Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either

Abstract

The intestinal microbiome plays a major role in the pathogenesis of liver disease, with a hallmark event being dysbiosis, or an imbalance of pathobionts and beneficial bacteria with the associated deleterious effects on their host. Reducing the number of intestinal bacteria with antibiotic treatment is generally advantageous in experimental liver diseases. Complete absence of intestinal microbiota as in germ-free rodents can be protective in autoimmune hepatitis and hepatic tumors induced by chemicals, or it can exacerbate disease as in acute toxic liver injury and liver fibrosis/cirrhosis. In alcoholic liver disease, nonalcoholic fatty liver disease, and autoimmune cholangiopathies, germ-free status can be associated with worsened or improved hepatic phenotype depending on the experimental model and type of rodent. Some of the unexpected outcomes can be explained by the limitations of rodents raised in a germ-free environment including a deficient immune system and an altered metabolism of lipids, cholesterol, xenobiotics/toxins, and bile acids. Given these limitations and to advance understanding of the interactions between host and intestinal microbiota, simplified model systems such as humanized gnotobiotic mice, or gnotobiotic mice monoassociated with a single bacterial strain or colonized with a defined set of microbes, are unique and useful models for investigation of liver disease in a complex ecosystem.

Keywords: antibiotics; germ-free; humanized rodents; liver disease; microbiota.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.

Use of germ-free mice in preclinical liver disease models. Germ-free mice have an immature immune system and a significantly altered metabolism related to lipids, cholesterol, xenobiotics/toxins, and bile acids. They can be colonized with only one known bacterial strain (monoassociated), a specific set of known bacterial strains, or human feces. Monoassociation and colonization with several bacteria are unique models to investigate the effect of single or multiple bacterial strains on experimental disease. Transmissibility of disease can be investigated by microbiota transfer into gnotobiotic mice. Humanized gnotobiotic mice allow the testing of microbiome-centered therapies to treat disease. Gnotobiotic rodents oftentimes have a more normalized immune system and metabolism than germ-free mice. Gnotobiotic mice can be subjected to preclinical models of liver disease to examine the impact of colonized microbes on the disease process.