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Faculty of Medicine and Life SciencesUniversity of TampereFaculty of Medicine and Life Sciences

Pathogenesis and genetics of alcoholic liver cirrhosis

Liver cirrhosis is the irreversible end stage of chronic liver disease. In Western countries more than 90% of cirrhosis is caused by excessive ethanol consumption. However, only a minority (10-20%) of alcohol abusers ever develop liver cirrhosis during their lives. Our group has previously reported a link between alcoholic liver cirrhosis and bacterial recognition receptor CD14 genetics supporting the hypothesis of the involvement of intestinal bacteria and their endotoxins in the pathogenesis of cirrhosis. This observation has been confirmed by other groups.

We have collected a large unique series of autopsy cases with normal, fatty or cirrhotic liver and have also performed genome wide analysis of the blood samples of the autopsy cases to be able to find new genetic loci that could associate with the risk of cirrhosis. However, it seems that gut bacterial diversity and its changes may affect the risk of cirrhosis maybe more that genetic factors of the host. In healthy individuals, normal gut microbiota consists mainly of bacteria belonging to the Clostridium coccoides (cluster XIVa) and Clostridium leptum group (cluster IV), Bacteroides spp., Bifidobacterium spp. and Enterobacter spp. Enterobacter spp. belongs to a large Enterobactericaea family consisting of several gram-negative bacteria. The liver is continually exposed to gut derived bacteria and bacterial components because ca. 70% of its blood supply is from the portal vein, which is the direct venous outflow of the intestine. Chronic alcohol abuse has been shown to change intestinal bacterial population by decreasing the numbers of Clostridium (gram-positive, anaerobe) and Bacteroidetes (gram-negative, anaerobe) and increasing the numbers of aerobic Proteobacteria (gram-negative, facultatively or obligately anaerobic). Up to date it has been difficult to study the association between gut bacteria population and liver cirrhosis. This is due because the normal composition of human intestinal microbiota has not yet been totally resolved, mainly due to its richness of species and high inter- and intra-individual differences between persons.  Another restrictive factor for determining the spectrum of intestinal bacteria has been methodological limitations with conventional bacterial culturing: only 30 -40% of intestinal bacteria are cultivable on normal plates. In this study project we have developed quantitative real time qPCR methods to overcome the problems of conventional culturing. In order to be able to use autopsy gut samples we have also studied the effect of post-mortem time on gut bacterial populations. Recently we found that cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression. CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p=0.004). The present project with a unique possibility to combine gut bacterial population studies with immunohistochemistry and genetics can lead to a new concept of the pathogenesis of alcoholic liver cirrhosis as well as new prevention and treatment perspectives.

Järveläinen HA, Orpana A, Perola M, Savolainen VT, Karhunen PJ, Lindros KO: Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease. Hepatology 2001, 33:1148-1153.

Tuomisto S, Karhunen PJ, Vuento R, Aittoniemi J, Pessi T. Evaluation of postmortem bacterial migration using culturing and real-time quantitative PCR. J Forensic Sci. 2013 Jul;58(4):910-6.

Tuomisto S, Karhunen PJ, Pessi T. Time-dependent post mortem changes in the composition of intestinal bacteria using real-time quantitative PCR. Gut Pathog. 2013 Nov 25;5(1):35.

Tuomisto S, Pessi T, Collin P, Vuento R, Aittoniemi J, Karhunen PJ. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. BMC Gastroenterol. 2014 Feb 24;14(1):40. [Epub ahead of print]

 
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Last update: 21.3.2014 13.52 Muokkaa

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