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We thank Dr. Fujita and colleagues for their comments and this opportunity to discuss the questions raised regarding our recent investigation on bacterial DNA translocation in patients with cirrhosis.

As pointed out by Dr. Fujita, cytosine-guanine dinucleotide (CpG) motifs present in bacterial DNA are strongly immunogenic ingredients in inducing a proinflammatory host response and have been intensively studied in the past. However, the presence of bacterial DNA in patients with cirrhosis and ascites is a relatively new line of research that still will require more efforts in answering the bunch of questions raised as the investigation goes on.

In addition to the hypotheses stated in the text to explain the relationship between bacterial DNA and earlier and more frequent deaths among patients with advanced cirrhosis, other explanations may be possible. The effects of CpGs on the mitochondrial apoptotic pathway are being studied in an experimental mouse model and will certainly generate new lines of investigation. In this model, liver injury seems to be mediated by CpG DNA, but is really caused by tumor necrosis factor-α. Moreover, in a subsequent study by the same authors, CpG DNA is reported to prevent liver injury by modulating the expression of certain kinases. Anyhow, translation of these results to patients with cirrhosis will need specifically designed studies. Another example is the implication of hepatoprotective protein A20 binding and inhibitor of NF-kappaB (ABIN-1) in a rat model of hemorrhagic shock. Decreased levels of expression of this protein have been associated with increased apoptosis, which in turn, is induced by CpG DNA. These data will provide new insights on the wide effects of bacterial DNA on the host, as well as the fine-tuned immune response established to challenge these bacterial products.

It is likely that the consequences of the multiple immune reactions induced by the presence of bacterial DNA may be indeed different according to the field of research. Patients with advanced cirrhosis are characterized by a marked immune and hemodynamic instability. This fact makes them even more sensitive to the presence of bacterial DNA and likely other bacterial products that may further promote instability than patients without cirrhosis. According to our level of actual knowledge, it is not possible to assess which, among many, are the main reasons promoting a poor prognosis in patients with presence of bacterial DNA. New and multiple lines of research will be needed to answer these and probably many other questions that will likely arise in the future.

Pedro Zapater*, Rubén Francés†, Jose Such†, * Clinical Pharmacology Unit, Hospital General Universitario de Alicante Alicante, Spain, † Liver Unit, Hospital General Universitario de Alicante Alicante, Spain.