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.

Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders

“…76 Alcohol consumption can increase intestinal bacterial and fungal dysbiosis, which contribute to disease susceptibility, loss of gut barrier function, and progression of liver injury. [77][78][79][80] Mice given antibiotics develop less severe liver injury, and do not have intestinal reductions in occludin expression, with ethanol feeding. 74,81 However, germ-free mice, which lack commensal bacteria, develop more severe ethanol-induced injury than conventionally housed mice (with commensal bacteria).…”

“…Although patients with NAFLD or NASH have alterations in their intestinal microbiomes, the specific alterations in phyla and species have not been as well defined as they have for patients with ALD. 77,103 Changes in the immune response and metabolome shaped by these microbes might have greater effects than the specific microbe strains themselves. Moreover, it is a challenge to compare findings from different studies, because they use different methods for diagnosis of NAFLD (such as ultrasonography, magnetic resonance imaging, and biopsy), and include patients with different stages of disease, which are associated with distinct microbiome profiles.…”

“…Moreover, it is a challenge to compare findings from different studies, because they use different methods for diagnosis of NAFLD (such as ultrasonography, magnetic resonance imaging, and biopsy), and include patients with different stages of disease, which are associated with distinct microbiome profiles. 77,103,104 One of the most common findings is that microbiomes of patients with NAFLD or NASH are enriched in gram-negative bacteria, whereas gram-positive bacteria are reduced-specifically, the abundance of butyrate-producing bacteria are reduced. 77,[103][104][105] In mice on a high-fat diet, sodium butyrate feeding reduced dysbiosis, endotoxemia, and liver inflammation and fat.…”

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

“…During recent years, many studies at the preclinical and experimental level have shed light on the relationship between ALD and gut microbiota. Dysbiosis and SIBO have been shown as relevant disease factors in both human and mouse models . Microbiota in individual with ALD is characterized by marked enrichment of Enterobacteriaceae and reduction of Bacteroidetes and Lactobacillus .…”

Modulating the Intestinal Microbiota: Therapeutic Opportunities in Liver Disease

“…Stool Bacteroidaceaeae and Clostridiales XIV predicted 90-day hospitalizations independent of such clinical predictors as Child-Pugh class and model for end-stage liver disease (commonly known as MELD) score. [58][59][60] Bajaj et al 61 demonstrated distinct gut microbial profiles associated with ACLF in hospitalized patients. The cirrhosisto-dysbiosis ratio was lower in those with ACLF and also those with renal failure.…”