In this study, we confirmed that HIV-related CD4+ lymphocyte depletion was associated with microbial translocation and established a link between HIV-related microbial translocation and the severity of liver disease. These data suggest that microbial translocation may be a novel mechanism by which HIV accelerates liver disease.
The link between HIV and microbial translocation was already made by Brenchley et al.10
We confirm their cross sectional analyses and extend these observations by finding that microbial translocation is chiefly evident after CD4+ lymphocyte depletion and in individuals with cirrhosis. By studying persons before and after HIV seroconversion, we were able to account for differences between subjects in the ‘baseline’ levels of these markers and to examine the association of HIV infection before CD4+ lymphocyte depletion occurs. These data support the proposed role of microbial translocation in the pathogenesis of HIV-related disease.
Two subjects with CD4+ lymphocyte depletion were noted to have extremely high LPS levels and an additional two subjects had very high sCD14 levels. However, we do not believe that these outlier data disproportionately contribute to the results because non-parametric tests were used that assessed rank order rather than absolute value. In addition, we repeated the analyses by Winsorizing 29
and associations between LPS and HIV CD4+ lymphocyte depletion remained (p=0.011 → p=0.013).
In this investigation, the risk of cirrhosis was 7.0 fold higher in persons with CD4+ lymphocyte depletion, a finding that is consistent with (or stronger than) what has been reported by other investigators. 2, 30, 31
Liver disease was also strongly associated with microbial translocation. While not proven, these findings are consistent with the hypothesis that microbial translocation contributes to both immune activation and progression of liver disease ().
Figure 3 HIV-related intestinal CD4+ lymphocyte depletion and microbial translocation contribute to HCV progression. An integrated model shows that microbial translocation is dependent on HIV-related CD4+ lymphocyte depletion. Microbial translocation is critical (more ...)
Microbial translocation has previously been associated with liver disease. For example, elevated LPS levels were associated with HCV-related liver disease by Caradonna et al., and LPS levels diminished in those who achieved interferon-related virus suppression.32
Additionally, in animal models alcohol has been linked to LPS and cirrhosis.15, 33–35
Interestingly, like HIV infection, alcohol use is strongly associated in epidemiologic studies with HCV-related liver disease progression.36–40
In fact, for each (alcohol or HIV-infection) there is a more than additive association with HCV-related liver disease, but the mechanism is not known.2, 36–39
Microbial translocation is central to the pathogenesis of alcohol-related liver disease.13, 15, 33–35
Recent work in murine models suggests a model in which LPS activation of TLR4 increases stellate cell susceptibility to inflammatory stimuli.16
While not evaluated experimentally, this work provides a context in which chronic LPS stimulation might have more than an additive effect on the liver disease caused by a second process like chronic viral hepatitis. Interestingly, the effect of alcohol on liver disease progression can be abrogated by gut sterilization with antimicrobials.15
Recent literature in an acute liver injury model has further suggested that replacement of LPS producing bacteria with so-called probiotic flora diminishes acute liver injury.41
We are not aware of studies extending this work to chronic viral hepatitis. We did not find a confounding effect of alcohol in our study, though alcohol use remains a difficult variable to quantify in experimental human studies.
Of the markers studied, we found the strongest associations among liver disease, HIV-related CD4+ lymphocyte depletion, and the amount of AAL-reactive IgG specific for the alpha galactose epitope, which is a recently described biomarker closely correlated with liver fibrosis and cirrhosis.28
The heterophillic alpha-galactose epitope is most notably a major antigen on Gram-negative micro-organisms. Thus, although the natural source for the alpha-galactose antigen stimulating production of the AAL-reactive IgG is not currently known, given its correlation with the other markers of microbial translocation it is tempting to speculate that it is derived from translocated components of intestinal microorganisms.
We, and others, have observed that the progression of HCV-related liver disease appears to be diminished in injection drug users when compared to persons who acquire infection by transfusion or other routes, even after adjusting for age.22, 42
We have also previously reported that liver enzyme values are lower when HCV-infected persons have been injecting in the preceding months.43
Interestingly, we found that active injection drug use was associated with higher levels of protective EndoCAb IgM, which bind LPS. Higher binding antibodies produced in response to chronic LPS stimulation could provide a mechanism for diminished liver disease progression among active injection drug users.
In the absence of an experimental model, we cannot exclude the possibility that microbial translocation is a result of liver disease progression and not a cause. Kupffer cells bind LPS44
and other gut-derived microbial products and shunting of portal blood past the liver is a well known consequence of cirrhosis and could explain the elevated levels of plasma LPS.45
Indeed, HIV remained associated with liver disease when LPS levels were included in a multivariable model. Admittedly, we were only adjusting for a single LPS determination and consequently underestimating microbial translocation. However, it is most plausible that microbial translocation is both a cause and an effect of liver disease progression and systemic immune activation. As with alcohol-related liver disease, it is possible that abundant microbial translocation promotes hepatic fibrogenesis, which in turn ultimately increases portal systemic shunting and the abundance of circulating microbial products in a positive feedback loop.
While these data suggest that HIV-related microbial translocation could contribute to liver disease progression among persons with chronic hepatitis C, future studies are needed to dissect how HIV-related microbial translocation causes liver disease progression and to investigate therapeutic interventions.