The gut microbiome may contribute to susceptibility to developing alcoholic liver disease

Alcoholic liver disease (ALD) is a major public health issue, yet the underlying mechanisms between ethanol consumption and injury to the liver are poorly understood.  Alcoholics vary in their susceptibility to developing ALD and alcoholic hepatitis (AH) despite consuming similar amounts of alcohol.  Taken together, this evidence suggests that other factors contribute to the onset and progression of ALD other than direct toxicity of alcohol.  Intestinal inflammation and pro-inflammatory bacterial products have also been observed in ALD patients and preclinical mice models, and intestinal dysbiosis has been observed in patients with alcohol dependency.  With this in mind, a team of European researchers devised a strategy to demonstrate microbiome dysbiosis as a casual driver of liver injury. 

The researchers transplanted human gut microbiota into germ-free mice, and the mice were then placed on a high-alcohol diet.  Microbiota were harvested from human alcoholic patients with or without AH (or low severity AH).  Mice transplanted with AH-microbiota had marked increases in symptoms of liver disease as compared to those mice that received microbiota transplants from non-AH alcoholic patients.  These include severe liver inflammation (including increases in T lymphocytes and natural killer cells), more necrosis in the liver, and higher intestinal permeability.  Enterobacteria counts were high in sever-AH patients and faecalibacterium genus was associated with AH-microbiota with low severity.  In an interesting spin, the researchers also transferred microbiota from an alcoholic patient without AH to mice with liver lesions.  Interestingly, mice who had received these microbiota displayed a reduction in serum alanine aminotransferase levels and a decrease in liver regeneration, suggesting that these microbiota could even possibly reverse alcohol-induced liver lesions. 

These findings not only support an association between the gut microbiome and susceptibility to developing alcoholic liver disease, but also provide evidence that these bacteria may drive disease onset.  These were important findings that support microbiota-causal effect rather than dysbiosis as a consequence of liver disease.  This data could perhaps promote development of novel diagnostic techniques that assess the gut microbiome or bacterial metabolites of alcoholic patients.  Methods such as manipulating the microbiome as a therapeutic approach for these patients could also be explored. 

The microbiome’s role in pediatric intestinal failure and associated liver disease

Gray's anatomy schematic of the liver.

On Wednesday we talked about children who suffer from short bowel syndrome (SBS), specifically highlighting the role of the gut microbiome alongside its relationship to parenteral nutrition (PN).  In addition to demonstrating microbial dysbiosis in children with SBS, intestinal dysbiosis was noticed in patients receiving PN, while those who had been weaned off showed bacterial overgrowth. 

SBS can also lead to intestinal failure (IF) and further complications.  Among the many, PN and disrupted bowel function have both been shown to lead to IF-associated liver disease (IFALD), which can result in severe illness and even death.  Steatosis, a pathological indication used to describe abnormal lipid retention in cells, has been observed in liver histological samples. 

The cause of IFALD remains unclear, but findings from studying other liver disorders suggest involvement of the gut microbiome.  Intestinal overgrowth has been postulated for quite some time now, but evidence is lacking and the exact biological underpinnings that lead to liver injury remain unclear.  Researchers in Finland sought to address this, estimating that IF-induced disruptions to the gut microbiome of pediatric patients played a direct role in causing this liver damage. 

Twenty-three pediatric patients developing IF were selected for this study.  Researchers collected fecal samples to analyze microbiota populations and took liver biopsies to examine inflammatory damage and fibrotic tissue morphology.  In line with previous findings, the microbiomes of patients with IF had limited bacterial diversity and species richness as compared to those of healthy children and adults. 

A strong correlation was observed between microbiota composition and liver steatosis, and different microbiota strains were shown to be associated with different stages of the disease progression.  Additionally, an overabundance of microbiota in the Proteobacteria phylum was observed in patients undergoing PN.  The Proteobacteria phylum contains many opportunistic pathogenic bacteria, including E. coli.  Interestingly, Proteobacteria species produce lipopolysaccharides, which are known toxins to the liver.  The researchers were also able to model that bacterial composition was a strong predictor of liver steatosis than nutrition history or bowel length post-resection surgery. 

These findings led the researchers to propose that intestinal resection, alongside PN, disrupts the intestines, and consequently native microbiota populations.  The disruption and species decline invites opportunistic bacteria, such as those in the Proteobacteria phylum, to populate the intestine.  These bacteria release of lipopolysaccharides into the blood stream, and upon reaching the liver, induce inflammatory toxic damage leading to steatosis. 

This study complements Wednesday’s discussion and helps us makes better sense of a convoluted disease complication that has drastic consequences.  Understanding the microbiome’s influence on post-SBS liver disease can help clinicians make informed decisions to rescue pediatric patients from these ailments.  

Saliva may be able to predict severity of cirrhosis

Cirrhosis is a disease of the liver in which healthy liver tissue is replaced with scar tissue, preventing the liver from properly functioning. Scientists at Virginia Commonwealth University found that changes in the microbiome of saliva were found in cirrhosis patients in comparison to individuals without the disease.

The scientists analyzed the bacterial contents of both stool samples and salivary samples from patients with varying degrees of cirrhosis as well as healthy controls.  Previous studies had shown that cirrhosis patients had altered fecal microbiomes and in this study, they found that patients also had altered salivary microbiomes. 102 individuals with cirrhosis were studied including 43 of them who previously had hepatic encephalopathy (HE), a severe result of liver disease that results in confusion, coma, and can even lead to death.

Patients who previously had HE saw a decrease in bacteria in their saliva that were normally in the body and an increase in bacteria that were pathogenic, including Enterobacteriaceae and Enterococcaceae, Similar results were found in their stool samples. Of the 102 patients, 38 of them were hospitalized within 90 days of the study.  Those 38 individuals had greater salivary dysbiosis than those who were not hospitalized.

They also looked at an additional 43 individuals without cirrhosis and 43 with cirrhosis and looked at the inflammatory profile in the saliva. They found that the cirrhosis patients had immune deficiencies that were similar to that in the gut.

This study showed that the salivary microbiome was similar to the fecal microbiome in patients with cirrhosis. This provides evidence that you may be able to use saliva to predict the disease severity of patients with the disease as well as providing a tool for testing treatment options for patients with the disease. 

Microbiome link between cystic fibrosis and liver disease

Scientists have discovered a possible link between the microbiome and liver disease in individuals with cystic fibrosis.  Cystic fibrosis (CF) is a genetic disease that can be fatal and affects 30,000 people in the United States with another 1,000 diagnosed every year. While pulmonary disease is the most common cause of death in patients with CF, liver disease results in 2.5% of deaths and occurs in up to 72% of patients with the disease.  Approximately 5-7% of  these liver diseased CF patients have cirrhosis, a disease marked by the replacement of healthy liver tissue with scar tissue, preventing the liver from properly functioning.

A team of scientists from University of Colorado Medical Center recently published a study pertaining to CF patients with liver disease  in PLoS One. They studied 11 adolescents with CF and cirrhosis as well as 19 age-matched adolescents with CF without liver disease. They found that the two groups of patients had different gut microbiomes, leading the researchers to believe that there is communication between the gut bacteria and the liver, specifically in CF patients.

Patients with CF and cirrhosis had more severe lesions in their intestines than those without liver disease. Also, specific bacteria were less abundant in cirrhosis patients (e.g. Bacteroidetes) and others more abundant (e.g. Firmicutes) compared to CF patients without liver disease.    Similar ratios have been seen in other studies of liver disease and obesity.  However, we must remember that in complex diseases like CF, the microbiome is only one component of a very dynamic ailment, and at least one other disease study has measured the opposite Bacteroidetes/Firmicutes abundances.

Despite differences in previous studies and the lack of a mechanism relating the microbiome to cirrhosis, this identification of bacterial differences between CF patients with and without liver diseases is promising. The authors of the study point out that the sample size was small and this was only meant to be a pilot study but further longitudinal studies may now be warranted to investigate the development of cirrhosis in cystic fibrosis patients.