Circulating bugs in blood in alcoholic liver disease!
Authors: Gabriel Perlemuter
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 1284 We often equate bacteria with infectious diseases. It may be time, however, to change our way of thinking. According to the work of Puri and colleagues, published in this issue of hepatology,1 alcoholic liver disease (ALD) may be a noncommunicable disease associated with bacteria that circulate in a sterile environment, such as the circulatory system! The first demonstration that bacteria play a role in the pathophysiology of ALD came from studies on the involvement of endotoxins. Endotoxins are lipopolysaccharide (LPS) components of the walls of gram‐negative bacteria. Under healthy conditions, only a small amount of LPS translocates from the intestinal microbiota (IM) into the portal vein. Alcohol consumption increases intestinal permeability, leading to a higher load of LPS in the portal vein. In liver, LPS contributes to the activation of Kupffer and hepatic stellate cells, paving the way for alcoholic hepatitis and fibrosis. Technical difficulties in studying the IM previously hampered advances in our knowledge of its role in ALD. However, the development of new and less costly DNA sequencing technologies over the last few years has led to a large gain in our knowledge concerning the IM and its roles in the relationship between the gut and the liver, particularly in ALD. Individual susceptibility to alcohol‐induced liver injury has now been shown to be substantially driven by the IM.2 Moreover, the manipulation of bacterial species of the IM by fecal transfer2 or the addition of probiotics or fiber, such as pectin,3 to the diet has shown that it is possible to prevent and even improve alcohol‐induced liver lesions. Evaluation of the IM has also been proposed as a new method to improve the diagnoses of patients and the prediction of their outcomes. For example, a cirrhosis dysbiosis ratio could serve to evaluate the severity of cirrhosis.4 ALD is associated with the disruption of gut homeostasis, itself related to alcohol‐induced dysbiosis. The mechanisms involved in increased gut permeability include dysregulation of epithelial tight junction proteins and alterations of the mucus layer2 and host defenses against bacteria, such as antimicrobial defensin peptide levels.5 Puri and colleagues determined the circulating blood microbiome using innovative methods that allow qualitative and quantitative analyses of bacterial DNA. They compared patients with moderate or severe alcoholic hepatitis to non‐alcohol‐consuming individuals and heavy drinkers without liver disease. Each group displayed a specific blood microbiome profile. The authors used a predictive functional metagenomic approach to show specific activation of the type III secretion system, which has been linked to gram‐negative bacteria, in all alcoholic patients. Moreover, the patients with severe alcoholic hepatitis displayed increased isoprenoid synthesis through mevalonate and anthranilate degradation, known modulators of gram‐positive bacterial growth and biofilm production, respectively.1 This study has several strengths: it shows that there is a specific circulating microbiome in ALD, which can vary according to the severity of liver injury, possibly representing a specific signature. Moreover, the connection between the anticipated pathophysiological mechanisms of ALD and the functional relevance of the circulating microbiome is logical. Nevertheless, there are also some limitations: the absence of liver biopsy precludes any strong correlation between liver lesions and the circulating microbiome. Moreover, some patients were treated with antibiotics, which may affect the results. This could paradoxically be transformed into a strength as it reflects the true life of patients with ALD. Another important limitation is the absence of IM component analysis. Although the blood microbiome is most likely derived from the IM, the contribution of other locations, such as the mouth, skin, or any other part of the body, cannot be ruled out. In addition, blood and intestinal microbiomes differ considerably from each other, suggesting that the intestinal barrier, host defense, and liver may act as filters.6 We currently do not know whether the circulating microbiome is only a bystander to what happens, mainly in the gut and possibly the liver, or a true player in the pathophysiology of ALD. For example, bacteria may translocate and participate in the onset of type 2 diabetes in mouse models of the disease.7 Thus, translocation of living bacteria suggests the circulation of living bacteria in the bloodstream and that the blood microbiome could be a true player in ALD. Even in the absence of living bacteria, a circulating microbiome could play a role by mechanisms other than translocation, for example, by modifying host immune function. The presence of bacterial content or of possibly living bacteria in the blood is a truly new paradigm. We have learned and continue to teach our students that the blood is sterile under healthy and noninfectious conditions. Indeed, we regularly perform blood cultures from patients with fever to search for bacteremia or sepsis. In the absence of infection, blood cultures should remain sterile, meaning that there are no culturable bacteria, because blood provides a suitable growth medium. However, we now know from Puri and colleagues that circulating bacterial contents are present in the blood in ALD. Of course, bacterial contents are not necessarily indicative of living bacteria. They can be bacterial membrane components or, as shown in the work of Puri et al., bacterial DNA.1 It must be emphasized that the lack of culturability in blood is not synonymous with nonviability. "Dormancy" refers to cells which are not presently culturable (viable) but not "dead" in the sense of an operationally irreversible loss of viability. Dormant bacteria can indeed return to a state of replication, depending on the experimental conditions.8 Many additional studies will be necessary to precisely identify the role of the blood microbiome. The findings of Puri and colleagues open new avenues to understanding ALD pathophysiology. The composition of the IM in feces may change depending on many parameters, such as nutritional status, diet, treatments, or hemorrhage. Results concerning IM components can also vary depending on the method of feces recovery, the reproducibility of sequencing, and even the source of funding, i.e., academic or industrial. We can hope that study of the blood microbiome in clinical practice will circumvent some of these limitations. If a specific signature of the blood microbiome is associated with each stage of ALD severity, it will be possible to more accurately phenotype patients than with the current diagnostic tools. Despite many limitations, a pilot study has shown that changes in blood microbiota profiles are associated with liver fibrosis in obese patients.9 The level of circulating bacterial DNA before treatment could thus identify severe alcoholic hepatitis patients at high risk of infection if given prednisolone.10 Accordingly, we can imagine that a biomarker based on the blood microbiome may predict the occurrence of complications and the prognosis of patients. Finally, if we are confident in science, we can hope that targeting the metabolic pathways associated with blood microbiome modifications and signatures will improve the health of patients and their prognosis. Author names in bold designate shared co‐first authorship.