World J Gastroenterol 2014; Dec 7;20(45):16795-16810

Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. New insights into an old relationship.

Valerio Giannelli1, Vincenza Di Gregorio1, Valerio Iebba2, Michela Giusto1, Serena Schippa2, Manuela Merli1* and Ulrich Thalheimer3*

1) Gastroenterology Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy

2) Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy

3) Liver Unit, Royal Devon and Exeter Foundation Trust, Exeter, UK

*Ulrich Thalheimer and Manuela Merli have equally contributed as senior authors

 

Abstract

Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria (i.e. gram negative species) and a decrease in autochthonous familiae. Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences. We therefore described the features of the complex interaction between gut microbiota and cirrhotic host, the so called “gut-liver axis”, with a particular attention to the acquired risk of bacterial translocation (BT), systemic inflammation and the relationship with systemic infections in the cirrhotic patient. We found a large literature supporting the concept of the strict interplay between gut bacteria and liver disease. Gut microbiota alteration appears to be rather common in advanced liver disease and it sustains the concept of how gut microbiota phenotype and the presence of pathological BT are determinant factors for liver function and hepatic chronic inflammation. Herein, we also described the relevance of the clinical consequences of microbiota alteration. The clinical implications of dysbiosis is that future therapeutic approaches to liver cirrhosis, especially in decompensated patients, should consider the gut-liver axis. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.

PMID: 25492994

 

Supplement:

There is an emerging attention toward the role of gut microbiota in liver disease. By virtue of its anatomical location, blood supply and immunological repertoire, the liver is theoretically predisposed to confront and interact with those microbes and products of microbe-gut that traverse the gut barrier and gain access to the bloodstream. The consequences of this interaction have emerged already in the middle of the last century with the recognition of the relationship between hepatic coma and the absorption of nitrogenous metabolites from the intestine.

Given that the microbiome in healthy individuals exerts so many important homeostatic effects, such as metabolic and immunological functions, we intended to perform a research on the potential impact of an altered microbiome in liver disease. We hypothesized that the higher prevalence of gut dysbiosis among cirrhotic patients could confer upon them a higher risk of infection due to the prevalence of enteric pathogens bacteria and also cause a pro-inflammatory state which can elicit and predispose to cirrhosis decompensation (1).

A legitimate question arises when you approach the gut microbiota in liver disease; is it the liver disease which modifies the gut bacteria or is it the gut dysbiosis which contributes to cause liver disease?

A significant small intestinal bacterial overgrowth occurs in cirrhosis. On culture-independent sequencing, cirrhotic patients have been noted to have a higher relative abundance of potentially pathogenic families such as Enterobacteriaceae and lower commensal bacteria such as Clostridiales incertae sedis XIV, Lachnospiraceae and Ruminococcacea (2). These commensals usually prevent bacterial overgrowth and generate beneficial short-chain-fatty-acids which are essentials for enterocyte metabolism. Indeed, the most recent studies on gut microbiota in cirrhosis indicate that microbiota is modified after the onset of liver disease but in turn it seems that gut dysbiosis worsens the clinical course of liver disease once it is present. Cirrhotic patients are exposed to a higher risk of dysbiosis because of causes. The alteration in intestinal motility, the increased gastric pH and the reduced bile acid concentration in the colon, secondary to cirrhosis, may lead to a failure in the control of bacterial intestinal growth. Not all bacteria are able to translocate to blood stream or to the lymphatic vessels, and in healthy people, bacteria present in the autochthonous flora are able to translocate in low numbers from the gut lumen; moreover, during their passage through the epithelial barrier or in the mesenteric lymph nodes (MLN) they are physiologically killed. These events mean that MLN are normally sterile. The presence of enteric-derived bacteria in MLN and in the venous blood stream occurs more frequently in patient with cirrhosis compared with controls, and among cirrhotic patients bacterial translocation (BT) is approximately 5-6 folds more frequent in Child C compared to Child A-B. In experimental studies the prevalence of BT in cirrhotic animals with spontaneous bacterial peritonitis is twice higher than in those without. The species that more frequently translocate are Enterobacteriaceae, Enterococcus spp and Proteus spp, while, obligate anaerobes are rarely able to cross the gastrointestinal barrier. In some cases, the translocation of viable bacteria may induce “spontaneous” bacterial infections while the translocation of bacterial fragments may produce a pro-inflammatory state due to the release of cytokines and nitric oxide.

Which are the clinical consequences of the cirrhosis “fingerprint” of gut microbiota?

There are still few data on the role of dysbiosis as a promoting factor for the development of infections in cirrhosis. A significant preponderance of gram negative species has been found in stool samples from cirrhotic patients who developed systemic inflammatory response syndrome (SIRS) and from those who died from acute on chronic liver failure. Within these groups a lower ratio of F. prausnitzii/E. coli and higher endotoxin levels have been found compared with patients with cirrhosis but without SIRS.

Figure 1 Microbiota

Figure 1. Genomics and metagenomics analysis of gut microbiota. Once DNA extraction and quality control have been done (i.e.workflow for assaying DNA purity and concentration), metagenomic sequences from the gut microbiota are generated by pyrosequencing selected 16S rRNA regions from microbial genomes (4)

 

The higher preponderance in cirrhotic stool and intestinal mucosa of those species of gram negative and positive bacteria (Enterobacteriaceae, Streptococcus spp. and Enterococcus faecalis) that are most widely involved in systemic infections, along with the loss of non pathogenic commensal bacteria, suggest a critical interaction of intestinal dysbiosis and risk of infection in cirrhosis. The imbalance between commensal and pathogenic taxa could potentiate BT and has been associated with clinical decompensation of cirrhosis and death. The advent of molecular techniques, mainly based on Polymerase Chain Reaction (PCR) of the bacterial ribosomal 16S rDNA sequence are now allowing to perform a complete description of the entire bacterial community of a sample, by means of PCR based techniques (Figures 1-2).

Figure 2 MicrobiotaFigure 2. Example of a microbiota structure at different taxonomic levels. Each color depicts a different phylum, class, order, family and genus

 

The clinical relevance of gut dysbiosis is not merely confined to the risk of overt infection, but may also be associated with a chronic pro-inflammatory state. The hepatic immune system tolerates a low grade passage of bacterial products into blood and lymphatic stream, to avoid uncontrolled immune responses, a phenomenon known as “liver tolerance”. The first immunological response to the presence of bacteria (or MAMPs) is driven by the activation of the innate immune system. In particular, translocated bacterial products augment the activation of hepatic immune cells through pattern recognition receptors including Toll-like-receptors (TLRs). The activated TLR system induces the production of cytokine such as IL-1 and IL-6 and type I IFN. This kind of inflammation without infection has been defined as sterile inflammation and is mostly driven by the “hepatic” activation of TLR-4 receptor. In TLR-4 mutant mice which were unable to activate the TLR-4 pathway in response to LPS presentation, the exposure to LPS was not reflected by any change in portal hypertension, angiogenesis, fibrosis, and pro-inflammatory state (3). These observations seem to indirectly demonstrate the vicious cycle existing between gut-dysbiosis, the pro-inflammatory state driven by BT and the worsening of portal hypertension.

The potential therapeutic options are fascinating because they might allow the possibility to interrupt the vicious cycle existing between gut dysbiosis and liver disease. To date, relative small randomized controlled trials have been addressed to evaluate the effects of gut flora manipulation in patient with cirrhosis (1). Future studies in this field are welcome and will increase our knowledge about the interrelationship between the gut-liver-axis.

Figure 3 Microbiota

Figure 3. Association between gut flora, systemic inflammation and the complications of cirrhosis

 

References

  1. Giannelli V, Di Gregorio V, Iebba V, Giusto M, Schippa S, Merli M, Thalheimer U 2014 Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol 20:16795-16810
  2. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, Noble NA, Unser AB, Daita K, Fisher AR, Sikaroodi M, Gillevet PM 2014 Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 60:940-947
  3. Zhu Q, Zou L, Jagavelu K, Simonetto DA, Huebert RC, Jiang ZD, DuPont HL, Shah VH 2012 Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol 56:893-899
  4. Del Chierico F, Gnani D, Vernocchi P, Petrucca A, Alisi A, Dallapiccola B, Nobili V, Lorenza P 2014 Meta-omic platforms to assist in the understanding of NAFLD gut microbiota alterations: tools and applications. Int J Mol Sci 15:684-711

 

Contacts

Prof Manuela Merli ,

Gastroenterology Department of Clinical Medicine,

Sapienza University of Rome, Italy.

Mail: Manuela.merli@uniroma1.it

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann