Download PDF
Semin Liver Dis 2025; 45(01): 052-065
DOI: 10.1055/a-2516-2361
Review Article

Role of Intestinal Barrier Disruption to Acute-on-Chronic Liver Failure

Julian Pohl
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Dimitrios Aretakis
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Frank Tacke
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Cornelius Engelmann
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
2   Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
3   Institute for Liver and Digestive Health, University College London, London, United Kingdom
,
Michael Sigal
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
4   Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
› Author Affiliations

Funding None.
› Further Information
 
 PDF Download Permissions and Reprints


Abstract

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut–liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut–liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.


#

Keywords

liver cirrhosis - acute-on-chronic liver failure - gut - bacterial translocation - systemic inflammation
Lay Summary

ACLF is a life-threatening complication of decompensated liver cirrhosis, characterized by a high short-term mortality (28 days). Heavy alcohol consumption and infections are significant triggers for ACLF. Research has shown that the gut plays a key role in the onset and progression of this condition. This is largely due to a weakened intestinal barrier, imbalances in gut bacteria, and the translocation of pathogens from the intestine into the systemic circulation, all of which worsen ACLF. This review examines the connection between the gut and liver in ACLF and discusses potential treatments, such as medications and probiotics, that target this link. A better understanding of these mechanisms could lead to improved treatment and prevention strategies, ultimately enhancing patient outcomes.

Acute-on-chronic liver failure (ACLF) is a distinct syndrome in patients with decompensated liver cirrhosis characterized by organ failure and high short-term mortality.[1] The severity of ACLF is determined by the degree (number) of organ failures.[2] In addition to excessive alcohol consumption, infections are considered the main precipitating events causing ACLF.[3] These can trigger overwhelming but dysfunctional immunological responses that can lead to multiorgan failure and death. There is emerging evidence that the intestine can act as a key player in the pathogenesis of ACLF. Bidirectional interactions between the liver and the gut seem to be involved in the initiation of ACLF and aggravate disease, as suggested by multiple studies.[3] [4] [5] [6] The intestine can play important roles in the development of ACLF by different means: Firstly, the disruption of the mucosal barrier observed in liver cirrhosis can facilitate subsequent translocation of bacteria, resulting in extraintestinal infections. Indeed, a large proportion of infections in ACLF are driven by bacteria that reside in the gastrointestinal tract.[7] Secondly, in addition to translocation, an impaired mucus barrier may result in an increased direct exposure of the mucosa to bacteria that trigger aberrant inflammatory responses that have a systemic impact and therefore significantly affect liver integrity.[8] Thirdly, gut dysbiosis, which was recently identified as a hallmark of liver cirrhosis and ACLF, can also be considered a result of disrupted homeostasis in the intestine and may contribute to aberrant inflammation and facilitate expansion and translocation of facultative pathogens ([Fig. 1]).[9]

Zoom Image
Fig. 1 Schematic illustration of the interplay of liver and gut in regard of ACLF. ACLF, acute-on-chronic liver failure; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharides; PAMPs, pathogen-associated molecular patterns; RIPK1, receptor-interacting protein kinase 1; SCFA, short-chain fatty acids; TLR4, toll-like receptor 4

The contribution of the intestine to progression of chronic liver diseases (CLDs) and the onset of ACLF represents an active field of investigation that will likely yield new diagnostic and therapeutic opportunities. This review highlights recent advances in our understanding of the gut–liver axis in ACLF and its implications for the current and future clinical management of this condition.

Definition of Acute-on-Chronic Liver Failure

Liver cirrhosis is a disease that spans a large clinical spectrum ranging from compensated, asymptomatic stages to decompensated liver cirrhosis and ultimately ACLF. Compensated cirrhosis has a good prognosis with a median transplant-free survival of over 12 years.[10] Of these patients, 5 to 7% progress to “decompensated liver cirrhosis” within 1 year and become symptomatic.[10] “Decompensated cirrhosis” is defined by developing cirrhosis-related complications such as jaundice, ascites, gastrointestinal hemorrhage, or hepatic encephalopathy (HE); patients at this stage of the disease have a median transplant-free survival of only 2 years.[11] Since the beginning of the 2000s, a subgroup of these (“decompensated”) patients has been identified that has a very high short-term mortality (28-day mortality), establishing the term ACLF.[12] Since then, ACLF has been accepted as a complex syndrome characterized by acute decompensation (AD) of CLD accompanied by single- or multiorgan failure. Depending on the number of organ failures, mortality in ACLF without transplantation ranges between 23 and 74% within 28 days.[1] [11] [13] In 2023, the European Association for the Study of the Liver (EASL) published their first clinical practice guidelines for ACLF.[2]

Definitions of ACLF and organ failure vary in different regions in the world (e.g., NASCELD—North America, APASL—Asia), which have a different level of evidence supporting the definition. Here, we mainly focus on the definitions proposed the EASL Chronic Liver Failure (EASL-CLIF) Consortium in Europe that has been derived from large prospective observational trials ([Table 1]).[2] [14]

Table 1

CLIF-organ failure score system

Organ system

1 point

2 points

3 points

Liver

Bilirubin < 6 mg/dL

Bilirubin 6–11.9 mg/dL

Bilirubin ≥ 12 mg/dL

Kidney

Creatinine < 1.5 mg/dL

Creatinine 2–3.4 mg/dL

Creatinine ≥ 3.5 mg/dL or renal replacement therapy

Creatinine 1.5–1.9 mg/dL

Brain (West Haven Score)

Grade 0

Grade 1–2

Grade 3–4

Coagulation

INR < 2.0

INR 2,1–2,4

INR ≥ 2,5

Cardiovascular

MAP ≥ 70 mm Hg

MAP < 70 mm Hg

Vasopressor therapy

Lung

PaO2/FiO2 > 300

SpO2/FiO2 > 357

PaO2/FiO2 201–300

SpO2/FiO2 215–357

PaO2/FiO2 ≤ 200

PaO2/FiO2 ≤ 214

Abbreviations: INR, international normalized ratio; MAP, mean arterial pressure.


Source: Reproduced from Jalan Saliba et al.[30]


Note: Organ failure in dark blue, organ dysfunction in light blue.


According to the EASL-CLIF definition, the most common identifiable triggers for ACLF are proven bacterial infections or (excessive) alcohol consumption (∼80% of cases).[3] Other common precipitants of ACLF are fungal infections or gastrointestinal hemorrhage.[2] In cases of unknown precipitators, bacterial translocation (BT) is suspected to play an important role.[15]

Therapeutic strategies for ACLF are limited. They typically involve addressing the underlying triggers and contributing factors. This includes treating infections or addressing alcohol-associated hepatitis with prednisone (if Maddrey's discrimination function > 32 or MELD score > 25).[16] [17] [18] Liver transplantation currently remains the only curative treatment option for these patients.[19] One-year survival rates after liver transplantation are high (>80%) and do not differ between patients with ACLF with one or two organ failures and patients who are transplanted without ACLF.[19] [20] In ACLF with three or more organ failures, the 1-year survival after transplantation—depending on the study—remained the same or was slightly reduced in ACLF-3 compared with ACLF-1 and -2 but was associated with more postoperative complications and longer hospitalization.[19] [20] If liver transplantation is not possible, treatment of ACLF focuses on managing complications within a multidisciplinary setting. In severely ill patients with multiorgan failure, recovery is unlikely, so palliative care should be considered.[19] [21]

Systemic inflammation is considered a key driver of ACLF. Although we are just beginning to appreciate the role of intestinal dysfunction in ACLF, various novel therapeutic approaches are currently under investigation that are at least partially linked to addressing the impaired intestinal barrier. Such approaches aim at improving intestinal barrier (e.g., via FXR agonists), improve microvascular dysfunction (e.g., simvastatin), or reduce systemic exposure to pathogen-associated molecular patterns that trigger aberrant inflammation (e.g., TLR4 antagonists or extracorporeal perfusion devices).[15] [22] [23] [24]


#

The Role of Bacterial Infections in Acute Decompensated Cirrhosis/Acute-on-Chronic Liver Failure

“Overt/extraintestinal” bacterial infections are a common trigger of AD in cirrhosis and the onset of ACLF.[25] [26] [27] Spontaneous bacterial peritonitis (SBP), respiratory infection, urinary tract infection (UTI), and soft tissue infection are the most common infection sites in cirrhosis patients.[28] Gram-negative bacterial infections are more likely to be community-acquired (mostly SBP), whereas gram-positive bacterial infections are strongly associated with hospitalization (e.g., catheterization).[28] In SBP, 1- and 12-month mortality rates are high with around 33 and 66%, respectively. Infections other than SBP also increase the mortality of patients with liver cirrhosis drastically to 30 and 63% after 1 and 12 months, respectively. This corresponds to a 3.75-fold mortality increase.[26]

In around one-third of ACLF patients, bacterial infections can be identified as a precipitating event.[13] [25] [29] [30] [31] The incidence of bacterial infections during the course of ACLF is significantly higher compared with AD without ACLF (28 days; 46 vs. 18%, respectively).[31]

Furthermore, in ACLF cases without an identifiable trigger, the cause of this drastic clinical deterioration remains unclear but the presence of high-grade systemic inflammation even in the absence of proven bacterial infections indicates that “unproven” infections may contribute to the development of organ injury. The gut serves as a reservoir for a multitude of bacteria, some of which have been linked to infections and systemic inflammation, possibly triggering ACLF.[15]

The PREDICT study, which prospectively followed patients admitted to hospitals for AD, identified three different courses of decompensated cirrhosis: stable decompensated cirrhosis, unstable decompensated cirrhosis, and pre-ACLF.[3] In the pre-ACLF group, patients developed ACLF within 90 days of hospitalization, resulting in a higher transplant-free mortality. In this group, the rate of bacterial infections within the 6-month observational period was 72.5%. This was significantly higher than the rate of infections in the unstable group (57.1%), in which infections were in turn more prevalent than in the stable compensated group (40.5%).[3] This underlines the significant role of bacterial infections in the disease course of liver cirrhosis patients.

Bacterial infections significantly reduce the transplant-free survival in patients with lower ACLF grades 1 to 2, whereas in ACLF-3 patients, the transplant-free survival rate is not significantly different between patients with or without infection.[31]

In most cases, the bacterial infections that trigger ACLF are due to endogenous bacteria that colonize the gastrointestinal tract.[32] Translocation of such bacteria to cause infections such as pneumonia, SBP or UTI may result from a disrupted homeostasis in the gut. This condition—dysbiosis—is observed in patients with ACLF and is characterized by a pathological shift in the microbiota composition caused by a relative overabundance of bacteria that can trigger ACLF, such as Escherichia coli, Klebsiella spp., or enterococci. The deregulation of homeostatic processes that control the gut barrier and microbiota composition should therefore be explored as key processes that trigger or aggravate ACLF.

Physiological Gut Barrier

In healthy individuals, the interplay between the gut epithelium, intestinal immune cells, and the microbiome acts in concert to maintain a physical and functional barrier separating the external environment from our internal domain.[33]


#
#

Physiological Gut Integrity

The gut epithelium forms a surface of around 30 m2. It is the first layer of defense against infections and coordinates the mucosal immune system.[34] [35] Despite being just a monolayer of cells, the epithelium is highly efficient at shielding the organism from luminal bacteria.[36] [37] Firstly, a layer of mucus (mainly produced by goblet cells) builds a physical barrier and prevents direct contact between epithelial cells and intestinal bacteria or other intraluminal content.[38] [39] Second, the epithelium produces various types of antimicrobial proteins that target microbes (e.g., defensins).[40] The tight connection between epithelial cells via desmosomes (macula adherens), adherens junctions (AJ) (zonula adherens), and tight junctions (TJ) (zonula occludens, ZO) represents another layer of defense against bacteria.[41]

The intestine boasts a high regenerative capacity with almost all its epithelial cells being replaced within 1 week. Stem cells constantly give rise to new cells that mature while migrating towards the surface.[42] [43] As these cells exit the crypts and move toward the surface, they differentiate into several different types, each taking on important intestinal functions. These cell types include absorptive enterocytes (the most abundant), mucus-producing goblet cells (which also release antimicrobial substances), hormone-releasing enteroendocrine cells, and tuft cells, which all are important for an efficient barrier.[40] [44] As these cells reach the top, they either undergo programmed cell death (apoptosis) or are shed into the lumen of the intestine. The antimicrobial, metabolic, and physical barrier properties of the epithelium rely on this functional cellular turnover and differentiation, and disruption of these processes results in barrier loss.[43] [45] [46]

Gut Barrier and Microbiota in Acute-on-Chronic Liver Failure

Patients with liver cirrhosis and ACLF are more prone to bacterial infections. While the reasons are likely multidimensional, gut barrier disruption and overwhelming/dysfunctional immune responses represent important factors.[47] [48] [49] Several reports suggest that ACLF is associated with a disruption of the intestinal barrier. The intercellular connections that bind the epithelial cells can be altered in liver disease, either by factors, which lead to CLD, or by CLD itself. It was shown that alcohol (the most common cause for liver cirrhosis in the Western World and common precipitator of ACLF) can lead to increased intestinal permeability.[50] [51] This is due to effects on the expression of the important TJ-proteins ZO-1 and claudin-1.[52] [53] Moreover, there is evidence that acetaldehyde (a metabolite of alcohol) negatively influences TJ- and AJ-integrity via dysregulation of protein kinases and protein phosphatases.[54] [55] [56] [57]

The detrimental role of portal hypertension (PHT)—in the further course of CLD progression—on gut integrity and systemic inflammation has been shown in many studies. It was demonstrated that patients suffering from PHT, particularly those with clinically significant PHT (hepatic venous-portal gradient > 10 mm Hg), exhibit elevated levels of pro-inflammatory chemokines and cytokines in their blood, along with markers indicating increased intestinal permeability, such as nucleotide-binding oligomerization domain 2 (NOD2) and toll-like receptor 2 (TLR-2).[58] These changes might be attributed to changes in blood circulation, neo-angiogenesis, and likely also to alterations in the intestinal barrier.[58] [59] Patients with PHT who undergo transjugular intrahepatic portosystemic shunt or nonselective beta blocker (NSBB) treatment show a decrease in markers of systemic inflammation and intestinal permeability, indicating an effect of PHT on systemic inflammation and BT.[58] [60] [61] [62] [63] Studies using electron microscopy revealed that the spaces between enterocytes in the lower duodenum and jejunum were expanded in patients with cirrhosis compared with a control group.[64] [65] Additionally, their microvilli were noticeably shorter and broader, although their TJ remained unchanged.[65] The implications of these observations on BT are still not fully understood. It is hypothesized that systemic inflammation might be a result of PHT. However, after resolution of PHT, the risk for further hepatic decompensation and ACLF remains high, as systemic inflammation is not completely resolved.[59]


#
#

Intestinal Dysbiosis

The microbiota in the gut fulfils various physiological functions relevant to barrier integrity. Intestinal dysbiosis has been linked to various diseases, although the exact mechanisms are not fully understood.[66] [67] Disruption of homeostasis and loss of beneficial anaerobes prompts a boost of microbes such as E. coli, Klebsiella and enterococci, which serve as a reservoir for extraintestinal infections in patients with liver cirrhosis and ACLF. Thus, a healthy microbiota is not only a marker of health but functionally contributes to gut barrier homeostasis, while dysbiosis represents a state of barrier disruption and increased risk for infections.[66] A contributing factor to intestinal dysbiosis in patients with CLD is the reduction and altered composition of bile acids produced by the liver.[68] [69] [70] [71] Dysbiosis also impairs the production of beneficial bacterial metabolites, such as short-chain fatty acids (SCFA), butyrate and propionate, which are used by colonocytes as a source of energy. The oxidative metabolism of SCFA in turn reduces oxygen levels in the colon lumen, which is essential for beneficial anaerobes to survive and restricts the niche available for pathogens and pathobionts,[72] a process that has been termed colonization resistance. At the same time, dysbiosis augments the generation of harmful compounds like ethanol and lipopolysaccharides. These changes can further exacerbate liver damage and inflammation.[73]

Numerous studies have revealed that intestinal dysbiosis contributes significantly to impairment of the intestinal barrier, liver injury and inflammation in patients with ACLF. Dysbiosis can lead to increased intestinal permeability, allowing for translocation of bacterial products into the portal circulation, which subsequently promotes systemic inflammation and organ failure. These mediators not only cause local and systemic inflammatory response but can also further disrupt epithelial TJ and accelerate barrier dysfunction, exacerbating mucosal (and systemic) inflammation.[74] [75] Intestinal microbiota are affecting the differentiation or activation of intestinal immune cells, and thus represents an important component of the mucosal barrier.[76]

Disruption of intestinal homeostasis thus leads not only to an increased risk of intestinal infections by classic enteritis pathogens (e.g., salmonellosis) but also to an expansion of resident facultative aerobes such as E. coli, Klebsiella or Citrobacter species.[77] Indeed, such alterations are also observed in the microbiota of patients with liver cirrhosis and may represent a key risk factor for extraintestinal translocation and infection with these species frequently observed as precipitating events in ACLF.[31]

A reduction in gut microbial diversity and gut microbial imbalances may play a role in the onset and exacerbation of CLD or although these changes may be also caused by CLD itself.[78] [79] In individuals with cirrhosis, certain microbial phyla have been linked to positive or negative outcomes in relation to decompensation and mortality. Exemplary the presence of cytolysin (an exotoxin) secreted by E. faecalis is independently associated with worse outcomes in patients with alcohol-induced hepatitis.[80] In most patients with alcohol-induced hepatitis E. faecalis was found in feces samples. Indicating that E. faecalis plays a detrimental role in one of the most common triggers for ACLF.[80]

In cirrhosis, as well as in cases of ACLF, a reduction in beneficial phyla (e.g., Ruminococcaceae, Lachnospiraceae or Bacteroidetes), as well as an increase of harmful phyla (e.g., Proteobacteria, Pasteurellaceae, Streptococcaceae, and Enterococcaceae) was observed.[73] [81] [82]

The most significant shift in microbial diversity, however, occurs as patients that progress from compensated to decompensated cirrhosis, rather than during the subsequent decompensation events throughout disease progression.[83] In these patients, there was a noticeable decrease in α/β-diversity, characterized by a reduction in beneficial commensal bacteria along with an increase of potentially harmful pathobionts.[83] This shift from beneficial bacteria (e.g., Lachnospiraceae, Ruminococcaceae) to pathogenic bacteria (e.g., Enterobacteriaceae, Enterococcaceae) leads—through the loss of beneficial bacteria—to reduced production of SCFA, which normally help to maintain intestinal integrity. Increased Enterobacteriaceae levels are linked to endotoxemia due to heightened intestinal permeability. Endotoxemia on the other hand correlates with worsened cirrhosis severity and complications. One of the most prominent endotoxins and mediator of sepsis (a major trigger for ACLF) is lipopolysaccharide (LPS), which is excreted by gram-negative bacteria, binds Toll-like-receptors subtype 4 (TLR4), a Pattern Recognition Receptors (PRR), which initiates a pro-inflammatory cascade. This pathway plays an important role in ACLF. It is known that intestinal alkaline phosphatase detoxifies bacterial LPS. An animal model study showed that recombinant Alkaline Phosphatase (recAP) can potentially prevent ACLF by inhibiting the TLR4-LPS pathway. Interestingly, it has been shown that the positive effects of recAP were limited to models of cirrhosis and ACLF, it does not protect from acute liver failure. The reason most likely being the upregulation of TLR4 receptors in cirrhosis compared with healthy livers.[84] LPS also induces necroptosis through receptor interacting protein kinase (RIPK) 1 activation. RIPK1-mediated necroptosis significantly contributes to brain edema, liver and kidney injury (acute tubular necrosis).[85] Inhibiting RIPK 1 with NEC-1 and RIPA56 can prevent ACLF development in experimental settings. Further, RIPK3 levels in patients with AD correlate with ACLF progression and mortality.[85]

After ACLF onset, the gut microbiota stabilizes in the short term, suggesting potential use as a diagnostic marker. Use of antibiotics, can be classified as “pulse disturbances” which only have moderate/recoverable impacts on microbiota composition, whereas the onset of ACLF can be seen as “press disturbance” highlighting the robustness of dysbiosis.[82] The imbalance between beneficial and harmful bacteria can be measured with the “Cirrhosis Dysbiosis Ratio” (CDR). A lower CDR is also associated with elevated endotoxin levels in patients with cirrhosis. Disease progression, HE, and infections lead to greater dysbiosis, with lower CDR and higher gram-negative taxa (e.g., Enterobacteriaceae). In stable cirrhosis, the microbiome remains relatively consistent.[86] Pro-inflammatory cytokines (TNF-α, IL-6, IL-2) correlate with specific bacterial families, including positive associations with Fusobacteriaceae and Veillonellaceae and negative correlations with Ruminococcaceae and Lachnospiraceae.[82] [87] Several phyla have been linked to levels of pro-inflammatory cytokines, e.g., IL-6 and TNF-alpha inversely with Ruminococcaceae and Lachnospiraceae. Altered microbial families, such as reduced Lachnospiraceae, were linked to clinical complications like HE, possibly due to reduced short-chain fatty acid (SCFA) production. Pasteurellaceae abundance was identified as an independent predictor of mortality in ACLF patients. The association of microbial families with pro-inflammatory cytokines underscores the need for therapies targeting microbial inflammation pathways. Gut dysbiosis (an imbalance in the microbiota) is more severe in ACLF patients compared with cirrhosis alone.[82]

Not only the composition of microbiota, but also their metabolites hold promise for enhancing outcome prediction in ACLF.[6] Reduced secondary bile acids, produced by beneficial microbiota like Ruminococcus spp., and elevated sulfated bile acids, such as taurocholenate sulfate, are linked to poor outcomes. Key tryptophan-derived metabolites, including indoxyl sulfate and indolepropionate, are significantly lower in ACLF, compromising intestinal barrier stability and increasing inflammation.[6] In contrast, harmful metabolites like p-cresol sulfate and o-cresol sulfate are elevated, reflecting microbial dysbiosis and impaired liver detoxification. Reduced levels of choline, betaine, and TMAO further indicate gut–liver axis dysfunction.[6] These changes might be used to enhance existing prognosis scores in ACLF.


#

Bacterial Translocation from the Gut

Disruption of the mucosal barrier and intestinal dysbiosis can lead to a condition known as BT.[88] This is defined as the translocation of bacteria or bacterial (by-) products such as DNA or lipopolysaccharides to the mesenteric lymph nodes and eventually also the systemic circulation.[89] [90] This process occurs in healthy individuals but is altered in cirrhosis due to e.g., PHT and its effects on the gut barrier, which in turn, contributes to decompensation and ACLF development by inducing systemic inflammation or facilitating the development of “endogenous” bacterial infections.[91] One example of “extreme” BT is SBP, mostly caused by E. coli.[92] [93] There is evidence that hyper-activation of the splanchnic sympathetic nervous system in bacterial peritonitis contributes to the translocation of gram-negative bacteria from the gut.[94]

The liver usually serves as filter against bacteria translocated into the portal or systemic blood circulation. This mechanism is mainly warranted by Kupffer cells (KC).[95] In patients with liver disease the phagocytic capacity of hepatic macrophages is reduced and therefore the bacterial dissemination into the systemic circulation increased.[96] Liver fibrosis and cirrhosis cause a shift of blood from the reduced liver sinusoids to larger collateral vessels with increased blood flow. This results in the impairment of KC microbial filtration function, as they not only lose their macrophage identity but also their ability to capture bacteria. In response to these changes, monocytes migrate into the liver and form KC-like syncytia within the collateral vessels to capture bacteria.[97]

BT is a key factor in systemic inflammation. Systemic inflammation is mainly driven by:

  • I) Bacteria translocating from the gut, which are mainly eliminated by intestinal innate immune cells, leading to the release of PAMPs (pathogen-associated molecular patterns). These PAMPs are released to the systemic circulation through the portal circulation and mesenteric lymph nodes, eventually leading to constant “sterile” inflammation. PAMPs are recognized by pattern-recognition receptors (PRR), mainly of the families of Toll-like (TLR) and NOD-like receptors, which trigger the production of pro-inflammatory cytokines such as TNF-α and interleukins.

  • II) The release of DAMPs (damage-associated molecular patterns) into the circulation due to hepatocyte damage/injury. These DAMPs eventually lead to even more inflammation in cirrhosis.

Systemic inflammation markers, such as the inflammatory cytokines interleukin-2 (IL-2), IL-8 or tumor necrosis factor (TNF)-α, are elevated in patients with ACLF compared with patients with AD. Interestingly, levels of these systemic inflammation markers resemble the patterns observed in patients with sepsis.[98] CLD patients develop a—multifactorial caused—state of immune paralysis like patients with sepsis.[99] The cirrhosis-associated-immunodeficiency phenotype (or “cirrhosis-associated immune dysfunction”, CAID) in ACLF is different from the phenotype in “stable” decompensated cirrhosis, as the immune response switches from a “pro-inflammatory” to an “immunodeficiency” phenotype, which makes patients with ACLF even more susceptible for bacterial infections.[99] [100] [101] [102] [103] In a state of constant systemic inflammation, “genuine” (extra-intestinal) bacterial infections can trigger an over-exaggerated immune response causing hepatic decompensation and ACLF.[90]


#

Therapy—Targeting the Gut–liver Axis

Farnesoid X Receptor Agonists

FXR is a nonsteroidal nuclear receptor expressed in the liver and the gut, with the highest expression in the ileum. Activation of FXR in intestinal epithelium is associated with:

  • - improvement of dysbiosis,

  • - improves PHT,

  • - maintaining the integrity of the gut barrier through upregulation of TJ-proteins and

  • - reduced BT ([Table 2]).[104] [105] [106]

Table 2

Overview of selected treatment options that target the gut–liver axis

Agent

substances

Indication in cirrhosis

Pros

Cons

Farnesoid X receptor (FXR) agonists[106] [107] [110] [111] [113]

Obeticholic acid, fexaramine

Primary biliary cholangitis, experimental

Improvement of microbiota composition, reduced bacterial translocation, reduction of portal hypertension, modulation of bile acid metabolism

Liver-related adverse events (jaundice, ascites, liver failure, etc.)

Nonselective beta-blocker (NSBB)[58] [116] [117] [118] [119] [120] [121] [122] [123]

Propranolol, carvedilol

Primary and secondary prophylaxis of variceal bleeding

Acceleration of intestinal transit time, reduction of bacterial translocation, reduction of dysbiosis, reduction of portal hypertension

Higher risk of death in patients with refractory ascites (low arterial pressure, higher risk of acute kidney injury and hepatorenal syndrome)

Antibiotics[123] [124] [125] [126] [127] [128] [129] [130]

Rifaximin

Recurrent hepatic encephalopathy

Improvement of microbiota composition, reduction of liver inflammation

No relevant safety concerns

Norfloxacin, trimethoprim–sulfamethoxazole, third-generation cephalosporin

Primary and secondary prophylaxis of spontaneous bacterial peritonitis, infection prevention in variceal bleeding

Reduction of bacterial translocation

Higher risk of emergence of multidrug-resistant bacteria

Probiotics[104]

Experimental

Improvement of microbiota composition, reduction of bacterial translocation

Positive effects are mostly individual

Fecal microbiota transplantation (FMT)[131] [132] [133]

Experimental

Evidence for improvement of survival, ascites, and hepatic encephalopathy resolution in ACLF

Complex treatment option, evidence derived only from small single-center studies

Lactulose[134] [135] [138] [139]

Hepatic encephalopathy (HE)

Improvement of microbiota composition, reduction of bacterial translocation, reduction of ammonia production, reduction of mortality in patients with overt HE

No relevant safety concerns

Moreover, the importance of the FXR pathway regarding hepatic decompensation was shown in multiple clinical studies. The rs56163822 G/T polymorphism, which is associated with decreased FXR transcription, is found significantly more often in patients developing SBP.[107] [108] [109] In another study, the impact of the FXR-single nucleotide polymorphism (SNPs) rs35724 minor allele on ascitic decompensation and liver-related death was shown to be beneficial, with the authors hypothesizing that rs35724 leads to an upregulation/activation of FXR signaling.[110]

The use of pharmacological FXR agonists has been shown to improve gut microbiota composition, boost the production of antimicrobial peptides, and increase the expression of proteins that form TJ, ultimately leading to reduced BT.[111] [112]

Further, FXR agonism has shown potential to ameliorate PHT in rat models through increased production of eNOS.[106]

Examples for prominent FXR agonists are obeticholic acid (OCA) and fexaramine.[104] [113] OCA is already used as a second-line therapy for primary biliary cholangitis (PBC). In patients with advanced cirrhosis (e.g., CHILD B or C) it is contraindicated, it can cause severe liver related adverse events, such as jaundice, ascites and liver failure. Since September 2024, OCA is no longer available in the European Union after the European Medicines Agency (EMA) revoked its authorization due to the agency's concerns regarding the drug's effectiveness in PBC. Still, there are several other FXR agonists, which have been studied for different indications in clinical and experimental studies, for e.g., steatotic or alcohol-associated liver disease.[113] [114] [115] In summary, while FXR agonists show promise in treating CLDs and may offer theoretical benefits for ACLF by improving PHT or BT and modulating bile acid metabolism and inflammation, clinical evidence supporting their use in ACLF is currently insufficient. Further studies are necessary to evaluate their safety and effectiveness in this specific context.


#

Nonselective Beta-Blocker

Nonselective beta-blockers (NSBB) are used in liver cirrhosis for treatment of PHT and prophylaxis of complications such as variceal bleeding. Another beneficial effect of NSBBs, is the acceleration of intestinal transit time and reduction of BT and dysbiosis ([Table 2]).[58] [116] There is evidence that it also reduces systemic inflammation, potentially even improving survival of ACLF patients compared with patients without NSBB treatment.[117] It is still uncertain whether this decrease in systemic inflammation is primarily due to the reduction of the hepatic venous pressure gradient or other effects of NSBB treatment. Another study revealed a reduction in white blood cell count (WBC) and C-reactive protein (CRP) due to NSBB treatment, which was not directly linked to the decrease in the hepatic venous pressure gradient. The underlying mechanisms behind these observations remain unclear, however.[118] Furthermore, the risk of sepsis episodes within one year in cirrhosis patients was reduced with NSBB treatment.[119] Contrary to these positive effects of NSBB treatment, there are also several safety concerns regarding the use of these drugs in patients with advanced cirrhosis. It has been shown that patients with refractory ascites have a higher risk of death on NSBB treatment compared with those who are not.[120] Potential underlying mechanisms include low arterial pressure, the risk of developing acute kidney injury and hepatorenal syndrome.[121] Additionally, NSBB treatment can also worsen fatigue, sexual dysfunction and weaken physical performance in patients with cirrhosis.[122]


#

Antibiotics, Probiotics and Fecal Microbiota Transplantation

Antibiotics in liver cirrhosis are recommended as primary or secondary SBP prophylaxis (e.g., norfloxacin), treatment for recurrent HE (rifaximin) or prevention of infections in cases of variceal bleeding (fluoroquinolones or third generation cephalosporines). These target mainly (gram-negative) bacteria from the gut, which leads to reduced BT and restoration of the gut immune system ([Table 2]). This improves the overall survival and reduces the risk of infections in specific stages of CLD.[123]

A study by Bajaj et al compared the outcomes of patients with primary and secondary SBP prophylaxis (fluoroquinolones/trimethoprim–sulfamethoxazole 75/25%). No difference in ACLF development was observed, although systemic inflammatory response syndrome (SIRS) episodes, intensive care unit (ICU) admission and inpatient mortality were higher in the primary prophylaxis group.[124] The authors hypothesize that the better outcome of patients on secondary prophylaxis might be associated with the clinical management, mainly regarding the identification of the infection site and therefore its faster treatment.

Rifaximin is a nonabsorbable, orally administered broad-spectrum antibiotic, indicated in patients with liver cirrhosis to treat recurrent HE.[125] Its effect on the gut-microbiome could be described as a “microbiome diversity regulator”, as the abundance of harmful bacteria is reduced while that of beneficial bacteria are increased.[126] No relevant effect on bacterial resistance is described in the literature.[126] Also, the risk of Clostridioides difficile infections was not observed to be increased.[127] In a study investigating the effect of rifaximin-a on the fibrosis progression of alcohol-associated liver disease by altering the gut microbiome, it had a positive effect on the gut microbiome and might help to halt the progression of fibrosis and AD by reducing liver inflammation.[127] In another study testing the combination of broad-spectrum antibiotic treatment vs. antibiotic treatment combined with rifaximin in critically ill ICU patients with overt HE, added rifaximin did not have any effect on patients with ACLF.[128] However, it is important to note that the effect on ACLF development was not studied, and the ACLF criteria were based on the APASL definition. There are many positive effects described in the literature regarding the effect of rifaximin on liver cirrhosis, but the evidence from clinical studies regarding these effects is still weak.[129]

In addition to the benefits of antibiotic treatment in the context of preventing the development of ACLF, it is essential to address their potential risks. These encompass antibiotic resistance and the depletion of commensal bacterial phyla, which are crucial considerations in clinical management. Notably, antibiotics such as norfloxacin can foster the emergence of multi-drug resistant pathogens. Therefore, prolonged utilization for the prevention of SBP should be strictly reserved for individuals at elevated risk of infectious complications.[130]

Probiotic agents, defined as bacterial species capable of altering the composition of the microbiome and enhancing mucosal integrity through the inhibition of pathogenic bacteria, are the subject of intense research.[104] Nevertheless, the evidence regarding their effectiveness is disparate. In a review by Wiest et al, the authors conclude that the beneficial outcomes of probiotic administration are contingent upon the genetic background of the host, the specific dietary habits, and the preexisting composition of the microbiome.[104]

Several studies showed positive effects of fecal microbiota transplantation (FMT) on the outcome of severe alcohol-associated hepatitis without ACLF. In these studies, prognostic scores (MELD, MELD-Na and Child Turcotte Pugh) and 3-month survival rates were improved.[131] [132] In 2022, a prospective open label randomized trial studied the effects of FMT on patients with severe alcohol-associated hepatitis-induced ACLF.[133] Patients either received a single FMT or standard medical treatment. In the intervention group not only 28- and 90-day-mortality, but also resolution of ascites and HE was significantly better compared with the control group. These results warrant further validation in the future as this study had several limitations such as the small sample size (34 patients).


#

Lactulose

Lactulose has been employed as a therapeutic intervention for the management of HE since 1966.[134] A Cochrane systematic review revealed that lactulose administration reduced mortality rates in patients with overt HE, decreasing this rate from 14% to 8.5%.[135] Although the effects responsible for its therapeutic efficacy in HE remains incompletely elucidated. it is well-established that they appear mostly mediated via interactions with the gut microbiome. These interactions encompass several mechanisms, including the acidification of the gut environment, promotion of beneficial microbial taxa, and reinforcement of intestinal barrier function ([Table 2]).[134]

It is noteworthy that only a minimal fraction, less than 0.4%, of orally administered lactulose is absorbed in the gastrointestinal tract. Experimental investigations have demonstrated that the predominant metabolism of lactulose occurs in the cecum and proximal colon. In this region, lactulose induces a marked reduction in pH levels and an increase in SCFAs. Research has indicated that the lowered pH contributes to diminished bacterial ammonia production.[136] Importantly, it mitigates ammonia production across various bacterial strains, even when pH is buffered under experimental conditions, suggesting a direct impact on ammonia production rather than solely an indirect effect.[137] [138] Furthermore, lactulose-induced reduction in fecal pH may lead to increased ammonia excretion.[134] Through fermentation, lactulose fosters the proliferation of beneficial bacterial taxa, which in turn produce SCFAs and contribute to pH reduction within the intestinal lumen.[134] Notably, in patients with HE, lactulose administration has been associated with decreased levels of bacterial DNA in the serum, a phenomenon potentially attributed to heightened SCFA production.[139]


#
#

Concluding Remarks

An increased understanding of the gut–liver axis has tremendously advanced our perspectives on the pathogenesis of ACLF. Still, insights into the gut–liver axis are predominantly derived from observations in individuals with either compensated or decompensated cirrhosis. Considering the distinct pathophysiology characterizing ACLF as separate from other phases of liver cirrhosis, the direct application of such findings to the ACLF cohort may be inappropriate. This delineation necessitates further research to elucidate the mechanisms specific to ACLF. In this regard it also important to get a better understanding of the underlying mechanisms of response to microbial signals of extra-hepatic organs in ACLF, such as brain and kidney.[140] [141] Future investigations should focus on deepening our understanding of this interaction and translating this knowledge into novel diagnostic and therapeutic strategies for patients with ACLF. The promising results obtained so far underscore the potential of a personalized medicine approach for managing this complex syndrome.


#
#

Conflict of Interest

F.T. reports research funding from AstraZeneca, MSD, Gilead, Agomab (funding to my institution), and consulting fees from “AstraZeneca, Gilead, GSK, Abbvie, BMS, Intercept, Ipsen, Pfizer, Novartis, Novo Nordisk, MSD, Sanofi, Boehringer.” C.E. reports grants from “European Union, Deutsche Forschungsgemeinschaft, Else Kröner Freseniusstiftung,” and consulting fees from “Boehringer Ingelheim; Albireo/Ipsen.” M.S. reports support for attending meetings and/or travel from “Abbvie.” J.P. reports support for attending meetings and/or travel from “Ipsen, Abbvie.” Rest of authors have nothing to declare.

  • References

  • 1 Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med 2020; 382 (22) 2137-2145
    Search in Google Scholar
  • 2 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol 2023; 79: 461-491
    Search in Google Scholar
  • 3 Trebicka J, Fernandez J, Papp M. et al; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol 2020; 73 (04) 842-854
    Search in Google Scholar
  • 4 Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18 (03) 167-180
    Search in Google Scholar
  • 5 Trebicka J, Amoros A, Pitarch C. et al. Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis. Front Immunol 2019; 10: 476
    Search in Google Scholar
  • 6 Bajaj JS, Reddy KR, O'Leary JG. et al. Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute-on-chronic liver failure and death in patients with cirrhosis. Gastroenterology 2020; 159 (05) 1715-1730.e12
    Search in Google Scholar
  • 7 Prado V, Hernández-Tejero M, Mücke MM. et al. Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis. J Hepatol 2022; 76 (05) 1079-1089
    Search in Google Scholar
  • 8 Fernández J, Clària J, Amorós A. et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology 2019; 157 (01) 149-162
    Search in Google Scholar
  • 9 Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 (Suppl. 01) S67-S81
    Search in Google Scholar
  • 10 D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (01) 217-231
    Search in Google Scholar
  • 11 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69: 406-460
    Search in Google Scholar
  • 12 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20 (03) 252-261
    Search in Google Scholar
  • 13 Moreau R, Jalan R, Gines P. et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
    Search in Google Scholar
  • 14 Bajaj JS. Defining acute-on-chronic liver failure: will East and West ever meet?. Gastroenterology 2013; 144 (07) 1337-1339
    Search in Google Scholar
  • 15 Schierwagen R, Gu W, Brieger A. et al; ACLF-I Investigators. Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure. Am J Physiol Cell Physiol 2023; 325 (01) C129-C140
    Search in Google Scholar
  • 16 Morales-Arráez D, Ventura-Cots M, Altamirano J. et al. The MELD score is superior to the Maddrey discriminant function score to predict short-term mortality in alcohol-associated hepatitis: a global study. Am J Gastroenterol 2022; 117 (02) 301-310
    Search in Google Scholar
  • 17 Gustot T, Fernandez J, Garcia E. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015; 62 (01) 243-252
    Search in Google Scholar
  • 18 Putignano A, Gustot T. New concepts in acute-on-chronic liver failure: Implications for liver transplantation. Liver Transpl 2017; 23 (02) 234-243
    Search in Google Scholar
  • 19 Sundaram V, Jalan R, Wu T. et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology 2019; 156 (05) 1381-1391.e3
    Search in Google Scholar
  • 20 Artru F, Louvet A, Ruiz I. et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol 2017; 67 (04) 708-715
    Search in Google Scholar
  • 21 Engelmann C, Thomsen KL, Zakeri N. et al. Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure. Crit Care 2018; 22 (01) 254
    Search in Google Scholar
  • 22 Lamatsch S, Sittner R, Tacke F, Engelmann C. Novel drug discovery strategies for the treatment of decompensated cirrhosis. Expert Opin Drug Discov 2022; 17 (03) 273-282
    Search in Google Scholar
  • 23 Agarwal B, Cañizares RB, Saliba F. et al. Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure. J Hepatol 2023; 79 (01) 79-92
    Search in Google Scholar
  • 24 Engelmann C, Herber A, Franke A. et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study). J Hepatol 2021; 75 (06) 1346-1354
    Search in Google Scholar
  • 25 Fernández J, Acevedo J, Castro M. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012; 55 (05) 1551-1561
    Search in Google Scholar
  • 26 Arvaniti V, D'Amico G, Fede G. et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010; 139 (04) 1246-1256 , 1256.e1–1256.e5
    Search in Google Scholar
  • 27 Borzio M, Salerno F, Piantoni L. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33 (01) 41-48
    Search in Google Scholar
  • 28 Bajaj JS, O'Leary JG, Reddy KR. et al; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012; 56 (06) 2328-2335
    Search in Google Scholar
  • 29 Arroyo V, Moreau R, Jalan R, Ginès P. EASL-CLIF Consortium CANONIC Study. Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis. J Hepatol 2015; 62 (1, Suppl): S131-S143
    Search in Google Scholar
  • 30 Jalan R, Saliba F, Pavesi M. et al; CANONIC study investigators of the EASL-CLIF Consortium. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014; 61 (05) 1038-1047
    Search in Google Scholar
  • 31 Fernández J, Acevedo J, Wiest R. et al; European Foundation for the Study of Chronic Liver Failure. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut 2018; 67 (10) 1870-1880
    Search in Google Scholar
  • 32 Wong F, Piano S, Angeli P. Reply to: correspondence on “clinical features and evolution of bacterial infection-related acute-on-chronic liver failure”. J Hepatol 2021; 75 (04) 1010-1012
    Search in Google Scholar
  • 33 Sigal M, Meyer TF. Coevolution between the human microbiota and the epithelial immune system. Dig Dis 2016; 34 (03) 190-193
    Search in Google Scholar
  • 34 Helander HF, Fändriks L. Surface area of the digestive tract - revisited. Scand J Gastroenterol 2014; 49 (06) 681-689
    Search in Google Scholar
  • 35 Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, Vallance BA. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol 2018; 39 (09) 677-696
    Search in Google Scholar
  • 36 Harnack C, Berger H, Liu L, Mollenkopf HJ, Strowig T, Sigal M. Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis. Gut Microbes 2023; 15 (01) 2233689
    Search in Google Scholar
  • 37 Earle KA, Billings G, Sigal M. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 2015; 18 (04) 478-488
    Search in Google Scholar
  • 38 Birchenough GM, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol 2015; 8 (04) 712-719
    Search in Google Scholar
  • 39 Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010; 12 (05) 319-330
    Search in Google Scholar
  • 40 Iftekhar A, Sigal M. Defence and adaptation mechanisms of the intestinal epithelium upon infection. Int J Med Microbiol 2021; 311 (03) 151486
    Search in Google Scholar
  • 41 Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol 2010; 5: 119-144
    Search in Google Scholar
  • 42 Barker N, van Es JH, Kuipers J. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449 (7165): 1003-1007
    Search in Google Scholar
  • 43 Harnack C, Berger H, Antanaviciute A. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat Commun 2019; 10 (01) 4368
    Search in Google Scholar
  • 44 Gerbe F, Sidot E, Smyth DJ. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 2016; 529 (7585): 226-230
    Search in Google Scholar
  • 45 Stolfi C, Maresca C, Monteleone G, Laudisi F. Implication of intestinal barrier dysfunction in gut dysbiosis and diseases. Biomedicines 2022; 10 (02) 10
    Search in Google Scholar
  • 46 Lin M, Hartl K, Heuberger J. et al. Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche. Nat Commun 2023; 14 (01) 3025
    Search in Google Scholar
  • 47 Van der Merwe S, Chokshi S, Bernsmeier C, Albillos A. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol 2021; 75 (Suppl. 01) S82-S100
    Search in Google Scholar
  • 48 Wasmuth HE, Kunz D, Yagmur E. et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (02) 195-201
    Search in Google Scholar
  • 49 Mookerjee RP, Stadlbauer V, Lidder S. et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (03) 831-840
    Search in Google Scholar
  • 50 Huang DQ, Mathurin P, Cortez-Pinto H, Loomba R. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol 2023; 20 (01) 37-49
    Search in Google Scholar
  • 51 Huang DQ, Terrault NA, Tacke F. et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023; 20 (06) 388-398
    Search in Google Scholar
  • 52 Wang Y, Tong J, Chang B, Wang B, Zhang D, Wang B. Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Mol Med Rep 2014; 9 (06) 2352-2356
    Search in Google Scholar
  • 53 Tang Y, Banan A, Forsyth CB. et al. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol Clin Exp Res 2008; 32 (02) 355-364
    Search in Google Scholar
  • 54 Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009; 50 (02) 638-644
    Search in Google Scholar
  • 55 Basuroy S, Sheth P, Kuppuswamy D, Balasubramanian S, Ray RM, Rao RK. Expression of kinase-inactive c-Src delays oxidative stress-induced disassembly and accelerates calcium-mediated reassembly of tight junctions in the Caco-2 cell monolayer. J Biol Chem 2003; 278 (14) 11916-11924
    Search in Google Scholar
  • 56 Seth A, Sheth P, Elias BC, Rao R. Protein phosphatases 2A and 1 interact with occludin and negatively regulate the assembly of tight junctions in the CACO-2 cell monolayer. J Biol Chem 2007; 282 (15) 11487-11498
    Search in Google Scholar
  • 57 Rao RK, Li L, Baker RD, Baker SS, Gupta A. Glutathione oxidation and PTPase inhibition by hydrogen peroxide in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 2000; 279 (02) G332-G340
    Search in Google Scholar
  • 58 Reiberger T, Ferlitsch A, Payer BA. et al; Vienna Hepatic Hemodynamic Lab. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol 2013; 58 (05) 911-921
    Search in Google Scholar
  • 59 Trebicka J, Reiberger T, Laleman W. Gut-liver axis links portal hypertension to acute-on-chronic liver failure. Visc Med 2018; 34 (04) 270-275
    Search in Google Scholar
  • 60 Schierwagen R, Alvarez-Silva C, Madsen MSA. et al. Circulating microbiome in blood of different circulatory compartments. Gut 2019; 68 (03) 578-580
    Search in Google Scholar
  • 61 Lehmann JM, Claus K, Jansen C. et al. Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. Liver Int 2018; 38 (05) 875-884
    Search in Google Scholar
  • 62 Berres ML, Lehmann J, Jansen C. et al. Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Liver Int 2016; 36 (03) 386-394
    Search in Google Scholar
  • 63 Berres ML, Asmacher S, Lehmann J. et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol 2015; 62 (02) 332-339
    Search in Google Scholar
  • 64 Norman DA, Atkins JM, Seelig Jr LL, Gomez-Sanchez C, Krejs GJ. Water and electrolyte movement and mucosal morphology in the jejunum of patients with portal hypertension. Gastroenterology 1980; 79 (04) 707-715
    Search in Google Scholar
  • 65 Such J, Guardiola JV, de Juan J. et al. Ultrastructural characteristics of distal duodenum mucosa in patients with cirrhosis. Eur J Gastroenterol Hepatol 2002; 14 (04) 371-376
    Search in Google Scholar
  • 66 Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2017; 2 (02) 135-143
    Search in Google Scholar
  • 67 Cani PD. Gut microbiota - at the intersection of everything?. Nat Rev Gastroenterol Hepatol 2017; 14 (06) 321-322
    Search in Google Scholar
  • 68 Dikopoulos N, Weidenbach H, Adler G, Schmid RM. Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II. Eur J Clin Invest 2003; 33 (01) 58-64
    Search in Google Scholar
  • 69 Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4 (05) 382-387
    Search in Google Scholar
  • 70 Axelson M, Sjövall J. Potential bile acid precursors in plasma–possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 1990; 36 (06) 631-640
    Search in Google Scholar
  • 71 Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304 (03) G227-G234
    Search in Google Scholar
  • 72 Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science 2018; 362 (6418): 362
    Search in Google Scholar
  • 73 Gómez-Hurtado I, Santacruz A, Peiró G. et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One 2011; 6 (07) e23037
    Search in Google Scholar
  • 74 Pandey A, Galeone A, Han SY. et al. Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila. Nat Commun 2023; 14 (01) 5667
    Search in Google Scholar
  • 75 Shemtov SJ, Emani R, Bielska O. et al. The intestinal immune system and gut barrier function in obesity and ageing. FEBS J 2023; 290 (17) 4163-4186
    Search in Google Scholar
  • 76 Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol 2023; 21 (11) 719-733
    Search in Google Scholar
  • 77 Lee JY, Tsolis RM, Bäumler AJ. The microbiome and gut homeostasis. Science 2022; 377 (6601): eabp9960
    Search in Google Scholar
  • 78 Zhu L, Baker SS, Gill C. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (02) 601-609
    Search in Google Scholar
  • 79 Bayoumy AB, Mulder CJJ, Mol JJ, Tushuizen ME. Gut fermentation syndrome: a systematic review of case reports. United European Gastroenterol J 2021; 9 (03) 332-342
    Search in Google Scholar
  • 80 Duan Y, Llorente C, Lang S. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575 (7783): 505-511
    Search in Google Scholar
  • 81 Chen Y, Yang F, Lu H. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (02) 562-572
    Search in Google Scholar
  • 82 Chen Y, Guo J, Qian G. et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015; 30 (09) 1429-1437
    Search in Google Scholar
  • 83 Bajaj JS, Peña-Rodriguez M, La Reau A. et al. Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis. Gut 2023; 72 (04) 759-771
    Search in Google Scholar
  • 84 Engelmann C, Adebayo D, Oria M. et al. Recombinant alkaline phosphatase prevents acute on chronic liver failure. Sci Rep 2020; 10 (01) 389
    Search in Google Scholar
  • 85 Kondo T, Macdonald S, Engelmann C. et al. The role of RIPK1 mediated cell death in acute on chronic liver failure. Cell Death Dis 2021; 13 (01) 5
    Search in Google Scholar
  • 86 Bajaj JS, Heuman DM, Hylemon PB. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (05) 940-947
    Search in Google Scholar
  • 87 Bajaj JS, Ridlon JM, Hylemon PB. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302 (01) G168-G175
    Search in Google Scholar
  • 88 Benten D, Wiest R. Gut microbiome and intestinal barrier failure–the “Achilles heel” in hepatology?. J Hepatol 2012; 56 (06) 1221-1223
    Search in Google Scholar
  • 89 Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979; 23 (02) 403-411
    Search in Google Scholar
  • 90 Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63 (05) 1272-1284
    Search in Google Scholar
  • 91 Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 (Suppl. 01) S49-S66
    Search in Google Scholar
  • 92 Piano S, Fasolato S, Salinas F. et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results of a randomized, controlled clinical trial. Hepatology 2016; 63 (04) 1299-1309
    Search in Google Scholar
  • 93 Wiest R, Rath HC. Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol 2003; 17 (03) 397-425
    Search in Google Scholar
  • 94 Worlicek M, Knebel K, Linde HJ. et al. Splanchnic sympathectomy prevents translocation and spreading of E. coli but not S. aureus in liver cirrhosis. Gut 2010; 59 (08) 1127-1134
    Search in Google Scholar
  • 95 Balmer ML, Slack E, de Gottardi A. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med 2014; 6 (237) 237ra66
    Search in Google Scholar
  • 96 Pose E, Coll M, Martínez-Sánchez C. et al. Programmed death ligand 1 is overexpressed in liver macrophages in chronic liver diseases, and its blockade improves the antibacterial activity against infections. Hepatology 2021; 74 (01) 296-311
    Search in Google Scholar
  • 97 Peiseler M, Araujo David B, Zindel J. et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science 2023; 381 (6662): eabq5202
    Search in Google Scholar
  • 98 Clària J, Stauber RE, Coenraad MJ. et al; CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology 2016; 64 (04) 1249-1264
    Search in Google Scholar
  • 99 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61 (06) 1385-1396
    Search in Google Scholar
  • 100 Albillos A, de la Hera A, González M. et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003; 37 (01) 208-217
    Search in Google Scholar
  • 101 Albillos A, de-la-Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet 2004; 363 (9421): 1608-1610
    Search in Google Scholar
  • 102 Papp M, Sipeki N, Vitalis Z. et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59 (03) 457-466
    Search in Google Scholar
  • 103 Márquez M, Fernández-Gutiérrez C, Montes-de-Oca M. et al. Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clin Exp Immunol 2009; 158 (02) 219-229
    Search in Google Scholar
  • 104 Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017; 67 (05) 1084-1103
    Search in Google Scholar
  • 105 Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25 (39) 5897-5917
    Search in Google Scholar
  • 106 Verbeke L, Farre R, Trebicka J. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
    Search in Google Scholar
  • 107 Lutz P, Berger C, Langhans B. et al. A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis. Dig Liver Dis 2014; 46 (11) 1047-1050
    Search in Google Scholar
  • 108 Van Mil SW, Milona A, Dixon PH. et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133 (02) 507-516
    Search in Google Scholar
  • 109 Marzolini C, Tirona RG, Gervasini G. et al. A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. Mol Endocrinol 2007; 21 (08) 1769-1780
    Search in Google Scholar
  • 110 Semmler G, Simbrunner B, Scheiner B. et al. Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension. J Gastroenterol Hepatol 2019; 34 (12) 2164-2172
    Search in Google Scholar
  • 111 Úbeda M, Lario M, Muñoz L. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 2016; 64 (05) 1049-1057
    Search in Google Scholar
  • 112 Verbeke L, Farre R, Verbinnen B. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 2015; 185 (02) 409-419
    Search in Google Scholar
  • 113 Sanyal AJ, Ratziu V, Loomba R. et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79 (05) 1110-1120
    Search in Google Scholar
  • 114 Schwabl P, Hambruch E, Seeland BA. et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66 (04) 724-733
    Search in Google Scholar
  • 115 Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol 2023; 79 (05) 1317-1331
    Search in Google Scholar
  • 116 Pérez-Paramo M, Muñoz J, Albillos A. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000; 31 (01) 43-48
    Search in Google Scholar
  • 117 Mookerjee RP, Pavesi M, Thomsen KL. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016; 64 (03) 574-582
    Search in Google Scholar
  • 118 Jachs M, Hartl L, Schaufler D. et al. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut 2021; 70 (09) 1758-1767
    Search in Google Scholar
  • 119 Jensen MD, Watson H, Vilstrup H, Jepsen P. Non-selective beta-blockers and risk of sepsis in patients with cirrhosis and ascites: results from a large observational study. Clin Epidemiol 2023; 15: 775-783
    Search in Google Scholar
  • 120 Sersté T, Melot C, Francoz C. et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52 (03) 1017-1022
    Search in Google Scholar
  • 121 Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023; 78 (04) 866-872
    Search in Google Scholar
  • 122 Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations. JHEP Rep Innov Hepatol 2019; 2 (01) 100063
    Search in Google Scholar
  • 123 Madsen BS, Havelund T, Krag A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective β-blockers. Adv Ther 2013; 30 (07) 659-670
    Search in Google Scholar
  • 124 Bajaj JS, Tandon P, OʼLeary JG. et al. Outcomes in patients with cirrhosis on primary compared to secondary prophylaxis for spontaneous bacterial peritonitis. Am J Gastroenterol 2019; 114 (04) 599-606
    Search in Google Scholar
  • 125 Bass NM, Mullen KD, Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
    Search in Google Scholar
  • 126 Yu X, Jin Y, Zhou W. et al. Rifaximin modulates the gut microbiota to prevent hepatic encephalopathy in liver cirrhosis without impacting the resistome. Front Cell Infect Microbiol 2022; 11: 761192
    Search in Google Scholar
  • 127 Israelsen M, Madsen BS, Torp N. et al; GALAXY, MicrobLiver Consortia. Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2023; 8 (06) 523-532
    Search in Google Scholar
  • 128 Kulkarni AV, Avadhanam M, Karandikar P. et al. Antibiotics with or without Rifaximin for acute hepatic Encephalopathy in critically ill patients with cirrhosis: a double-blind, randomized controlled (ARiE) trial. Am J Gastroenterol 2024; 119 (05) 864-874
    Search in Google Scholar
  • 129 Caraceni P, Vargas V, Solà E. et al; Liverhope Consortium. The use of rifaximin in patients with cirrhosis. Hepatology 2021; 74 (03) 1660-1673
    Search in Google Scholar
  • 130 Rimola A, García-Tsao G, Navasa M. et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000; 32 (01) 142-153
    Search in Google Scholar
  • 131 Philips CA, Pande A, Shasthry SM. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15 (04) 600-602
    Search in Google Scholar
  • 132 Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37 (03) 215-225
    Search in Google Scholar
  • 133 Sharma A, Roy A, Premkumar M. et al. Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial. Hepatol Int 2022; 16 (02) 433-446
    Search in Google Scholar
  • 134 Bloom PP, Tapper EB. Lactulose in cirrhosis: current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun 2023; 7 (11) 7
    Search in Google Scholar
  • 135 Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016; 4: CD003044
    Search in Google Scholar
  • 136 Vince A, Dawson AM, Park N, O'Grady F. Ammonia production by intestinal bacteria. Gut 1973; 14 (03) 171-177
    Search in Google Scholar
  • 137 Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia production in a fecal incubation system. Gastroenterology 1978; 74 (03) 544-549
    Search in Google Scholar
  • 138 Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol 1980; 13 (02) 177-191
    Search in Google Scholar
  • 139 Moratalla A, Ampuero J, Bellot P. et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2017; 37 (02) 212-223
    Search in Google Scholar
  • 140 Haase S, Wilck N, Haghikia A, Gold R, Mueller DN, Linker RA. The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol 2020; 50 (12) 1863-1870
    Search in Google Scholar
  • 141 Holle J, McParland V, Anandakumar H. et al. Gut dysbiosis contributes to TMAO accumulation in CKD. Nephrol Dial Transplant 2024; 39 (11) 1923-1926
    Search in Google Scholar

Address for correspondence

Michael Sigal, MD, PhD
Department of Hepatology and Gastroenterology
Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin
Germany   

Publication History

Article published online:
13 March 2025

© 2025. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med 2020; 382 (22) 2137-2145
    Search in Google Scholar
  • 2 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol 2023; 79: 461-491
    Search in Google Scholar
  • 3 Trebicka J, Fernandez J, Papp M. et al; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol 2020; 73 (04) 842-854
    Search in Google Scholar
  • 4 Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18 (03) 167-180
    Search in Google Scholar
  • 5 Trebicka J, Amoros A, Pitarch C. et al. Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis. Front Immunol 2019; 10: 476
    Search in Google Scholar
  • 6 Bajaj JS, Reddy KR, O'Leary JG. et al. Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute-on-chronic liver failure and death in patients with cirrhosis. Gastroenterology 2020; 159 (05) 1715-1730.e12
    Search in Google Scholar
  • 7 Prado V, Hernández-Tejero M, Mücke MM. et al. Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis. J Hepatol 2022; 76 (05) 1079-1089
    Search in Google Scholar
  • 8 Fernández J, Clària J, Amorós A. et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology 2019; 157 (01) 149-162
    Search in Google Scholar
  • 9 Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 (Suppl. 01) S67-S81
    Search in Google Scholar
  • 10 D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (01) 217-231
    Search in Google Scholar
  • 11 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69: 406-460
    Search in Google Scholar
  • 12 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20 (03) 252-261
    Search in Google Scholar
  • 13 Moreau R, Jalan R, Gines P. et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
    Search in Google Scholar
  • 14 Bajaj JS. Defining acute-on-chronic liver failure: will East and West ever meet?. Gastroenterology 2013; 144 (07) 1337-1339
    Search in Google Scholar
  • 15 Schierwagen R, Gu W, Brieger A. et al; ACLF-I Investigators. Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure. Am J Physiol Cell Physiol 2023; 325 (01) C129-C140
    Search in Google Scholar
  • 16 Morales-Arráez D, Ventura-Cots M, Altamirano J. et al. The MELD score is superior to the Maddrey discriminant function score to predict short-term mortality in alcohol-associated hepatitis: a global study. Am J Gastroenterol 2022; 117 (02) 301-310
    Search in Google Scholar
  • 17 Gustot T, Fernandez J, Garcia E. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015; 62 (01) 243-252
    Search in Google Scholar
  • 18 Putignano A, Gustot T. New concepts in acute-on-chronic liver failure: Implications for liver transplantation. Liver Transpl 2017; 23 (02) 234-243
    Search in Google Scholar
  • 19 Sundaram V, Jalan R, Wu T. et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology 2019; 156 (05) 1381-1391.e3
    Search in Google Scholar
  • 20 Artru F, Louvet A, Ruiz I. et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol 2017; 67 (04) 708-715
    Search in Google Scholar
  • 21 Engelmann C, Thomsen KL, Zakeri N. et al. Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure. Crit Care 2018; 22 (01) 254
    Search in Google Scholar
  • 22 Lamatsch S, Sittner R, Tacke F, Engelmann C. Novel drug discovery strategies for the treatment of decompensated cirrhosis. Expert Opin Drug Discov 2022; 17 (03) 273-282
    Search in Google Scholar
  • 23 Agarwal B, Cañizares RB, Saliba F. et al. Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure. J Hepatol 2023; 79 (01) 79-92
    Search in Google Scholar
  • 24 Engelmann C, Herber A, Franke A. et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study). J Hepatol 2021; 75 (06) 1346-1354
    Search in Google Scholar
  • 25 Fernández J, Acevedo J, Castro M. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012; 55 (05) 1551-1561
    Search in Google Scholar
  • 26 Arvaniti V, D'Amico G, Fede G. et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010; 139 (04) 1246-1256 , 1256.e1–1256.e5
    Search in Google Scholar
  • 27 Borzio M, Salerno F, Piantoni L. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33 (01) 41-48
    Search in Google Scholar
  • 28 Bajaj JS, O'Leary JG, Reddy KR. et al; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012; 56 (06) 2328-2335
    Search in Google Scholar
  • 29 Arroyo V, Moreau R, Jalan R, Ginès P. EASL-CLIF Consortium CANONIC Study. Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis. J Hepatol 2015; 62 (1, Suppl): S131-S143
    Search in Google Scholar
  • 30 Jalan R, Saliba F, Pavesi M. et al; CANONIC study investigators of the EASL-CLIF Consortium. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014; 61 (05) 1038-1047
    Search in Google Scholar
  • 31 Fernández J, Acevedo J, Wiest R. et al; European Foundation for the Study of Chronic Liver Failure. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut 2018; 67 (10) 1870-1880
    Search in Google Scholar
  • 32 Wong F, Piano S, Angeli P. Reply to: correspondence on “clinical features and evolution of bacterial infection-related acute-on-chronic liver failure”. J Hepatol 2021; 75 (04) 1010-1012
    Search in Google Scholar
  • 33 Sigal M, Meyer TF. Coevolution between the human microbiota and the epithelial immune system. Dig Dis 2016; 34 (03) 190-193
    Search in Google Scholar
  • 34 Helander HF, Fändriks L. Surface area of the digestive tract - revisited. Scand J Gastroenterol 2014; 49 (06) 681-689
    Search in Google Scholar
  • 35 Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, Vallance BA. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol 2018; 39 (09) 677-696
    Search in Google Scholar
  • 36 Harnack C, Berger H, Liu L, Mollenkopf HJ, Strowig T, Sigal M. Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis. Gut Microbes 2023; 15 (01) 2233689
    Search in Google Scholar
  • 37 Earle KA, Billings G, Sigal M. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 2015; 18 (04) 478-488
    Search in Google Scholar
  • 38 Birchenough GM, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol 2015; 8 (04) 712-719
    Search in Google Scholar
  • 39 Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010; 12 (05) 319-330
    Search in Google Scholar
  • 40 Iftekhar A, Sigal M. Defence and adaptation mechanisms of the intestinal epithelium upon infection. Int J Med Microbiol 2021; 311 (03) 151486
    Search in Google Scholar
  • 41 Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol 2010; 5: 119-144
    Search in Google Scholar
  • 42 Barker N, van Es JH, Kuipers J. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449 (7165): 1003-1007
    Search in Google Scholar
  • 43 Harnack C, Berger H, Antanaviciute A. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat Commun 2019; 10 (01) 4368
    Search in Google Scholar
  • 44 Gerbe F, Sidot E, Smyth DJ. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 2016; 529 (7585): 226-230
    Search in Google Scholar
  • 45 Stolfi C, Maresca C, Monteleone G, Laudisi F. Implication of intestinal barrier dysfunction in gut dysbiosis and diseases. Biomedicines 2022; 10 (02) 10
    Search in Google Scholar
  • 46 Lin M, Hartl K, Heuberger J. et al. Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche. Nat Commun 2023; 14 (01) 3025
    Search in Google Scholar
  • 47 Van der Merwe S, Chokshi S, Bernsmeier C, Albillos A. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol 2021; 75 (Suppl. 01) S82-S100
    Search in Google Scholar
  • 48 Wasmuth HE, Kunz D, Yagmur E. et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (02) 195-201
    Search in Google Scholar
  • 49 Mookerjee RP, Stadlbauer V, Lidder S. et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (03) 831-840
    Search in Google Scholar
  • 50 Huang DQ, Mathurin P, Cortez-Pinto H, Loomba R. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol 2023; 20 (01) 37-49
    Search in Google Scholar
  • 51 Huang DQ, Terrault NA, Tacke F. et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023; 20 (06) 388-398
    Search in Google Scholar
  • 52 Wang Y, Tong J, Chang B, Wang B, Zhang D, Wang B. Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Mol Med Rep 2014; 9 (06) 2352-2356
    Search in Google Scholar
  • 53 Tang Y, Banan A, Forsyth CB. et al. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol Clin Exp Res 2008; 32 (02) 355-364
    Search in Google Scholar
  • 54 Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009; 50 (02) 638-644
    Search in Google Scholar
  • 55 Basuroy S, Sheth P, Kuppuswamy D, Balasubramanian S, Ray RM, Rao RK. Expression of kinase-inactive c-Src delays oxidative stress-induced disassembly and accelerates calcium-mediated reassembly of tight junctions in the Caco-2 cell monolayer. J Biol Chem 2003; 278 (14) 11916-11924
    Search in Google Scholar
  • 56 Seth A, Sheth P, Elias BC, Rao R. Protein phosphatases 2A and 1 interact with occludin and negatively regulate the assembly of tight junctions in the CACO-2 cell monolayer. J Biol Chem 2007; 282 (15) 11487-11498
    Search in Google Scholar
  • 57 Rao RK, Li L, Baker RD, Baker SS, Gupta A. Glutathione oxidation and PTPase inhibition by hydrogen peroxide in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 2000; 279 (02) G332-G340
    Search in Google Scholar
  • 58 Reiberger T, Ferlitsch A, Payer BA. et al; Vienna Hepatic Hemodynamic Lab. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol 2013; 58 (05) 911-921
    Search in Google Scholar
  • 59 Trebicka J, Reiberger T, Laleman W. Gut-liver axis links portal hypertension to acute-on-chronic liver failure. Visc Med 2018; 34 (04) 270-275
    Search in Google Scholar
  • 60 Schierwagen R, Alvarez-Silva C, Madsen MSA. et al. Circulating microbiome in blood of different circulatory compartments. Gut 2019; 68 (03) 578-580
    Search in Google Scholar
  • 61 Lehmann JM, Claus K, Jansen C. et al. Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. Liver Int 2018; 38 (05) 875-884
    Search in Google Scholar
  • 62 Berres ML, Lehmann J, Jansen C. et al. Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Liver Int 2016; 36 (03) 386-394
    Search in Google Scholar
  • 63 Berres ML, Asmacher S, Lehmann J. et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol 2015; 62 (02) 332-339
    Search in Google Scholar
  • 64 Norman DA, Atkins JM, Seelig Jr LL, Gomez-Sanchez C, Krejs GJ. Water and electrolyte movement and mucosal morphology in the jejunum of patients with portal hypertension. Gastroenterology 1980; 79 (04) 707-715
    Search in Google Scholar
  • 65 Such J, Guardiola JV, de Juan J. et al. Ultrastructural characteristics of distal duodenum mucosa in patients with cirrhosis. Eur J Gastroenterol Hepatol 2002; 14 (04) 371-376
    Search in Google Scholar
  • 66 Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2017; 2 (02) 135-143
    Search in Google Scholar
  • 67 Cani PD. Gut microbiota - at the intersection of everything?. Nat Rev Gastroenterol Hepatol 2017; 14 (06) 321-322
    Search in Google Scholar
  • 68 Dikopoulos N, Weidenbach H, Adler G, Schmid RM. Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II. Eur J Clin Invest 2003; 33 (01) 58-64
    Search in Google Scholar
  • 69 Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4 (05) 382-387
    Search in Google Scholar
  • 70 Axelson M, Sjövall J. Potential bile acid precursors in plasma–possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 1990; 36 (06) 631-640
    Search in Google Scholar
  • 71 Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304 (03) G227-G234
    Search in Google Scholar
  • 72 Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science 2018; 362 (6418): 362
    Search in Google Scholar
  • 73 Gómez-Hurtado I, Santacruz A, Peiró G. et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One 2011; 6 (07) e23037
    Search in Google Scholar
  • 74 Pandey A, Galeone A, Han SY. et al. Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila. Nat Commun 2023; 14 (01) 5667
    Search in Google Scholar
  • 75 Shemtov SJ, Emani R, Bielska O. et al. The intestinal immune system and gut barrier function in obesity and ageing. FEBS J 2023; 290 (17) 4163-4186
    Search in Google Scholar
  • 76 Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol 2023; 21 (11) 719-733
    Search in Google Scholar
  • 77 Lee JY, Tsolis RM, Bäumler AJ. The microbiome and gut homeostasis. Science 2022; 377 (6601): eabp9960
    Search in Google Scholar
  • 78 Zhu L, Baker SS, Gill C. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (02) 601-609
    Search in Google Scholar
  • 79 Bayoumy AB, Mulder CJJ, Mol JJ, Tushuizen ME. Gut fermentation syndrome: a systematic review of case reports. United European Gastroenterol J 2021; 9 (03) 332-342
    Search in Google Scholar
  • 80 Duan Y, Llorente C, Lang S. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575 (7783): 505-511
    Search in Google Scholar
  • 81 Chen Y, Yang F, Lu H. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (02) 562-572
    Search in Google Scholar
  • 82 Chen Y, Guo J, Qian G. et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015; 30 (09) 1429-1437
    Search in Google Scholar
  • 83 Bajaj JS, Peña-Rodriguez M, La Reau A. et al. Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis. Gut 2023; 72 (04) 759-771
    Search in Google Scholar
  • 84 Engelmann C, Adebayo D, Oria M. et al. Recombinant alkaline phosphatase prevents acute on chronic liver failure. Sci Rep 2020; 10 (01) 389
    Search in Google Scholar
  • 85 Kondo T, Macdonald S, Engelmann C. et al. The role of RIPK1 mediated cell death in acute on chronic liver failure. Cell Death Dis 2021; 13 (01) 5
    Search in Google Scholar
  • 86 Bajaj JS, Heuman DM, Hylemon PB. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (05) 940-947
    Search in Google Scholar
  • 87 Bajaj JS, Ridlon JM, Hylemon PB. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302 (01) G168-G175
    Search in Google Scholar
  • 88 Benten D, Wiest R. Gut microbiome and intestinal barrier failure–the “Achilles heel” in hepatology?. J Hepatol 2012; 56 (06) 1221-1223
    Search in Google Scholar
  • 89 Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979; 23 (02) 403-411
    Search in Google Scholar
  • 90 Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63 (05) 1272-1284
    Search in Google Scholar
  • 91 Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 (Suppl. 01) S49-S66
    Search in Google Scholar
  • 92 Piano S, Fasolato S, Salinas F. et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results of a randomized, controlled clinical trial. Hepatology 2016; 63 (04) 1299-1309
    Search in Google Scholar
  • 93 Wiest R, Rath HC. Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol 2003; 17 (03) 397-425
    Search in Google Scholar
  • 94 Worlicek M, Knebel K, Linde HJ. et al. Splanchnic sympathectomy prevents translocation and spreading of E. coli but not S. aureus in liver cirrhosis. Gut 2010; 59 (08) 1127-1134
    Search in Google Scholar
  • 95 Balmer ML, Slack E, de Gottardi A. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med 2014; 6 (237) 237ra66
    Search in Google Scholar
  • 96 Pose E, Coll M, Martínez-Sánchez C. et al. Programmed death ligand 1 is overexpressed in liver macrophages in chronic liver diseases, and its blockade improves the antibacterial activity against infections. Hepatology 2021; 74 (01) 296-311
    Search in Google Scholar
  • 97 Peiseler M, Araujo David B, Zindel J. et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science 2023; 381 (6662): eabq5202
    Search in Google Scholar
  • 98 Clària J, Stauber RE, Coenraad MJ. et al; CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology 2016; 64 (04) 1249-1264
    Search in Google Scholar
  • 99 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61 (06) 1385-1396
    Search in Google Scholar
  • 100 Albillos A, de la Hera A, González M. et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003; 37 (01) 208-217
    Search in Google Scholar
  • 101 Albillos A, de-la-Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet 2004; 363 (9421): 1608-1610
    Search in Google Scholar
  • 102 Papp M, Sipeki N, Vitalis Z. et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59 (03) 457-466
    Search in Google Scholar
  • 103 Márquez M, Fernández-Gutiérrez C, Montes-de-Oca M. et al. Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clin Exp Immunol 2009; 158 (02) 219-229
    Search in Google Scholar
  • 104 Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017; 67 (05) 1084-1103
    Search in Google Scholar
  • 105 Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25 (39) 5897-5917
    Search in Google Scholar
  • 106 Verbeke L, Farre R, Trebicka J. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
    Search in Google Scholar
  • 107 Lutz P, Berger C, Langhans B. et al. A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis. Dig Liver Dis 2014; 46 (11) 1047-1050
    Search in Google Scholar
  • 108 Van Mil SW, Milona A, Dixon PH. et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133 (02) 507-516
    Search in Google Scholar
  • 109 Marzolini C, Tirona RG, Gervasini G. et al. A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. Mol Endocrinol 2007; 21 (08) 1769-1780
    Search in Google Scholar
  • 110 Semmler G, Simbrunner B, Scheiner B. et al. Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension. J Gastroenterol Hepatol 2019; 34 (12) 2164-2172
    Search in Google Scholar
  • 111 Úbeda M, Lario M, Muñoz L. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 2016; 64 (05) 1049-1057
    Search in Google Scholar
  • 112 Verbeke L, Farre R, Verbinnen B. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 2015; 185 (02) 409-419
    Search in Google Scholar
  • 113 Sanyal AJ, Ratziu V, Loomba R. et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79 (05) 1110-1120
    Search in Google Scholar
  • 114 Schwabl P, Hambruch E, Seeland BA. et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66 (04) 724-733
    Search in Google Scholar
  • 115 Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol 2023; 79 (05) 1317-1331
    Search in Google Scholar
  • 116 Pérez-Paramo M, Muñoz J, Albillos A. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000; 31 (01) 43-48
    Search in Google Scholar
  • 117 Mookerjee RP, Pavesi M, Thomsen KL. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016; 64 (03) 574-582
    Search in Google Scholar
  • 118 Jachs M, Hartl L, Schaufler D. et al. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut 2021; 70 (09) 1758-1767
    Search in Google Scholar
  • 119 Jensen MD, Watson H, Vilstrup H, Jepsen P. Non-selective beta-blockers and risk of sepsis in patients with cirrhosis and ascites: results from a large observational study. Clin Epidemiol 2023; 15: 775-783
    Search in Google Scholar
  • 120 Sersté T, Melot C, Francoz C. et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52 (03) 1017-1022
    Search in Google Scholar
  • 121 Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023; 78 (04) 866-872
    Search in Google Scholar
  • 122 Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations. JHEP Rep Innov Hepatol 2019; 2 (01) 100063
    Search in Google Scholar
  • 123 Madsen BS, Havelund T, Krag A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective β-blockers. Adv Ther 2013; 30 (07) 659-670
    Search in Google Scholar
  • 124 Bajaj JS, Tandon P, OʼLeary JG. et al. Outcomes in patients with cirrhosis on primary compared to secondary prophylaxis for spontaneous bacterial peritonitis. Am J Gastroenterol 2019; 114 (04) 599-606
    Search in Google Scholar
  • 125 Bass NM, Mullen KD, Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
    Search in Google Scholar
  • 126 Yu X, Jin Y, Zhou W. et al. Rifaximin modulates the gut microbiota to prevent hepatic encephalopathy in liver cirrhosis without impacting the resistome. Front Cell Infect Microbiol 2022; 11: 761192
    Search in Google Scholar
  • 127 Israelsen M, Madsen BS, Torp N. et al; GALAXY, MicrobLiver Consortia. Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2023; 8 (06) 523-532
    Search in Google Scholar
  • 128 Kulkarni AV, Avadhanam M, Karandikar P. et al. Antibiotics with or without Rifaximin for acute hepatic Encephalopathy in critically ill patients with cirrhosis: a double-blind, randomized controlled (ARiE) trial. Am J Gastroenterol 2024; 119 (05) 864-874
    Search in Google Scholar
  • 129 Caraceni P, Vargas V, Solà E. et al; Liverhope Consortium. The use of rifaximin in patients with cirrhosis. Hepatology 2021; 74 (03) 1660-1673
    Search in Google Scholar
  • 130 Rimola A, García-Tsao G, Navasa M. et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000; 32 (01) 142-153
    Search in Google Scholar
  • 131 Philips CA, Pande A, Shasthry SM. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15 (04) 600-602
    Search in Google Scholar
  • 132 Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37 (03) 215-225
    Search in Google Scholar
  • 133 Sharma A, Roy A, Premkumar M. et al. Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial. Hepatol Int 2022; 16 (02) 433-446
    Search in Google Scholar
  • 134 Bloom PP, Tapper EB. Lactulose in cirrhosis: current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun 2023; 7 (11) 7
    Search in Google Scholar
  • 135 Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016; 4: CD003044
    Search in Google Scholar
  • 136 Vince A, Dawson AM, Park N, O'Grady F. Ammonia production by intestinal bacteria. Gut 1973; 14 (03) 171-177
    Search in Google Scholar
  • 137 Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia production in a fecal incubation system. Gastroenterology 1978; 74 (03) 544-549
    Search in Google Scholar
  • 138 Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol 1980; 13 (02) 177-191
    Search in Google Scholar
  • 139 Moratalla A, Ampuero J, Bellot P. et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2017; 37 (02) 212-223
    Search in Google Scholar
  • 140 Haase S, Wilck N, Haghikia A, Gold R, Mueller DN, Linker RA. The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol 2020; 50 (12) 1863-1870
    Search in Google Scholar
  • 141 Holle J, McParland V, Anandakumar H. et al. Gut dysbiosis contributes to TMAO accumulation in CKD. Nephrol Dial Transplant 2024; 39 (11) 1923-1926
    Search in Google Scholar

   Permissions and Reprints
Zoom Image
Fig. 1 Schematic illustration of the interplay of liver and gut in regard of ACLF. ACLF, acute-on-chronic liver failure; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharides; PAMPs, pathogen-associated molecular patterns; RIPK1, receptor-interacting protein kinase 1; SCFA, short-chain fatty acids; TLR4, toll-like receptor 4