors that sustain the integrity of the intestinal
barrier, on the one hand, and the immunological and 'detoxifying'functions of the liver, on the other, are pivotal
to this protective function.
Could the microbiota play a more fundamental role in the pathogenesis of liver diseases, per se ? This is now
an exciting area of investigation given accumulating evidence from animal models and now also, albeit to a
lesser extent, from human studies, that disturbances in the microbiota may be linked, either directly or indirectly,
to the causation and progression of liver diseases as diverse as alcoholic liver disease [23], NAFLD and nonalcoholic steatohepatitis (NASH) [5], total parenteral nutrition (TPN)/intestinal failure-associated liver disease
(IFALD) [24] and primary sclerosing cholangitis (PSC) [25,26]. Indeed, inflammatory mediators have also been
implicated in the development and maintenance of the hyperdynamic circulation that is a feature of portal
hypertension [27], in impairing liver function and in contributing to hemostatic failure [28].
In exploring the pathogenesis of microbiota-liver interaction in disease, three critical payers emerge: the
microbiome, the intestinal barrier and the immune response in the liver where toll-like receptors (TLRs) and
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TLR-4, in particular, appear to play a key role [6,7,29].

The role of these factors is exemplified by how lipopolysaccharide (LPS), a glycolipid derived from the outer
membrane of Gram-negative bacteria, is handled in health and disease. In health, the integrity of the intestinal
barrier, comprising the adherent mucus layer, the enterocyte with its microvilli, the tight junctions between
epithelial cells as well as the secretion of various factors such as defensins, prevent translocation allowing only
minute amounts of microbial products to reach the liver [30]. Those that do reach the liver are immobilized or
destroyed before they can access the systemic circulation [31]. For example, the systemic circulation is
normally protected from endotoxemia by the binding of LPS by LPS receptors and, TLR-4 in particular, located
on the surface of hepatic sinusoidal endothelial cells, hepatic stellate cells and Kupffer cells; among others
[32,33].
In liver disease, an overgrowth of Gram-negatives allied to impaired gut barrier function allows whole
organisms, through the process referred to as translocation, and/or LPS to gain access to the portal system. If
translocation occurs, bacterial components such as LPS arriving in the portal system activate the inflammasome
complex resulting in a cascade of pro-inflammatory cytokine production, which ultimately leads to liver injury
and can progress to fibrosis [29]. Activation of inflammasome pathways is initiated via binding of LPS to TLR-4
receptors located on the cell surface of Kupffer cells, in particular. The primary step in all inflammasomemediated reactions is cleavage and activation of caspase-1, which in turn cleaves and activates the procytokines pro-IL-1 and pro-IL-18. The ultimate result of these pathways is the production of tumor necrosis
factor alpha (TNF) and interferon gamma that induce liver injury [34]. Kupffer cells appear to play a major role
in inflammasome-mediated pathways as animal studies that have shown that Kupffer cell depletion leads to the
attenuation of experimental liver damage [31].
The gut microbiota in liver disease
Small intestinal bacterial overgowth
A link between the gut microbiota and chronic liver disease was first reported by Hoefert over 80 years ago [35].
Small intestinal bacterial overgrowth (SIBO) was the first aspect of the microbiota to attract attention in relation
to liver disease. By virtue of well-documented changes in gut motility and transit, on the one hand, and intestinal
permeability, on the other [36], subjects with chronic liver disease are predisposed to intestinal stasis and
bacterial translocation from the gut lumen to the portal circulation. It should come as no surprise, therefore, that
not only has SIBO been shown to be common across a broad spectrum of chronic liver diseases but that its
occurrence is also predictive of the severity of liver disease, per se , and of such important clinical complications
as encephalopathy and SBP [37]. Other factors also contribute, for example, the incidence of SIBO has been
shown to be up to three times higher in alcoholics than in non-alcoholic controls [38] and local immune
responses are impaired in cirrhosis [39].
The possibility that the microbiota might contribute to the pathogenesis of liver disease and not just its
complications was first suggested by the demonstration that components of the microbiota can metabolize
alcohol to acetaldehyde [40], a molecule considered to play a major role in liver injury in alcohol-related liver
disease. The subsequent demonstration, in animal models, that modulation of the microbiota could induce both
the metabolic and inflammatory components of NAFLD [5] further illustrated the contribution of the microbiota to
liver disease. Indeed, a clinical illustration of the latter role had been demonstrated decades previously by the
unfortunate occurrence of sometimes fatal steatohepatitis among some individuals who had undergone the
jejuno-ileal bypass procedure for morbid obesity; an occurrence that was directly linked to the development of
SIBO in the bypassed intestine. More recently, Wigg and colleagues studied 23 NASH and 23 control subjects
and documented SIBO in 50% of their NASH patients but only 22% of controls had SIBO; furthermore, levels of
TNFwere increased in the NASH patients [41].
Quantitative or qualitative changes in the microbiota
Molecular techniques, such as those based on sequence divergences of the small subunit ribosomal ribonucleic
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acid (16S rRNA) of bacteria [2] are now being directed at the investigation of the microbiota in liver disease. It is
important to emphasize that the vast majority of such studies, in man, are based on the evaluation of fecal
samples. Bajaj and colleagues remind us of the limitations of this approach by demonstrating significant
differences between the fecal microbiota and that associated with the mucosa in their population of patients with
cirrhosis. Indeed, in this study, the mucosal microbiota alone differentiated between those cirrhotics who had
and did not have encephalopathy [42].
Chen and colleagues studied 36 patients with cirrhosis and 24 healthy controls using 454 pyrosequencing of the
16S ribosomal RNA variable region 3 (V3) followed by real-time quantitative polymerase chain reaction (qPCR)
and found that, in cirrhosis, Bacteroidetes were reduced, Proteobacteria and Fusobacteria increased,

Enterobacteriaceae , Veillonellaceae , Streptococcaceae increased and Lachnospiraceae reduced [43]. Others

have confirmed many of these findings [44-46]. That such findings are not mere epiphenomena but might have
some clinical relevance is suggested by associations between microbial population shifts and disease severity
[43], HE [44], liver inflammation [44] and, given the increased numbers of members of the family

Enterobacteriaceae, [45,46] with SBP and bacteremia. As enteric pathogens increase in liver disease, so do the
numbers of important commensals, such as Bifidobacteria spp, decrease [47].
Several mechanisms have been identified relevant to the involvement of the microbiota in the pathogenesis of
NAFLD/NASH [48]. First, the role of the microbiota in the pathogenesis of obesity per se , as well as the
metabolic syndrome, has been extensively investigated. Initial evidence from animal studies revealed
differences in the microbiome between obese and lean animals, the obese animals possessing a microbiome
that was more efficient at extracting calories from the diet [49-53]. Similarly, germ-free mice gain less weight
than their normally colonized counterparts with the latter developing a higher percentage of body fat and more
adipose tissue then their germ-free counterpart despite eating fewer calories from a similar diet [49].
Furthermore, when the microbiota from the cecum of the conventionally raised mice were transplanted into adult
germ-free mice a 57% increase in body fat content and insulin resistance was noted in the previously germ-free
animals within just 14 days. In analogous experiments, the cecal microbiota from either lean or obese mice was
transplanted into germ-free mice; the recipient from the obese donor mouse gained significantly more weight
and became more efficient at extracting calories from its diet than the recipient of the microbiota from the lean
mouse [49]. Other mechanisms that promote obesity include increased production of short chain fatty acids
(SCFA); these, in turn, induce a slowing of intestinal transit and, thereby, enhance nutrient absorption [48]. That,
as suggested by observations in man, genetic factors also play a role is indicated by the work of Parks and
colleagues that demonstrated, using a systems genetics approach, a strong relationship between host genotype
and gut microbiota plasticity in over 100 inbred strains of mice [54]. Specific strains have been associated with
an important role in these effects. Thus, Akkermansia mucophilia , a mucin-degrading bacterium that resides in
the mucus layer on the surface of the intestinal epithelium has been shown to reverse fat-mass gain and
associated metabolic changes in animals fed with a high-fat diet [55].
Changes in gut microbiota composition have also been demonstrated in obese humans [51,56] and
characteristic microbial signatures linked to Type 2 diabetes and the metabolic syndrome [57-59]. Interestingly,
evidence from both laboratory animal models and human studies supports a role for TLR-4 in the pathogenesis
of obesity and related inflammation [60,61]. In contrast, mice lacking TLR5, normally expressed on the intestinal
mucosa and acting to defend against infection, are predisposed to metabolic syndrome [62].
Furthermore, interventions, whether dietary or surgical, that result in weight loss will alter the microbiota and
may contribute to the weight loss and beneficial metabolic effects of these strategies [63,64].
Not surprisingly, changes in the microbiota have also been demonstrated in both animal models and human
subjects with NAFLD and NASH [65-70]. The activation, by the microbiota, of pro-inflammatory cytokines (e.g.,
TNF), appears relevant to progression from steatosis to NASH. Complex interactions between the
inflammasome and the microbiota may also play a role; as a consequence of defective/deficient inflammasome
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sensing intestinal microbial populations change leading to translocation and the appearance of increased
amounts of bacterial products in the portal circulation; substances that are known to lead to the progression of
NAFLD and NASH [71].
Turning to alcoholic liver disease one must recognize the roles that alcohol ingestion alone can play [40]. These
include a direct effect on the microbiota leading to the proliferation of Gram-negative bacteria in the gut with the
consequent production of endotoxin and the aforementioned ability of these same bacteria to produce
acetaldehyde, which impairs the integrity of the intestinal barrier. Not only is the microbiota qualitatively and
quantitatively different, in alcoholics, from that of non-alcoholics but it is also capable of producing endogenous
ethanol from the fermentation of carbohydrates [72]. Other effects of alcohol conspire to increase permeability,
promote transfer of endotoxin across the intestinal epithelium and impair the host immune response [40].
Immunological reactions to the microbiota
Immune responses involving the microbiota have been invoked in the pathophysiology of a number of liver
diseases thought to have an immunological or 'auto-immune'basis.
PSC, a disease characterized by inflammation and fibrotic destruction of the intra- and/or extra-hepatic biliary
ducts features marked expression of TLR4, the pathway activated by bacterial LPSs [6]. It has been postulated
that a loss of immune tolerance to endotoxin plays a role in the initial immunologically mediated injury to biliary
epithelial cells and subsequent progression in PSC [6]. PSC is commonly associated with ulcerative colitis
involving the entire colon (pan-colitis); the extent of involvement in the colon in ulcerative colitis been shown to
correlate with levels of bacterial-derived endotoxin concentrations in the portal vein [73]. A further microbiotamediated mechanism has been proposed in the case of PSC: cross-reactivity between microbial antigens and
human tissue components. In PSC atypical anti-nuclear cytoplasmic antibodies [p-ANCA] recognize both tubulin
beta isoform 5 in human neutrophils and the bacterial cell division protein FtsZ [6,26].
Cross reactivity has also been implicated in the pathogenesis of primary biliary cirrhosis (PBC) and related
autoimmune liver diseases. TLRs, specifically TLR4, have again been invoked in the pathogenesis of PBC [74].
PBC is characterized by the presence of anti-mitochondrial antibodies (AMA) and, particularly, the M2
component of AMA. AMA cross-reacts with bacterial components, such as Escherichia coli pyruvate
dehydrogenase-E2 [75,76]. Half of PBC patients also have IgG3 antibodies that cross-react with Lactobacillus

delbrueckii and other fecal bacteria [77].

The microbiota &hepatic carcinogenesis
Hepatocellular carcinoma is a common and much feared complication of several liver diseases such as those
related to hepatitis B and C, hemochromatosis, alcohol and NAFLD. In experimental animals components of the
gut microbiota have been shown to potentiate the hepatic carcinogenic effects of both carcinogenic chemicals
and hepatitis viruses [78] and microbial production of deoxycholic acid has been shown to promote obesityassociated HCC through the induction of a senescence-associated phenotype (SASP) in hepatic stellate cells,
which, in turn, secrete inflammatory and tumor-promoting factors in the liver [79]. Conversely, manipulation of
the microbiota to enhance the production of proprionate reduces malignant transformation [80].
Therapeutic impact of modulating the microbiota
Antibiotics
Infectious complications
The role of antibiotics in the management of SBP and bacteremia is an essential component of everyday clinical
hepatology practice [81,82]. Antibiotic therapy may have other effects, which may reflect its ability to remove
organisms involved in the generation of endodoxin and, thereby, ameliorate the hyperdynamic circulation that is
thought to contribute so prominently to the maintenance of portal hypertension [82]. A clinical benefit emanating
from intervening in this process may be the demonstrated ability of antibiotics to, not only prevent related
infections, but also reduce re-bleeding rates from variceal hemorrhage [28,83,84].
Hepatic encephalopathy
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The poorly absorbed (and, therefore, primarily active within the gut) antibiotic rifaximin has been shown in highquality clinical trials to benefit overt [85] and sub-clinical [86] encephalopathy. What is not clear is how rifaximin
generates these benefits or, more precisely, what changes in the microbiota are primarily responsible for these
improvements in HE [87]? Interestingly, improvements in cognition in relation to rifaximin therapy in minimal HE
were not associated with significant changes in microbial abundance but rather in alterations in gut bacterial
linkages and metabolites [88]. It has also been proposed that rifaximin may exert a beneficial effect in liver
disease through suppressing the production of deoxycholic acid in the colon [89].
Intestinal failure associated liver disease
SIBO has long been thought to contribute to IFALD, given its prevalence among so many subjects with
intestinal failure; whether antibiotic prophylaxis will prevent this complication of intestinal failure remains to be
resolved [90].
Probiotics
Experimental
NAFLD
In the well characterized mouse model of obesity, the ob/ob mouse, the probiotic cocktail VSL#3 was as
effective as an anti-TNFantibody in reducing liver inflammation though this effect was not mediated through a
suppression of hepatic expression of TNF[91]. While Li and colleagues found little effect of VSL#3 on hepatic
steatosis in the ob/ob mouse, another group found that the same probiotic preparation prevented the onset of
steatosis in a less dramatic animal model of NAFLD, the diet-induced obese mouse [92]. Further evidence to
support the contention that probiotic effects may be model dependent is suggested by the observation that this
same cocktail had no effect on steatosis or steatohepatitis in NASH induced by a methionine-choline-deficient
diet [93]. As elsewhere, effects may also be strain specific [94]. Prebiotics may also have a role as
demonstrated by their ability to ameliorate liver inflammation through a glucagon-like peptide-2 (GLP-2)dependent effect on the gut barrier [95].
Alcoholic liver disease
That gut barrier effects are of considerable importance in the pathogenesis of alcoholic liver disease is
supported by the observation that an impact on intestinal permeability appeared crucial to the ability of

Lactobacillus rhamnosus GG (L GG) to reduce steatosis and inflammation in a rat model [96], as well as other
studies in alcohol-related liver injury and elsewhere demonstrating the ability of certain probiotics to beneficially
influence components of the gut barrier [97]. Wang and colleagues have provided a molecular basis for the
action of the probiotic Lactobacillus rhamnosus GG (LGG), one of the most widely studied organisms in this
context. They demonstrated that the restoration of barrier function associated with alcohol-induced liver injury
was mediated through the recovery of hypoxia-inducible factor (HIF) and trefoil factor in gut epithelial cells [98].
Complications of liver disease
Probiotic supplementation with Lactobacillus spp and Bifidobacterium spp has been shown to suppress
potentially pathogenic bacteria, such as E. coli [99], resulting in a decrease in bacterial translocation, which, in
turn, seems to ameliorate liver injury and inflammation [100-102].
A variety of probiotic preparations have been studied in relation to the various complications of liver disease
with mixed results in terms of effects on bacterial translocation but with beneficial effects on HE [103].
Effects on acute liver injury &chronic liver disease
In an experimental model of liver injury, supplementation with Lactobacillus paracasei decreased the
concentration of Enterobacteriacea and increased that of Lactobacilli, Bifidobacteria and Bacteroides, thereby,
modulating the expression of TNFand other pro-inflammatory cytokines in the liver [104].
Clinical
Despite the considerable volume of experimental data described earlier and an ever-increasing interest in the
potential benefits of probiotics the literature on the clinical impact of probiotics in liver disease and its
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complications is scanty [90,103,105]. To date, studies of probiotics in liver disease have, generally, been small
in size and their results far from conclusive. Whether safety concerns, namely, the potential for orally
administered organisms to access the systemic circulation directly in those with porta-systemic shunting is
responsible for the lack of studies, is not clear [105].
NAFLD/NASH
There have been no randomized clinical trials of probiotics in NAFLD or NASH despite some preliminary data
suggesting that probiotics are safe in these disorders and may improve liver function and decrease markers of
lipid peroxidation in NAFLD/NASH [106].
Alcoholic liver disease
Kirpich and colleagues randomized 66 Russian males with alcoholic psychosis to 5 days of therapy with a
combination of Bifidobacterium bifidum and Lactobacillus plantarum or standard therapy. The probiotic group
showed restoration of fecal levels of bifidobacteria and lactobacilli toward and, in comparison to the control
group, experienced a reduction in levels of alanine transaminase [102].
Complications of liver disease
Portal hypertension
Jayakumar and colleagues were unable to show any effect of 8 weeks treatment with the probiotic cocktail,
VSL#3, on portal pressures in their patients with decompensated cirrhosis [107].
Encephalopathy
Here again the literature is small and inconclusive with a recent Cochrane Systematic Review concluding that,
despite reduction in blood ammonia level, probiotics did not produce consistent effects on clinical outcomes in
HE [108]; clinical effects in minimal HE for prebiotics, probiotics and synbiotics may be more robust though still
inferior to those lactulose [109]. Probiotic supplementation, by increasing the levels of Lactobacilli and reducing
the level of E. coli , has been shown to reduce blood ammonia concentrations and improve minimal
encephalopathy [110].
Infectious complications
Despite a sound rationale for their use and some experimental data there is no convincing evidence to suggest
that probiotic preparations can assist in the treatment and/or prevention of these feared complications of chronic
liver disease.
Effects on acute liver injury &chronic liver disease
Studies looking at the impact of probiotics on the natural history of chronic liver disease in general or on specific
entities, such as PSC, have been very few and, to date, negative [103,105].
Future directions
The importance of the microbiome-gut-liver axis has long been recognized clinically and is now being explored
and its complexities revealed experimentally. In coming years studies of the microbiome in human disease will
rapidly move from being purely descriptive to being mechanistic and will tell us precisely what bugs or bugderived molecules do how the microbiome can be beneficially manipulated. Only then will the promise of
interventions such as probiotics [103,105] and fecal transplantation [111] be realized and precise microbial
manipulations employed in the prevention and treatment of liver disease and its complications.
Expert commentary
Recent and ongoing research supports the concept of a microbiota-gut-liver axis that plays a central role in
homeostasis in health and, when disrupted, contributes to the initiation and maintenance of such important
complications of liver disease as portal hypertension, SBP and bacteremia. Evidence suggesting a direct role
for components of the microbiota in the genesis of NAFLD and it progression to NASH is compelling and there
is some evidence indicating a pathogenetic role for the microbiota in other liver diseases. Each of these
scenarios shares a number of common elements: changes, be they quantitative or qualitative, in the microbiota,
impaired functioning of the intestinal epithelial barrier and dysfunctional immunological/metabolic responses in
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the liver. Of particular interest are those observations that have linked specific metabolic products of the
microbiota with liver injury and even carcinogenesis. Despite a considerable amount of encouraging animal data
and its theoretical appeal, efforts to manipulate the microbiota in man through the provision of prebiotics and/or
probiotics have been few and far between in liver disease and results to date have not been very encouraging.
Perhaps, more drastic approaches, such as fecal transplantation, are needed but remain untested. Antibiotic
strategies targeted at the microbiota, in contrast, are effective in encephalopathy and in the treatment and
prevention of infectious complications of liver disease, although how, precisely, at a microbiological level this is
achieved is not known. The glaring deficit in this field is the lack of high-quality human studies of non-antibiotic
interventions, on the one hand, and of how precisely changes in the microbiota influence liver function and
contribute to liver injury, on the other.
Five-year view
By 2018, the era of descriptive studies of qualitative and quantitative changes in the microbiota in any number
of disease states will be long past and the field will have moved on to focus on the precise metabolic and
immunologic signatures generated by the microbiota that are relevant to liver disease. Along similar lines,
therapeutic efforts will have shifted from the use of whole bacteria to the application of small molecules derived
from bacteria and to the intricacies of microbe-host and diet-microbiota interactions. Microbiota-directed
therapies will have become central to the management of obesity and its related inflammatory conditions and
immunologically driven liver disorders based on interactions with bacterial components will have been
conclusively defined.
Financial &competing interests disclosure

The authors have no 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. This includes
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received
or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
*The concept of the gut-liver axis has now been extended to the microbiota-gut-liver axis.
*Fundamental roles for the microbiota in immunity and metabolism highly relevant to liver function and disease.
*Extensive animal and accumulating human data to indicate a pivotal role of the microbiota in important
complications of chronic liver disease.
*Emerging literature supporting a possible role of the microbiota in the basic pathogenesis of certain liver
diseases, such as non-alcoholic fatty liver disease.
*With the exception of the role of antibiotics in hepatic encephalopathy, spontaneous bacterial peritonitis and
other infectious complications little data on the therapeutic benefits of microbiota manipulation in liver disease.
*Experimental and very limited human data suggests that microbiota modification may ameliorate liver
abnormalities linked to metabolic syndrome.
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Syst. Rev . (11), CD008716 (2011).

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AuthorAffiliation
Eamonn M Quigley, *Author for correspondence: equigley@tmhs.org; e.quigley@ucc.ie
Howard P Monsour, Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical
College, Houston, Texas, USA
MeSH: Anti-Bacterial Agents -- therapeutic use, Biological Therapy, Feces -- microbiology, Hepatic
Encephalopathy -- microbiology, Host-Pathogen Interactions, Humans, Intestines -- drug effects, Liver -- drug
effects, Liver Diseases -- diagnosis, Liver Diseases -- therapy, Peritonitis -- microbiology, Probiotics -therapeutic use, Risk Factors, Treatment Outcome, Intestines -- microbiology (major), Liver -- microbiology
(major), Liver Diseases -- microbiology (major), Microbiota (major)
Substance: Anti-Bacterial Agents;
Publication title: Expert Review of Gastroenterology & Hepatology
Volume: 7
Issue: 8
Pages: 723-32
Publication year: 2013
Publication date: Nov 2013
Year: 2013
Publisher: Informa Healthcare
Place of publication: London
Country of publication: United Kingdom
Publication subject: Medical Sciences--Gastroenterology
ISSN: 1747-4124
Source type: Scholarly Journals
Language of publication: English
Document type: Reviews, Journal Article
DOI: http://dx.doi.org/10.1586/17474124.2013.848167
Accession number: 24134195
ProQuest document ID: 1445084933

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Document URL: http://search.proquest.com/docview/1445084933?accountid=46437

Copyright: 2013 xxx
Last updated: 2014-06-11
Database: ProQuest Health & Medical Complete

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Bibliography
Citation style: APA 6th - American Psychological Association, 6th Edition
Quigley, E. M., & Monsour, H. P. (2013). The gut microbiota and the liver: Implications for clinical practice.
Expert Review of Gastroenterology & Hepatology, 7(8), 723-32.
doi:http://dx.doi.org/10.1586/17474124.2013.848167

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