Bacterial Translocation in Liver Cirrhosis

Lorraine Cunningham, Alan O’Sullivan-Weekes & Sarah Ward

Introduction

Bacterial translocation (BT) can be defined as the passage of bacterial flora from the intestinal lumen to mesenteric lymph nodes (MLNs) or other extra-intestinal sites (Manuela Merli et al, 2015). Several studies have demonstrated the importance of BT in cirrhosis and it’s role in the pathogenesis of spontaneous bacterial peritonitis (SBP) (Runyon BA et al, 1994). Although the mechanisms driving the translocation of the gut flora in cirrhosis are not fully understood, recent evidence suggests that translocation of bacteria and bacterial products, such as endotoxin from the intestinal lumen into the systemic circulation, is a key factor in the pathogenesis of chronic liver diseases and the development of complications in cirrhosis (Kirsten E. Pijls et al 2013). In addition to changes in the intestinal flora and the immune system, dysfunction of the intestinal epithelial barrier may also contribute to BT (Kirsten E. Pijls et al, 2013). This review discusses the multiple mechanisms involved in the process of BT, with an emphasis on alterations in intestinal flora and mucosal barrier function (Reiner Wiest et al, 2014).

Compartments involved in pathological bacterial translocation

GALT

Gut associated lymphatic tissue (GALT) is a defence organ against bacteria. The bacteria microbial-associated molecular patterns (MAMPs) are recognised by pattern- recognition receptors (PRR). In response to bacterial translocation, gut epithelial cells release chemokines. This will attract dendrite cells (DCs) to the mucosa. DCs induce production and maturation of B and T cells which are then released into the blood. In cirrhotic patients, a reduction of B cells can be seen. The degree to which this contributes to BT is unknown. Reduction of T cells causes an accumulation of bacteria in the MLN and to the spreading of bacteria to extra-intestinal sites (Reiner Wiest et al, 2014).

MLN

Part of the GALT and play a role in the adaptive and the innate immune response (Bellot et al, 2013). Normally bacteria transported to MLN by DCs are killed without inducing systemic immunity. Immune-suppression permits the translocation of bacteria from intestines, which can cause sepsis and death (Reiner Wiest et al, 2014). Patients with cirrhosis have systemic immune alterations which may promote development of infections and BT. Examples of these alterations include: decreased activity of reticuloendothelial system (RES) which are a defence against bacteraemia and other haematogenous infections. This will have an effect on bacterial products such as endotoxin or bacterial DNA (Bellot et al, 2013). Advanced cirrhosis is associated with a decrease in both cellular and humoral components of the immune response (Bellot et al, 2013).

MECHANICAL COMPONENTS

MAMPs secreted by the paneth cells are directly linked to bacteria and lipopolysaccharide, (LPS) exposure. These play a role in the balance of the intestinal host microbial interphase (Reiner Wiest et al, 2014). Paneth cells are located at the bottom of each intestinal crypt. MAMPs secreted include: alpha-defenins in response to bacteria and LPS; Lysozme and secondary phospholipase A2 involved in local defence against bacteria; Beta-defensins antimicrobial peptides are expressed by most epithelial cells of the intestines (Garcia-Tsao et al, 2005).

SECRETARY COMPONENTS

MAMPs secreted by the paneth cells are directly linked to bacteria and lipopolysaccharide, (LPS) exposure. These play a role in the balance of the intestinal host microbial interphase (Reiner Wiest et al, 2014). Paneth cells are located at the bottom of each intestinal crypt. MAMPs secreted include: alpha-defenins in response to bacteria and LPS; Lysozme and secondary phospholipase A2 involved in local defence against bacteria; Beta-defensins antimicrobial peptides are expressed by most epithelial cells of the intestines (Garcia-Tsao et al, 2005).

MUCUS

This prevents direct contact of bacteria with the microvilli. In recent studies on alcoholics a thickness of the mucosa in the duodenum can be seen. This indicates a change in relation to cirrhosis and/or alcohol. An absence of bile has been shown to increase BT. In cirrhosis a decrease in the concentration of bile salts can be observed leading to an increase in BT (Reiner Wiest et al, 2014). A study preformed on rats with cirrhosis found that the administration of conjugated bile acids led to reversal of small intestinal bacterial overgrowth (SIBO), reduced rate of BT and increased survival (Riordan and williams, 2006).

IGA ANTIBODIES

Secreted into the gut lumen where it binds and aggregates bacteria. IgA also neutralise toxins. A reduced amount of igA wil cause an increase in BT. In cirrhotic patients a decrease of faecal igA concentration and decreased secretion on igA can be observed. This may show a link between igA, BT and development of infections in cirrhosis but is yet to be proven (Reiner Wiest et al, 2014).

BACTERIAL OVER-GROWTH

Small intestinal bacterial overgrowth (SIBO) is an increased number and/or abnormal type of bacteria in the small intestines. This is one of the main factors promoting BT. In experimental studies, it has been shown that cirrhotic rats with ascites and BT have a higher rate of SIBO compared to those without. Studies have also revealed that SIBO is more common in patients with cirrhosis than in controls, especially in patients with advanced liver dysfunction and that have a history of SBP (Bellot et al, 2013). Increased faecal counts of both gram-positive and gram-negative bacteria species have been reported when SIBO is present (Riordan and williams, 2006).

Pathophysiology of BT

Making studies using experimental models is the main way in which we study pathogenesis of the BT. This is due to the difficulty in accessing MLNs in patients with cirrhosis. In experimental models, BT is defined as a MLN-positive culture, 56% of rats with CCl4-induced cirrhosis and ascites had BT but in animals without ascites it drops to more like 0-10%. Patients with cirrhosis and BT had a higher degree of liver dysfunction in comparison to patients without BT. (Pablo Bellot et al, 2013) Ascites from the Greek word meaning “baglike” is a gastroenterological term for an accumulation of fluid in the around the stomach area. The medical condition is also called peritoneal cavity fluid and is most usually due to cirrhosis. (Pedersen JS et al, 2015) BT was investigated at two stages of experimental portal hypertension in another study, acute (meaning when shunting is minimal) and chronic (meaning when shunting is extensive and is like the portal hypertension of cirrhosis). In this study they found that BT is a command event in the acute portal hypertension model most likely because of a greater mesenteric inflammation. However, no difference in the rate of BT in chronic portal hypertensive was detected in rats (15 days after portal vein ligation) compared with control rats. It has been noticed that patients with cirrhosis and ascites and the presence of bacterial DNA in serum, a surrogate marker of BT, had the same degree of portal hypertension as patients without bacterial DNA. (Pablo Bellot et al, 2013) There are at least three mechanisms that influence the pathogenesis of BT which are: (Pablo Bellot et al, 2013) • Small intestinal bacterial overgrowth • Increased intestinal permeability • Immune alterations of cirrhosis