Bacteriophages as Therapeutic Targets in the Alleviation of Alcoholic Liver Disease Symptoms

Simran Kaur ‘20

Scanning electron micrograph of Escherichia coli
Fig 1. Naturally occurring gut bacteria, such as E. faecalis, can be targeted using bacteriophages.

The acute form of alcohol-induced liver disease, alcoholic hepatitis, has a high mortality rate, and therapy is insufficiently effective. It is known to be promoted by gut microbiota. Cytolysin, a cell-destroying substance secreted by Enterococcus faecalis, is a major cause of hepatocyte apoptosis, consequent liver injury, and progression of hepatic disease. Patients diagnosed with alcohol-dependence present with significantly higher concentrations of E. faecalis in their gut microbiota. Researchers in this experiment hypothesized that cytolysin-targeted bacteriophages, when administered, would decrease hepatic cytolysin amounts and alleviate hepatitis symptoms. 

Mice were used as models in the experiment and were placed on a gradual binge-ethanol diet in order to induce alcoholism. On day 16 of the experiment, the mice were given a large final dose of ethanol (5g/ kg of body weight) and euthanized 9 hours later. 5 x 108 colony-forming units of a cytolytic E. faecalis strain were administered to the experimental group every third day, concurrently with the ethanol-based diet. 1010 plaque-forming units of E. faecalis targeted bacteriophages were gavaged to the experimental mice on day 15 of the experiment. 

The mice that received the ethanol diets and cytolytic E. Faecalis, but not the bacteriophages,  displayed severe hepatic injury, made evident by elevated levels of alanine amino-transferase, and significant hepatic inflammation. Mice that received the bacteriophages presented with lessened hepatic injury and inflammation, and significantly reduced levels of cytolysin in the liver, indicating an improvement in hepatic function. The administration of bacteriophages did not affect intestinal absorption or hepatic metabolism of ethanol. Cytolytic E. faecalis bacteriophages did not affect the composition of the gut microbiota, but significantly reduced fecal amounts of E. faecalis. The results suggest cytolysin levels as an effective biomarker of alcohol-induced hepatitis. However, future studies are necessary to determine the safety of bacteriophages as a therapeutic target in alcohol-induced hepatic disease in human patients. 

References:

  1. Y. Duan, et al., Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease. Nature, (2019). doi: 10.1038/s41586-019-1742-x
  2. Image retrieved from: https://commons.wikimedia.org/wiki/File:E._coli_Bacteria_(16578744517).jpg

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