Bacterial Translocation In Cirrhosis Research Articles

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis

ObjectiveTargeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in...

Presepsin as a biomarker of bacterial translocation and an indicator for the prescription of probiotics in cirrhosis.

The gut-liver axis and bacterial translocation are important in cirrhosis, but there is no available universal biomarker of cellular bacterial translocation, for which presepsin may be a candidate. To evaluate the relationship of the blood presepsin levels with the state of the gut microbiota in cirrhosis in the absence of obvious infection. This study included 48 patients with Child-Pugh cirrhosis classes B and C and 15 healthy controls. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of presepsin were measured. A total of 22 patients received a probiotic (Saccharomyces boulardii) for 3 months. Presepsin levels were higher in patients with cirrhosis than in healthy individuals [342 (91-2875) vs 120 (102-141) pg/mL; P = 0.048]. Patients with elevated presepsin levels accounted for 56.3% of all included patients. They had lower levels of serum albumin and higher levels of serum total bilirubin and overall severity of cirrhosis as assessed using the Child-Pugh scale. Patients with elevated presepsin levels had an increased abundance of the main taxa responsible for bacterial translocation, namely Bacilli and Proteobacteria (including the main class Gammaproteobacteria and the minor taxa Xanthobacteraceae and Stenotrophomonas), and a low abundance of bacteria from the family Lachnospiraceae (including the minor genus Fusicatenibacter), which produce short-chain fatty acids that have a positive effect on intestinal barrier function. The presepsin level directly correlated with the relative abundance of Bacilli, Proteobacteria, and inversely correlated with the abundance of Lachnospiraceae and Propionibacteriaceae. After 3 months of taking the probiotic, the severity of cirrhosis on the Child-Pugh scale decreased significantly only in the group with elevated presepsin levels [from 9 (8-11) to 7 (6-9); P = 0.004], while there were no significant changes in the group with normal presepsin levels [from 8 (7-8) to 7 (6-8); P = 0.123]. A high level of presepsin before the prescription of the probiotic was an independent predictor of a greater decrease in Child-Pugh scores (P = 0.046), as well as a higher level of the Child-Pugh scale (P = 0.042), but not the C-reactive protein level (P = 0.679) according to multivariate linear regression analysis. The level of presepsin directly correlates with the abundance in the gut microbiota of the main taxa that are substrates of bacterial translocation in cirrhosis. This biomarker, in the absence of obvious infection, seems important for assessing the state of the gut-liver axis in cirrhosis and deciding on therapy targeted at the gut microbiota in this disease.

Recombinant VEGF-C (Cys156Ser) improves mesenteric lymphatic drainage and gut immune surveillance in experimental cirrhosis

Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homoeostasis and immunity. In cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given the established role of vascular endothelial growth factor-C (VEGF-C) in improving LVs, we hypothesised that VEGF-C treatment could ameliorate the functions of mLVs in cirrhosis. In this study, we developed a nanoformulation comprising LV-specific growth factor, recombinant human VEGF-C (Cys156Ser) protein (E-VEGF-C) and delivered it orally in different models of rat cirrhosis to target mLVs. Cirrhotic rats were given nanoformulation without VEGF-C served as vehicles. Drainage of mLVs was analysed using tracer dye. Portal and systemic physiological assessments and computed tomography were performed to measure portal pressures and ascites. Gene expression and permeability of primary mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cells in mesenteric lymph nodes (MLNs) were quantified by flow cytometry. Endogenous and exogenous gut bacterial translocation to MLNs was examined. In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of mLVs, reduced their diameter, and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C rats compared with vehicle rats. In MLNs of E-VEGF-C animals, CD8+CD134+ T cells were increased, whereas CD25+ regulatory T cells were decreased. Both endogenous and exogenous bacterial translocation were limited to MLNs in E-VEGF-C rats with reduced levels of endotoxins in ascites and blood in comparison with those in vehicle rats. E-VEGF-C treatment upregulated the expression of vascular endothelial-cadherin in LyECs and functionally improved the permeability of these cells. E-VEGF-C treatment ameliorates mesenteric lymph drainage and portal pressure and strengthens cytotoxic T-cell immunity in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and reduce pathogenic gut bacterial translocation in cirrhosis. A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in different models of rat liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vesselproliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limited bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy thus holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.

Review article: therapeutic aspects of bile acid signalling in the gut-liver axis.

SummaryBackgroundBile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues.AimThis review summarises important aspects of bile acid‐mediated crosstalk between the gut and the liver (“gut‐liver axis”) as well as recent findings from experimental and clinical studies.MethodsWe performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease.ResultsIntestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid‐mediated gut‐liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target.ConclusionsExperimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.

Ginkgolide-A attenuates bacterial translocation through activating PXR and improving antimicrobial peptide Reg 3A in experimental cirrhosis

Background and aimsBacterial translocation (BT) is strongly associated with disease progression and poor outcome in cirrhotic patients. The role of Pregnane X receptor (PXR) in regulating bacterial translocation in cirrhosis is unknown. We previously showed that Ginkgolide-A (GA), a natural PXR ligand, attenuated BT in cirrhotic mice by abrogating inflammation along the gut-liver-axis, and by protecting small intestinal tight junctions (TJ). Here, we aimed to investigate the effect of GA in activating PXR and associated antimicrobial peptides (AMPs) in regulating BT in experimental cirrhosis. MethodsMale Swiss albino mice were administered CCl4 (0.5 mL/kg body-weight, i.p twice a week) for 12 consecutive weeks. After the 12th week, mice were randomized and administered with GA (100-mg/kg body-weight, oral) every-day for 2 weeks. At termination, blood, gut and liver tissues were collected for molecular studies. ResultsGA treatment to cirrhotic mice significantly increased the expression of small intestinal PXR and Regenerating family member 3 alpha (Reg3A), which were otherwise reduced in CCl4 cirrhotic mice. Moreover, compared to naive mice a significantly reduced Lactobacillus, and increased Bacteroides and Enterococcus 16s rRNA levels were observed in the small intestine and liver of cirrhotic mice. Treatment with GA to cirrhotic mice significantly reduced intestinal overgrowth and translocation of Enterococcus and Bacteroides to the liver. Furthermore, GA treatment significantly attenuated intestinal permeability and BT marker soluble-CD14 (sCD14), which were increased in CCl4 cirrhotic mice. ConclusionThe study showed for the first time that, GA treatment to cirrhotic rodents attenuates BT, by improving PXR and Reg3A expression.

БАКТЕРИАЛЬНАЯ ТРАНСЛОКАЦИЯ В ПАТОГЕНЕЗЕ ОСЛОЖНЕНИЙ ЦИРРОЗА ПЕЧЕНИ

Background. Understanding of intestinal bacteria-host interaction physiology as well as bacterial translocation characteristics at the initial stages and in advanced cirrhosis emphasizes the importance of approaches minimizing the migration of microorganisms and their components from the intestinal lumen. Objective – to provide a brief review of publications highlighting the problem of bacterial intestinal translocation as the main mechanism for the development of bacterial infections and pro-inflammatory status in patients with liver cirrhosis. Material and methods. We performed the study and analysis of English- and Russian-language articles over the past 30 years contained in the following databases: PubMed, Cochrane Collaboration, UpToDate. The key words were: «intestinal microflora translocation», «bacterial translocation», «translocation markers». Results. Contemporary views on changes of the intestinal barrier and those of innate and adaptive immunity systems in liver diseases are considered. Data on possibility and signifcance of detecting bacterial translocation are presented.Current methods used for gut microbiome analysis as well as some areas for future research are discussed. Conclusion. A validated marker/markers is required to study bacterial translocation in cirrhosis.

Pregnane X receptor activation by its natural ligand Ginkgolide-A improves tight junction proteins expression and attenuates bacterial translocation in cirrhosis

Background and aimsPregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. MethodsSwiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. ResultsWhen compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. ConclusionIn conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.

Regulatory T Cells Restrict Permeability to Bacterial Antigen Translocation and Preserve Short‐Chain Fatty Acids in Experimental Cirrhosis

Intestinal permeability to translocation of bacterial products is increased in cirrhosis. Regulatory T cells (Tregs) remain central to the interplay between the host and microbial milieu. We propose that Tregs are involved in promoting gut barrier integrity and a balanced interaction with gut microbiota–derived short‐chain fatty acids (SCFAs). Carbon tetrachloride cirrhosis was induced in wild‐type and recombination activating gene 1 (Rag1)‐/‐ mice. Naive T cells and Treg cells were transferred into Rag1 ‐/‐ mice. Intestinal permeability was assessed in vivo after lipopolysaccharide (LPS) oral administration, and bacterial DNA presence was evaluated in mesenteric lymph nodes. Transcript and protein levels of tight‐junction (TJ) proteins were measured in colonic tissue. Intestinal T helper profile in response to Escherichia coli (E. coli) was determined by flow cytometry. SCFAs were measured by gas chromatography–mass spectrometry in colonic content before and after E. coli challenge. Rag1 ‐/‐ mice showed significantly increased permeability to LPS and bacterial DNA translocation rate compared with control mice. Naive T and Treg cotransfer significantly reduced gut permeability to bacterial antigen translocation and restored TJ protein expression in Rag1 ‐/‐ mice. Naive T and Treg replenishment in Rag1 ‐/‐ mice restrained proinflammatory differentiation of intestinal lymphocytes in response to E. coli. The main SCFA concentration resulted in significant reduction in Rag1 ‐/‐ mice after E. coli administration but remained unaltered after naive T and Tregs cotransfer. The reduced expression of SCFA receptors induced by E. coli was reestablished following naive T and Treg reconstitution in Rag1 ‐/‐ mice. Conclusion: The restriction of gut permeability, local inflammatory differentiation, and loss of bacteria‐derived SCFAs foster the value of Tregs in preventing bacterial translocation in cirrhosis.

Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial.

Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56years (±8.4), and model for end-stage liver disease score 12 (±3.9). Patients received rifaximin 550-mg BD (n=36) or placebo BD (n=18). Blood and fecal (n=15) sampling were conducted at baseline and after 4weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor β-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n=34) or activated lipopolysaccharide binding protein (n=37) revealed no effect of rifaximin. Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Bacterial translocation markers in liver cirrhosis.

Bacterial translocation (BT) is an important mechanism in the development of infection in liver cirrhosis. The migration and colonization of bacteria and/or bacterial products from the bowel to mesenteric lymph nodes is a controlled process in healthy persons. Increased intestinal permeability, bacterial overgrowth and defect of gut-associated lymphatic tissue promote impaired BT in cirrhotics. We reviewed the reports on markers used for the evaluation of BT published between 1987 and 2016. We focused on the clinical consequences of BT in cirrhosis, as indicated by the values of the BT markers. Patients with cirrhosis are reported to have elevated levels of surrogate markers associated with BT compared with controls. The most widely used BT parameters are C-reactive protein, procalcitonin, bacterial DNA, endotoxin or lipopolysaccharide, lipopolysaccharide binding protein, calprotectin, and bactericidal/permeability increasing protein. High levels of these factors in serum and/or ascitic fluid in humans may be associated with advanced liver disease, hemodynamic instability, high levels of proinflammatory cytokines, susceptibility to the development of severe or recurrent infections, acute-on-chronic liver failure, hepatic encephalopathy, hepatorenal syndrome and poor prognosis during follow up. In conclusion, high levels of BT markers are associated with a high inflammatory response, increased complications of liver cirrhosis and occasionally high fatality rates.

Microbiome and bacterial translocation in cirrhosis

Qualitative and quantitative changes in gut microbiota play a very important role in cirrhosis. Humans harbour around 100 quintillion gut bacteria, thus representing around 10 times more microbial cells than eukaryotic ones. The gastrointestinal tract is the largest surface area in the body and it is subject to constant exposure to these living microorganisms. The existing symbiosis, proven by the lack of proinflammatory response against commensal bacteria, implies the presence of clearly defined communication lines that contribute to the maintenance of homeostasis of the host. Therefore, alterations of gut flora seem to play a role in the pathogenesis and progress of multiple liver and gastrointestinal diseases. This has made its selective modification into an area of high therapeutic interest. Bacterial translocation is defined as the migration of bacteria or bacterial products from the intestines to the mesenteric lymph nodes. It follows that alteration in gut microbiota have shown importance, at least to some extent, in the pathogenesis of several complications arising from terminal liver disease, such as hepatic encephalopathy, portal hypertension and spontaneous bacterial peritonitis. This review sums up, firstly, how liver disease can alter the common composition of gut microbiota, and secondly, how this alteration contributes to the development of complications in cirrhosis.

VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride-induced cirrhosis.

Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. Forty-six Sprague-Dawley rats with CCl4 -induced cirrhosis were randomized into two groups: VSL#3 group (n = 22) that received VSL#3 in drinking water, and water group (n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) (P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group (P = 0.03 vs. VSL#3 group) and 0/11 in the control group (P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group (P < 0.05). VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis.

Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression

Superimposed infection and/or inflammation precipitate renal failure in cirrhosis. This study aimed at testing the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed inflammation by upregulating expression of Toll-like receptor 4 (TLR4), NFκB, and cytokines. A well-characterized bile-duct ligated (BDL) model of cirrhosis, which develops renal failure following superimposed inflammatory insult with lipopolysaccharide (LPS), was used and selective gut decontamination was performed using norfloxacin. Sprague-Dawley rats were studied: Sham, Sham+LPS; BDL, BDL+LPS; an additional BDL and BDL+LPS groups were selectively decontaminated with norfloxacin. Plasma biochemistry, plasma renin activity (PRA) and cytokines and, protein expression of TLR4, NFκB, and cytokines were measured in the kidney homogenate. The kidneys were stained for TLR4, TLR2, and caspase-3. Endotoxemia was measured using neutrophil burst and Limulus amoebocyte lysate (LAL) assays. The groups treated with norfloxacin showed significant attenuation of the increase in plasma creatinine, plasma and renal TNF-α and renal tubular injury on histology. The increased renal protein expression of TLR4, NFκB, and caspase-3 in the untreated animals was significantly attenuated in the norfloxacin treated animals. PRA was reduced in the treated animals and severity of endotoxemia was also reduced. The results show for the first time that kidneys in cirrhosis show an increased expression of TLR4, NFκB, and the pro-inflammatory cytokine TNF-α, which makes them susceptible to a further inflammatory insult. This increased susceptibility to LPS can be prevented with selective decontamination, providing novel insights into the pathophysiology of renal failure in cirrhosis.

Bacterial translocation in cirrhosis is not caused by an abnormal small bowel gut microbiota

Sepsis is common in liver cirrhosis, and animal studies have shown the gut to be the principal source of infection, through bacterial overgrowth and translocation in the small bowel. A total of 33 patients were recruited into this study, 10 without cirrhosis and 23 with cirrhotic liver disease. Six distal duodenal biopsies were obtained and snap frozen for RNA and DNA extraction, or frozen for FISH. Peripheral venous bloods were obtained from 30 patients, including 17 chronic liver disease patients. Samples were analysed by real-time PCR, to assess total bacteria, bifidobacteria, bacteroides, enterobacteria, staphylococci, streptococci, lactobacilli, enterococci, Helicobacter pylori and moraxella, as well as TNF-α, IL-8 and IL-18. There was no evidence of bacterial overgrowth with respect to any of the individual bacterial groups, with the exception of enterococci, which were present in higher numbers in cirrhotic patients (P=0.04). There were no significant differences in any of the cytokines compared to the controls. The small intestinal mucosal microbiota in cirrhotic patients was qualitatively and quantitatively normal, and this shifts the focus of disease aetiology to factors that reduce gut integrity, failure of mechanisms to remove translocating bacteria, or the large bowel as the source of sepsis.

Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study

Bacterial translocation seems to precede the occurrence of overt bacterial infection in patients with cirrhosis. The presence of bacterial DNA in blood and ascites correlates with bacterial translocation and is frequent in patients with advanced cirrhosis without overt infection. Our aim was to search for bacterial DNA in patients with cirrhosis both with and without ascites, and to study its correlation with abnormal intestinal motility or permeability and the presence of bacterial overgrowth. Blood and ascites samples were obtained on day 1, and blood samples were taken twice a day for the following 3 days. Bacterial DNA was assayed by polymerase chain reaction using universal primers for rRNA 16 s. Oro-caecal transit time and bacterial overgrowth were assessed with Lactulose H(2) breath testing. Intestinal permeability was assessed by determining urinary lactulose and mannitol excretion with high performance liquid chromatography. We studied seven patients (six were male, age range was 42-78 years). Aetiology was alcohol in four, HCV in two, HBV in one; ascites was present in four and Child-Pugh grade was A in four and B in three. All patients had increased intestinal permeability, six had decreased transit time and one had bacterial overgrowth. In only one patient (with ascites), polymerase chain reaction was positive for bacterial DNA both in ascites and serum for all 4 days on which samples were taken. Increased intestinal permeability and abnormal motility were frequent without evidence of bacterial translocation in cirrhosis even without ascites. They are likely to be facilitators for bacterial translocation and thus precede it.

Translocación de productos de origen bacteriano en la cirrosis

Bacterial translocation (BT) is defined as the passage of viable bacteria through the intestinal barrier toward the mesenteric lymph nodes, where they may disseminate toward other systems. The pathogenesis of BT in cirrhosis involves three main factors: bacterial overgrowth, increased intestinal permeability, and immune system alterations. Recent findings indicate that the concept of BT could be broadened to include the presence of bacterial products (bacterial DNA and endotoxin) in mesenteric lymph nodes and other territories. Both bacterial DNA and endotoxin provoke sustained activation of the immune system with release of proinflammatory cytokines and effectors such as nitric oxide, which aggravate the hemodynamic alterations present in patients with cirrhosis. This article provides a detailed description of the abnormalities present in patients with cirrhosis that allow the existence of TB and the immune and clinical repercussions of this phenomenon.

Portal hypertension and its complications

Portal hypertension is responsible for most of the complications associated with cirrhosis, specifically variceal hemorrhage, ascites and hepatic encephalopathy. Progress in understanding the pathophysiology of portal hypertension and improvements in the diagnosis and management of its complications that have occurred over the last year are discussed. Endothelial dysfunction contributes to the pathogenesis of portal hypertension and may represent a novel therapeutic target. Hepatic venous pressure gradient measurements, when properly performed, are useful in the management of patients with cirrhosis. Hyponatremia in cirrhosis has prognostic value and novel aquaretic and other agents may provide alternative approaches to the management of chronic liver disease. The mechanisms for bacterial translocation in cirrhosis that predisposes patients to infectious complications, such as spontaneous bacterial peritionitis, are being explored. Adrenal insufficiency is common in septic patients with advanced cirrhosis and corticosteroids may provide a survival benefit. Pulmonary disease complicates the management of patients with advanced liver disease. Significant advances continue to be made in the diagnosis and management of the complications of portal hypertension in the face of an increasing burden of chronic liver disease.

Fisiopatología de la translocación y la peritonitis bacteriana espontánea en la cirrosis

El mecanismo patogénico clave que inicia la peritonitis bacteriana espontánea (PBE) es la translocación bacteriana (TB), proceso por el cual las bacterias entéricas cruzan la barrera mucosa intestinal e infectan los ganglios linfáticos mesentéricos, y desde donde alcanzan la circulación sanguínea y, posteriormente, el líquido ascítico. La alta tasa de TB en la cirrosis se debe al daño en los 3 pilares que constituyen la barrera mucosa del intestino: equilibrio de la flora bacteriana intraluminal, integridad de la barrera epitelial intestinal y sistema inmunitario local. La diseminación sanguínea y el crecimiento de los gérmenes en el líquido ascítico que se produce en la PBE es consecuencia del daño en el sistema inmunitario que conlleva la cirrosis. La hiperproducción en el líquido ascítico de citocinas proinflamatorias y otras sustancias con propiedades vasoactivas contribuye a la vasodilatación arterial y a la insuficiencia renal que, con frecuencia, complica el curso de la PBE. Aun en ausencia de PBE, la translocación de bacterias y productos bacterianos desde la luz intestinal contribuye a la activación sistémica de las células inmunitarias en la cirrosis. The key pathogenic mechanism initiating spontaneous bacterial peritonitis (SBP) is bacterial translocation (BT), a process through which enteric bacteria cross the intestinal barrier and infect the mesenteric lymph nodes, thus entering the blood circulation and ascitic fluid. The high rate of bacterial translocation in cirrhosis is due to injury to the three pilars composing the intestinal mucosal barrier (the balance of intraluminal bacterial flora, the integrity of the intestinal epithelial barrier, and the local immune system). Blood dissemination and microbial growth in ascitic fluid resulting from SBP are a consequence of damage to the immune system in cirrhosis. Hyperproduction of proinflammatory cytokines and other vasoactive substances contributes to the arterial vasodilation and renal failure that frequently complicate the course of SBP. Even in the absence of SBP, translocation of bacteria and bacterial products from the intestinal lumen contribute to systemic inactivation of immune cells in cirrhosis.

Bacterial translocation (BT) in cirrhosis†

Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the complications of cirrhosis. Research on the pathogenesis of BT and its clinical significance transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review delineates multiple mechanisms involved in the process of BT, with an emphasis on alterations in intestinal flora and mucosal barrier function, particularly immunological defense mechanisms. Current knowledge on the innate and adaptive immune response that allows a "friendly" communication between bacteria and host is summarized, and alterations occurring in cirrhosis that may facilitate BT are discussed. In addition, definition of a "pathological" BT is proposed together with an analysis of the anatomical site and route of BT. Finally, therapeutic approaches for the prevention of BT in experimental and human cirrhosis are reviewed. Future research in the field of BT in cirrhosis will allow the development of new therapeutic targets in the prevention of infections and other complications of cirrhosis.

Bacterial translocation and its consequences in patients with cirrhosis

Bacterial translocation is the passage of viable bacteria from the intestinal lumen to mesenteric lymph nodes and other extraintestinal sites. Spontaneous bacterial peritonitis is the main clinical consequence of bacterial translocation in cirrhosis. Translocation of bacterial products of viable or non-viable bacteria, such as endotoxin and/or bacterial DNA, through the intestinal wall could stimulate the immune system and the hyperdynamic circulatory state in cirrhosis with clinical consequences that are under evaluation. Bacterial translocation is currently considered the passage of viable gut flora across the intestinal barrier to extraluminal sites. Aerobic Gram-negative bacilli are the most common translocating bacteria. Intestinal bacterial overgrowth, impairment in permeability of the intestinal mucosal barrier, and deficiencies in local host immune defences are the major mechanisms postulated to favour bacterial translocation in cirrhosis. Bacterial translocation is a key step in the pathogenesis of spontaneous bacteraemia and spontaneous bacterial peritonitis in cirrhosis. Translocation of intestinal bacterial products from viable or non-viable bacteria, such as endotoxin and bacterial DNA, has recently been associated with pathophysiological events, such as activation of the immune system and derangement of the hyperdynamic circulatory status in cirrhosis. Clinical consequences of these effects of bacterial products are presently under investigation.