Liver International ISSN 1478-3223

REVIEW ARTICLE

Pathological bacterial translocation in cirrhosis: pathophysiology,

diagnosis and clinical implications
Pablo Bellot1,2, Rubén Francés1,2 and Jose Such1,2
1 Liver Unit, Hospital General Universitario de Alicante and Miguel Hernández University, Elche, Alicante, Spain
2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

Keywords Abstract
bacterial DNA – bacterial translocation – Bacterial translocation (BT) is defined by the passage of viable indigenous
cirrhosis – portal hypertension bacteria from the intestinal lumen to mesenteric lymph nodes (MLNs) and
other territories, and its diagnostic criteria rely on the isolation of viable bac-
teria in MLNs. Small intestinal overgrowth, increased intestinal permeability
Correspondence
and immunological alterations are the main factors involved in its pathogen-
Dr José Such, Liver Unit, Hospital General
esis. BT is obviously difficult to identify in patients with cirrhosis, and alter-
Universitario de Alicante, C/ Pintor Baeza 10,
CP: 03010 Alicante, Spain
native methods have been proposed instead. Bacterial DNA detection and
Tel: +34965913928
species identification in serum or ascitic fluid has been proposed as a reliable
Fax: +34965933468 marker of BT. Bacterial products, such as endotoxin, or bacterial DNA can
e-mail: such_jos@gva.es translocate to extra-intestinal sites and promote an immunological response
similar to that produced by viable bacteria. Therefore, pathological BT plays
Received 12 April 2012 an important role in the pathogenesis of the complications of cirrhosis, not
Accepted 27 August 2012 only in infections, but by exerting a profound inflammatory state and exacer-
bating the haemodynamic derangement. This may promote in turn the
DOI:10.1111/liv.12021 development of hepatorenal syndrome, hepatic encephalopathy and other
portal hypertension-related complications. Therapeutic approaches for the
prevention of BT in experimental and human cirrhosis are summarized.
Finally, new investigations are needed to better understand the pathogenesis
and consequences of translocation by viable bacteria (able to grow in cul-
ture), or non-viable BT (detection of bacterial fragments with negative cul-
ture) and open new therapeutic avenues in patients with cirrhosis.

Bacterial infections are frequent complications in
patients with cirrhosis, with an incidence on admission
or development during hospitalization of about 32%
(1, 2). This incidence contrasts with that of nosocomial
infections in the general population, which is 5 to 7%.
Bacterial infections in patients with cirrhosis are associ-
ated with a poor prognosis and an increased risk of
mortality (3). Moreover, bacterial infections or the use
of antibiotics as a surrogate marker of infection are the
most important independent variables associated with
failure to control bleeding from oesophageal varices (4).
Bacterial infections in addition to being an important
prognostic factor for the development of variceal bleed-
ing are clearly associated with its occurrence.
The most frequent infections in cirrhotic patients are
Spontaneous Bacterial Peritonitis (SBP), Urinary Tract
Infections and pneumonia, of which 80% are caused by
Gram-negative bacilli (GNB), especially Escherichia coli.
This fact suggests that most of the infection episodes in
patients with cirrhosis are of enteric origin. Passage of
viable bacteria from the intestinal lumen through the
intestinal wall and to mesenteric lymph nodes (MLNs)
and other sites is therefore the accepted pathogenic
mechanism to explain the development of spontaneous
infections, such as SBP or bacteraemia. This phenome-
non, first described in 1979, is defined as bacterial trans-
location (BT) (5). BT is also present in other clinical
scenarios different from liver cirrhosis such as haemor-
rhagic shock, intestinal obstruction, major trauma,
burns and severe acute pancreatitis (6, 7).
Bacterial translocation occurs in 25–30% of patients
with cirrhosis with liver dysfunction according to clini-
cal studies (8) and up to 45–78% of rats with cirrhosis
and ascites (9–11). BT not only is the key factor leading
to development of spontaneous bacterial infections but
also plays a role in the immune and haemodynamic
changes in advanced cirrhosis, either when translocation
is caused by viable bacteria or their fragments, such as
endotoxin or bacterial DNA, what we define as non-
viable BT.
Bacterial translocation may caused by viable bacteria,
thereby having the possibility of inducing ‘spontaneous’
bacterial infections, or by bacterial fragments, such as
endotoxin or bacterial DNA, that induce release of

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Bacterial translocation in cirrhosis
pro-inflammatory cytokines and nitric oxide. In this
manuscript, the term ‘pathological’ BT defines a morbid
stage associated with clinical and pathophysiological
implications in patients with cirrhosis, and we will dis-
cuss the mechanisms involved in the pathogenesis of
pathological BT, the available diagnostic techniques for
its detection and the consequences of the translocation
of bacteria and their products in patients with cirrhosis.
Pathophysiology of bacterial translocation
Our knowledge of the pathogenesis of BT is based
mainly on studies in experimental models because of
the obvious difficulty of accessing to MLNs in patients
with cirrhosis with the exemption of certain research
environments (8). In experimental models, BT is
defined as a MLN-positive culture, reaching 56% of rats
with CCl4-induced cirrhosis and ascites had BT while
this figure drops to 0–10% in animals without ascites
(10). Patients with cirrhosis and BT had a higher degree
of liver dysfunction (estimated by Child-Pugh score) in
comparison with patients without BT (8). In another
study, BT was investigated at two stages of experimental
portal hypertension: acute (when shunting is minimal);
and chronic (when shunting is extensive and mimics the
portal hypertension of cirrhosis). The authors of this
study found that BT is a frequent event in the acute por-
tal hypertension model probably because of a greater
mesenteric inflammation; however, there was no differ-
ence in the rate of BT in chronic portal hypertensive rats
(15 days after portal vein ligation) compared with con-
trol rats (12). Hence, portal hypertension alone may not
be a major factor in the development of BT in cirrhosis.
Recently, our group showed that patients with cirrhosis
and ascites and the presence of bacterial DNA in serum,
a surrogate marker of BT, had the same degree of portal
hypertension than patients without bacterial DNA (13).
These studies suggest that the degree of liver failure and
not portal hypertension per se plays an important role in
the pathogenesis of BT.
The mechanisms that influence the pathogenesis of
BT are at least three: intestinal bacterial overgrowth,
immune alterations of cirrhosis and increased intestinal
permeability.
Small intestinal bacterial overgrowth (SIBO)
Intestinal bacterial overgrowth is a very heterogeneous
syndrome characterized by an increased number and/or
abnormal type of bacteria in the small bowel (14). Most
authors consider diagnostic of SIBO to be the finding of
 105 colony-forming units per ml of proximal jejunal
aspiration. Therefore, the gold standard for diagnosing
SIBO is microbial investigation of jejunal aspirates.
However, some limitations difficult its application in
clinical practice: it is an invasive test, microbial investi-
gation places high demands on the quality of laboratory
work, distribution of bacterial overgrowth might be
32
Bellot et al.
irregular and more than one sample is needed to detect
it. Other non-invasive diagnostic methods more fre-
quently used in clinical practice are hydrogen and meth-
ane breath tests after glucose or lactulose challenge (15).
However, when breath tests are compared to properly
obtained quantitative jejunal cultures, no tests performs
perfectly.
Small intestinal bacterial overgrowth, which is likely
related with a slowed intestinal transit, low acid gastric
secretion, intestinal immunological factors and pancre-
atic and biliary secretions, is one of the main factors
promoting BT. A direct relationship between numbers of
a specific bacterial strain populating a segment of the
intestine and numbers of viable bacteria of this strain
present in MLN has been demonstrated in mice (16).
Moreover, experimental studies have shown that cir-
rhotic rats with ascites and BT have a higher rate of SIBO
compared with those without BT (17). The absence of
SIBO is associated with a low rate of BT (0–11%) and the
rate of BT is comparable to that observed in control rats
(18). However, the fact that BT is not present in 50% of
rats with SIBO suggests that other factors besides SIBO
are involved in the pathogenesis of BT. Clinical studies
have shown that SIBO is more common in patients with
cirrhosis than in controls, especially in patients with
advanced liver dysfunction (19) and in those with a his-
tory of previous episodes of SBP (20). However in these
studies, SIBO was estimated by the breath hydrogen test,
which is not a reliable method for diagnosis. In a study
that estimated SIBO by quantitative cultures of jejunal
aspirates, the occurrence of SBP did not correlate with
the presence of SIBO. Interestingly enough, however,
authors found a significant correlation among the inci-
dence of SBP and protein levels in ascitic fluid, a marker
of immunity local, and serum bilirubin levels (21).
Therefore, other factors such as immunological abnor-
malities and liver insufficiency may play a relevant role
in the pathogenesis of BT.
Increased intestinal permeability
The intestinal barrier is formed mainly by a mucinous
component secreted by intestinal epithelial cells and
intestinal epithelium per se, which forms a layer with
intercellular junctions (‘tight junctions’) that allow
selective passage of substances. Structural and functional
alterations in the intestinal mucosa that increase intesti-
nal permeability to bacteria and its products have been
described in cirrhosis. Experimental studies have
observed a mucous congestion, dilatation of intercellu-
lar spaces in the intestinal epithelium, oedema and sub-
mucosal inflammatory changes in the intestinal barrier
(22–25). However, it is not clear whether these struc-
tural changes are the cause or the result of BT.
The mucin secreted by epithelial goblet cells in large
amounts (3 L/day) form a thick layer of glycoproteins
that prevents a direct contact of the bacteria with
enterocyte microvilli. Furthermore, intestinal mucous
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Bellot et al.
secretions contain immunoglobulin A, which neutralizes
toxins and other bacterial products and binds to bacte-
ria thereby preventing its adhesion and colonization in
the intestinal epithelium.
Bile secretions also play a role in the prevention of
BT by inhibiting bacterial overgrowth, exerting a tro-
phic effect on intestinal mucosa and neutralizing endo-
toxin (26). Therefore, bile acids prevent BT and avoid
the passage of bacterial products from the lumen of
intestine (27, 28).
From a different perspective, studies have demon-
strated increased intestinal permeability to macromole-
cules in patients with advanced cirrhosis, especially in
those with previous episodes of SBP or hepatic encepha-
lopathy (29) or sepsis (30). Oxidative damage of intesti-
nal mucosa (31) and endotoxaemia, elevated levels of
NO and inflammatory cytokines may play a role in
increasing intestinal permeability in cirrhosis (32, 33).
Most studies of intestinal permeability are performed
with probes that measure paracellular permeability, such
as lactulose (29), while BT of living bacteria follows
mostly a transcellular route. Therefore, results obtained
in studies of intestinal permeability may not be associ-
ated with clinical consequences. This may explain why
the increase in intestinal permeability alone does not
seem to be a determining factor in the pathogenesis of
BT. Experimental studies have demonstrated that BT
occurs in up to 87% of rats with increased intestinal
permeability and SIBO, whereas none of the animals
with only increased intestinal permeability showed the
presence of BT (17). Furthermore, only therapy against
SIBO, without interfering in intestinal permeability, is
able to decrease the rate of BT in cirrhotic rats (34).
Immunological impairment
The intestinal tract is an active immune organ, contain-
ing essentially every type of leucocyte involved in
immune response. The intestinal immune system con-
sists of the gut-associated lymphoid tissue, the largest
immunological organ of the body, which comprises four
lymphoid compartments: Peyer’s patches, lamina pro-
pria lymphocytes [including dendritic cells (DCs)],
intraepithelial lymphocytes and MLN, which are involved
in both the adaptive and innate responses. Changes in
local and systemic immunity are clinically relevant to
promote BT in cirrhosis. Bacteria that translocate to
MLNs or to portal blood are usually phagocyted and
neutralized before they begin to grow and cause bactera-
emia or infections in immunocompetent patients.
Patients with cirrhosis have systemic immune altera-
tions that may promote the development of infections
and BT.
Some of these alterations are genetically driven. For
example, nucleotide-binding oligomerization domain-
containing protein 2 (NOD2) plays an important role in
the local immune system, recognizing bacterial mole-
cules (peptidoglycans) and stimulating an immune
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Bacterial translocation in cirrhosis
reaction. Recently, Appenrodt et al. demonstrated that
the occurrence of SBP was significantly increased in car-
riers of NOD2 variants, suggesting that local immune
alterations might be implicated in BT (35).
Advanced cirrhosis is associated with a decrease in
the cellular and humoral components of immune
response (36, 37) being correlated with the likelihood of
developing SBP (38). Cirrhosis has been also associated
with a decreased activity of the reticuloendothelial sys-
tem (RES) that is one of the most relevant defence
systems against bacteraemia and other infections acq-
uired haematogenously. The presence of porto-systemic
shunts and decreased phagocytic capacity of Kupffer
cells is associated with the development of bacteraemia
and SBP (39). The altered clearance capacity of RES
does not only affect viable bacteria but also bacterial
products such as endotoxin or bacterial DNA. Trans-
location of bacterial products promotes a chronic
inflammatory response and impairs further the haemo-
dynamic changes observed in cirrhosis. To date, few
studies have focused on the immunological alterations
of the intestinal barrier favouring BT in cirrhosis.
Inamura et al. have demonstrated a relationship among
decreased cellular proliferative capacity and interferon-
gamma synthesis by intraepithelial lymphocytes in
cirrhotic mice and rate of BT (40).
The synthesis of cytokines, particularly TNF-alpha,
interleukins and NO exacerbates oxidative damage in
the intestinal mucosa (41), which in turn increases
intestinal permeability probably favouring BT. From a
different perspective, our group has demonstrated that
administration of anti-TNF monoclonal antibodies to
cirrhotic rats with ascites was associated with a signifi-
cant decrease in the rate of BT (42). Therefore, the
inflammatory response induced by BT also acts on the
intestinal barrier permeability favouring bacteria and
other bacterial products translocation, thus creating a
feedback in which BT itself perpetuates the pathogenic
mechanisms that cause it.
However, portal hypertension-associated splanchnic
hyperaemia hinders the recruitment of leucocytes in
response to inflammatory stimulus such as leucotriene
administration (43), suggesting that the local immune
response is not sufficient to prevent the passage of bac-
teria from intestinal lumen to the systemic circulation.
Moreover, the ability of MLN to retain and destroy bac-
teria is reduced, possibly by the repetition of these
events. As a logical consequence of these local and sys-
temic immunological disorders, viable bacteria or their
products (endotoxin or bacterial DNA) may access the
systemic circulation and areas with low bactericidal
capacity such as ascitic fluid. These immunological
abnormalities as a whole play an important role in the
pathogenesis of BT, spontaneous bacteraemia, SBP and
the development of complications associated with BT.
In summary, these three disorders discussed previ-
ously (intestinal bacterial overgrowth, increased intesti-
nal permeability and immune system disorders) play a
33
Bacterial translocation in cirrhosis
relevant role in the pathogenesis of BT in cirrhosis,
which explain at least in part the high rate of BT with
respect to other clinical situations in which there is only
one pathogenic factor involved (Fig. 1).
Diagnostic methods of bacterial translocation
In experimental studies, BT is defined as a positive-
culture MLN. Studies of BT in humans are limited
because of the need for surgery and the removal of MLN
in non-optimal conditions (e.g. peri-operative anti-
biotics). Therefore, alternative approaches to diagnosing
BT in humans have been postulated.
Lipopolysaccharide (LPS) is a major component of
the gram-negative bacterial wall that when present in
systemic circulation in a patient might be considered a
surrogate marker of BT. However, there are several rea-
sons for not considering LPS measurement as a sole tool
in detecting BT: the Lymulus Amebocyte Lysate was
originally designed to measure LPS in water, and proto-
cols are not specifically directed to quantify LPS in bio-
logical samples. Furthermore, LPS levels have a short
half-life and may be influenced by several factors, such
as the concentration of LPS transporters, antibodies,
HDL and other immunogenetic, microbiological and
physiological variables (44), and because of the need of
using endotoxin-free systems for samples collection.
These drawbacks are reflected in the rate of endotoxin
detection in cirrhosis, which ranges from 0 to 93% in
different studies (45).
Fig. 1. Pathogenesis of bacterial translocation (BT). Factors involved in the process of BT include intestinal bacterial overgrowth, alterations
in mechanisms preventing attachment and penetration of bacteria (increased intestinal permeability) and, finally, local and systemic immune
responses. MLNs, mesenteric lymph nodes; PHT, portal hypertension; RES, reticulo-endothelial system.
34
Bellot et al.
Lipopolysaccharide binding protein (LBP) measure-
ment, a protein with a relatively long half-life synthe-
sized by the liver in response to bacteraemia or
endotoxaemia, has been proposed as a surrogate marker
of BT. Patients with elevated LBP levels have been
shown to have a pro-inflammatory state and haemo-
dynamic derangement, which may be reversed after
intestinal decontamination with norfloxacin (46). Inter-
estingly, a prospective study in non-infected patients
with cirrhosis and ascites shows a four-fold increase in
the risk of developing bacterial infections in patients
with an elevated LBP vs normal LBP (47). However,
LBP only reflects GNB and not gram-positive transloca-
tion, which represents a major drawback in the investi-
gation of BT (48).
Serum presence of peptidoglycan, a polymer consist-
ing of sugars and amino acids that forms part of the cell
wall of gram-positive bacteria, has been investigated as a
marker of BT in only one experimental model of haem-
orrhagic shock (49). However, more studies are needed
to confirm the utility of the detection of this bacterial
product as a surrogate marker of BT in cirrhosis.
Over the last decade, polymerase chain reaction-
based detection of bacterial DNA (bactDNA) has been
proposed as a surrogate marker for BT because it has
been detected in blood and ascites of approximately
one-third of patients with cirrhosis and culture-negative
ascites (50, 51), a value similar to that reported in other
studies in humans (8). Detection of bactDNA in biolog-
ical fluids in animals with experimental cirrhosis and
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Bellot et al.
ascites is associated with its simultaneous presence in
MLNs, in either culture-positive or culture-negative
MLNs (52). These data support the hypothesis that the
detection of bactDNA in biological fluids in patients
with advanced cirrhosis constitutes a surrogated marker
for the diagnosis of BT (Table 1). However, detection of
bacterial products does not imply the viability of the
accessing bacteria, and therefore the clinical conse-
quences of their presence may be different compared
with the presence of viable bacteria. The rates of bac-
tDNA detection in the literature in this setting are dif-
ferent; probably because of the fact that there is not a
standard method of detection that probably justifies
variations reported (35, 53, 54). Therefore, uniformity
of analytical methods is needed to ascertain its real value
in clinical setting.
Clinical implications of bacterial translocation
The immune system has traditionally been divided into
the innate and adaptive components. The adaptive com-
ponent is organized around two types of cells, B and T
lymphocytes, and it is based on the specificity of each
cell receptor for a particular antigen. Once a lymphocyte
recognizes an antigen, specific clonal expansion occurs
in the lymphocyte, which is necessary to generate an
effective immune response. However, the process by
which adaptive immune system produces a clonal
expansion of lymphocytes and their differentiation into
effector cells usually lasts 3–4 days, more than enough
time for host’s damage. By contrast, the innate immune
system component, which includes antimicrobial pep-
tides, macrophages, DCs and the alternative comple-
ment pathway, is activated immediately after infection,
and can rapidly control the replication of the pathogens.
Toll-like receptors (TLR) are a type of membrane
proteins involved in innate immune responses that rec-
ognize various conserved molecular patterns of patho-
gens (PAMPs). To date, 10 types of TLR have been
identified, each of which recognizes conserved struc-
tures of various pathogens or PAMPs. The most studied
Table 1. Different biological markers to identify bacterial translocation
Marker Origin/ Toll-like
of BT pathogen Half-life receptor
LPS GNB 2–3 h TLR4
LBP – 2–3 days – Long half-life
Peptidoglycan GPC (and 6–8 h TLR2
GNB)
Bacterial DNA GPC and 2–4 days TLR9
GNB
GNB, gram negative bacteria; GPC, gram positive cocci; TLR, toll-like receptor.
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Bacterial translocation in cirrhosis
TLR in cirrhosis are TLR-4, which recognizes LPS,
TLR-2, which is activated with the presence of the pepti-
doglycan wall component of GPC, and TLR-9, which
recognizes bactDNA. Activation of these receptors is fol-
lowed by the release of pro-inflammatory cytokines that
can worsen the haemodynamic changes of cirrhosis,
especially splanchnic vasodilation and hyperdynamic
syndrome. Riordan et al. investigated TLR expression in
peripheral blood mononuclear cells in patients with
cirrhosis, and they found that TLR-2 expression is up-
regulated, whereas TLR-4 expression is unaltered or
downregulated, suggesting an important stimulatory
role for GPC, but not for GNB (55). However, other
bacterial products than LPS, such as bactDNA, lipo-
proteins and heat-shock protein 60, could stimulate dif-
ferent TLRs. All known TLR agonists have been shown
to induce tumour necrosis factor (TNF) secretion by
monocytes. Therefore, it might be speculated that in cir-
rhosis, priming of mononuclear cells and associated
release of pro-inflammatory cytokines is mediated by an
upregulation of TLR expression (56).
Bacterial DNA, unlike the DNA of vertebrates,
contains multiple sets of unmethylated dinucleotides
(so-called ‘CpG motifs’) that through the interaction
with TLR-9 induce an inflammatory response (57). Our
group has previously shown that bactDNA activates cell-
mediated immune response and NO overproduction by
peritoneal macrophages from patients with cirrhosis
and ascites (58). Moreover, the presence of bactDNA in
patients with non-infected ascites is associated with a
soluble immune response similar to that in patients with
SBP. The bactDNA-associated inflammatory response
was directly proportional with the serum concentrations
of bactDNA, confirming the role of the translocation of
bacterial DNA in the immune response (59).
Bacterial translocation can also exacerbate the hepatic
and systemic haemodynamic abnormalities of liver cir-
rhosis. Experimental studies also suggested that BT is
associated with further deterioration of the hyperdy-
namic circulation of cirrhosis. Cirrhotic rats with BT
have an increased activity of endothelial nitric oxide
Pros Caveats
Widely used Influenced by several factors: LBP levels, serum
Validated in experimental lipoproteins
models Variable detection: 0–90%
Only detects BT from GNB
Indirect marker of BT
Predicts clinical outcomes Only detects BT from GNB
– Not widely validated
Long half-life Variable detection
Predicts clinical outcomes Not fully validated by other groups
Validated in experimental
models
35
Bacterial translocation in cirrhosis
synthase (eNOS) in mesenteric vasculature mediated by
increased levels of TNF-alpha and eNOS cofactor tetra-
hydrobiopterin (60). Studies in humans have demon-
strated that cirrhotic patients with increased levels of
LBP, an indirect marker of BT, have a more profound
systemic haemodynamic derangement, which could be
reversed after selective intestinal decontamination with
norfloxacin (46). Moreover, bacterial DNA transloca-
tion in patients with ascites and portal hypertension
aggravates the systemic circulatory dysfunction, further
exacerbating the peripheral vasodilation; which was
related with increased inflammatory state estimated by
the presence of higher plasma levels of TNF-a (13).
It has been suggested that the worsening of the hyperdy-
namic circulation and the inflammatory state associated
with BT may play a role in the complications of portal
hypertension, especially the development of hepatorenal
syndrome (HRS). Recently, experimental studies have
demonstrated that kidneys in cirrhosis show an
increased expression of TLR4, and the pro-inflamma-
tory cytokine TNF-a, which makes them susceptible to
a further inflammatory insult during BT (61). Angeli
et al. investigated the presence of bactDNA in patients
with refractory ascites, demonstrating that BactDNA
translocation was associated with an impaired cardio-
vascular and renal functions and a higher risk of HRS
Fig. 2. Clinical consequences of bacterial translocation. The activation of the immune system by TB causes an inflammatory response that
leads to a sustained worsening of the haemodynamic changes of cirrhosis, especially in the liver, systemic and renal circulation. The inflam-
matory response mediated by bacterial translocation may play a role in the pathogenesis of hepatic encephalopathy. SVR, systemic vascular
resistance.
36
Bellot et al.
and death (62). Recently, Kalambokis et al. showed that
rifaximin, a non-absorbable antibiotic, improves hae-
modynamic abnormalities and renal function in patients
with advanced cirrhosis (63). These results are in line
with other randomized control trial that found a lower
incidence of HRS in patients with advanced cirrhosis
and ascites treated with norfloxacin (64).
Endothelin 1 (ET-1) is the most potent mediator of
stellate cell contraction and in the liver, ET-1 receptors
predominate in hepatic stellate cells, which have an
important role in the regulation of intrahepatic portal
hypertension in cirrhosis (65). Both endotoxin itself and
cytokines released in response to BT are potent stimuli
for the production of ET-1, which may act in combina-
tion with cyclooxygenase products to increase portal
venous resistance during endotoxaemia (66, 67). During
BT, endotoxin (LPS) promotes an imbalance in the
expression of vasoconstrictors (endothelin-1) in relation
to the expression of vasodilator substances (NO, carbon
monoxide), thereby increasing hepatic vascular tone
(68). Therefore, both infections or BT may cause an
acute increase in portal pressure in patients with
cirrhosis, triggering a variceal bleeding (69). Recently,
our group have demonstrated that bactDNA trans-
location is associated with a more profound abnormal-
ity of the intrahepatic circulation, in the sense of worse
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Bellot et al.
hepatic endothelial dysfunction, as suggested by a
greater post-prandial increase in hepatic venous pres-
sure gradient in bactDNA-positive patients with cirrho-
sis and ascites (13).
Other studies have suggested that BT may be impli-
cated in hepatic encephalopathy (HE) pathogenesis. It is
a well-known fact that bacterial infections constitute a
trigger for HE in patients with cirrhosis. Previous stud-
ies on the pathogenesis of HE have focused on the dele-
terious role of toxins on the brain. However, in the last
decade, several studies suggest how inflammation and
infection exert synergistic effects with toxins such as
ammonia in the pathogenesis of HE (70, 71). Based on
the aforementioned, BT-associated inflammatory res-
ponse may have a role in the pathogenic mechanisms
involved in HE. SIBO is associated with BT in patients
with cirrhosis, estimated by the presence of bactDNA,
and with a higher prevalence of HE in one recent study
(72). Moreover, a relationship between minimal hepatic
encephalopathy (MHE) and SIBO had been also dem-
onstrated in patients with cirrhosis (73). Rifaximin, a
non-absorbable antibiotic, improves MHE in some clin-
ical studies (74, 75); suggesting that BT, including trans-
location of bacterial products, plays an important role
in the pathogenesis of HE.
Bacterial translocation, as a trigger for an abnormal
inflammatory state and haemodynamic derangement,
has prognostic implications in liver cirrhosis. In a multi-
centre study that included 156 patients with cirrhosis
and non-neutrocytic ascites, we observed that patients
with positive bactDNA in ascitic fluid and plasma had a
worse prognosis than patients with negative bactDNA
(76). In that study, acute-on-chronic liver failure was
the main cause of mortality in bactDNA-positive
patients; suggesting that BT may be associated with hae-
modynamic and clinical deterioration of the overall
clinical situation of patients with cirrhosis. Bruns et al.
also found that bactDNA detection in patients with
severe liver dysfunction (MELD score >15) is associated
with an increased mortality (54). These results are in
line with other studies that showed how intestinal
decontamination improves survival in patients with cir-
rhosis (64, 77), liver function parameters (78) and other
portal hypertension-related complications like throm-
bocytopaenia (79).
Summary
Advanced cirrhosis behaves like a chronic inflammatory
disease in which the immune system is exposed to a
continuous activation by bacteria and bacterial products
of intestinal origin, the so-called BT. The immuno-
logical abnormalities associated with cirrhosis and BT
perpetuate the translocation of bacteria and their prod-
ucts while exerting an effect on other systems, such as
the circulatory system. Therefore, BT is implicated in
some of the complications of cirrhosis, worsening
hyperdynamic circulation, renal function, intrahepatic
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Bacterial translocation in cirrhosis
endothelial dysfunction and HE (Fig. 2). It is notewor-
thy that much of the pro-inflammatory state of cirrhosis
is owing to the release of bacterial products into the
systemic circulation. Finally, note that the presence of
bacterial DNA fragments is a direct and sensitive marker
of BT and that seems to play a direct role in the
inflammatory response associated with BT, as well as
being a predictor of mortality in patients with cirrhosis
and ascites. Finally, we consider that more studies are
needed to increase understanding of the pathogenesis of
BT to open new therapeutic avenues in cirrhosis and
portal hypertension.
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