Background & Aims Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis, by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. Methods In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP), and interleukin (IL)-6 by ELISA, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. Results Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, I-FABP (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and IL-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for AST, P=.002 for ferritin) and fibrosis (P<.0001 for gamma-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for alpha-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). Conclusions LPS-induced local and systemic inflammation are associated with cirrhosis and predict progression to end-stage liver disease in patients with HBV or HCV infection.

We have derived a secondary structure model for 16S ribosomal RNA on the basis of comparative sequence analysis, chemical modification studies and nuclease susceptibility data. Nucleotide sequences of the E. coli and B. brevis 16S rRNA chains, and of RNAse T1 oligomer catalogs from 16S rRNAs of over 100 species of eubacteria were used for phylogenetic comparison. Chemical modification of G by glyoxal, A by m-chloroperbenzoic acid and C by bisulfite in naked 16S rRNA, and G by kethoxal in active and inactive 30S ribosomal subunits was taken as an indication of single stranded structure. Further support for the structure was obtained from susceptibility to RNases A and T1. These three approaches are in excellent agreement. The structure contains fifty helical elements organized into four major domains, in which 46 percent of the nucleotides of 16S rRNA are involved in base pairing. Phylogenetic comparison shows that highly conserved sequences are found principally in unpaired regions of the molecule. No knots are created by the structure.

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