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Alcoholic hepatitis is a liver disease associated with excessive drinking and treatment is limited. Animal experiments show that viral therapy can “cope” with the microorganisms that cause the disease.

In 1984, a microbiologist, Barry Marshall, performed a groundbreaking experiment. He took himself as an experimental subject and drank a whole flask of Helicobacter pylori (Helicobacter pylori) just to prove that this bacteria can cause Stomach ulcers [1] . Duan Yi et al. [2] A recent study published in Nature also explored the relationship between bacteria and disease, but did not take such an extreme approach . They are studying a liver disease called “alcoholic hepatitis”. By conducting mouse studies and analyzing samples of patients with alcoholic liver in detail, the researchers found a “bacterial culprit” that may be closely related to the disease.

Alcoholic hepatitis is related to excessive alcohol consumption, and because the disease is not well understood, treatment is difficult. Previous experiments in mice have shown that the disease may be related to Enterococcus faecalis (Enterococcus faecalis) inhabiting the intestinal tract [3] . However, Enterococcus faecalis is very common throughout the evolutionary tree. From humans to nematode worms, this bacterium is present in the intestines of many organisms. >. In healthy people, Enterococcus faecalis accounts for less than 0.1% of all fecal bacteria and is less than [5] . However, after antibiotic treatment, the number of Enterococcus species will increase significantly, becoming one of the most common microorganisms in the intestine [6] . Enterococcus faecalis can cause bacteremia and cause dental infections after heart, bladder, brain and root canal surgery. [7,8] .

Duan Yi and colleagues analyzed human fecal specimens. They found that Enterococcus faecalis was present in the stool of 80% of patients with alcoholic hepatitis, and about 30% of the Enterococcus faecium strains contained genes encoding the toxin “cytolysin”. In addition, compared with the control group without alcoholic hepatitis, the fecal Enterococcus faecalis content in patients with alcoholic hepatitis was nearly 3000 times higher. Of course, this is not enough to prove this fineBacteria are the cause. However, experimental data also showed that cytolysin in stool specimens is associated with disease mortality: 89% of patients with alcoholic hepatitis with cytolysin in stool will be hospitalized Death within 180 days; only 3.8% of patients died of the toxin in their stool.

Next, the researchers further examined the relationship between Enterococcus faecalis and liver disease in mice. They first colonized Enterococcus faecalis in the mouse intestines-some strains produce cytolysin and some cannot. The researchers then fed the mice a high-alcohol diet and a non-alcoholic diet. It was finally found that Only those mice that ate a high-alcohol diet and enterococcus faecalis could produce cytolysin in liver damage. > (See Figure 1a) .

Figure 1 | Alcoholic hepatitis.

Duan Yi et al. [2] reported the study of mice with alcoholic hepatitis and the analysis of fecal samples from patients with alcoholic hepatitis .

a) The authors found that alcoholic hepatitis is related to enterocologenous enterococcus faecalis. These bacteria can damage or kill liver cells. Researchers believe that a high-alcohol diet increases the permeability of the intestinal wall, allowing bacteria to transfer from the gut to the liver.

b) To find new treatments for alcoholic hepatitis, researchers have tried using phage, a virus that targets cytolysin-producing Enterococcus faecalis as a specific target. After phage treatment, mice infected with Enterococcus faecalis on a high-alcohol diet did not develop alcoholic hepatitis.

The researchers then isolated an Enterococcus faecium strain with or without cytolysin from stool samples of patients with alcoholic hepatitis and transplanted the strain into sterile mice (without natural microorganisms) . It was found that mice that ingested a high-alcohol diet and had cytolysin-producing Enterococcus faecalis in the intestine had a series of hepatocyte damage or death; they received the same diet but intestinal colonization did not produce lysing Enterococcus faecalis mice did not show similar symptoms.

To further investigate the pathogenic mechanism of Enterococcus faecalis, the researchers isolated liver cells from mice and found that cell death caused by cytolysin was dose-dependent. Regardless of whether the mice ate a high-alcohol diet, their liver cells responded to cytolysins the same. This shows that alcohol does not directly damage liver cells, leading to alcoholic hepatitis, but by increasing the permeability of the intestinal wall, the enterococcus faecalis producing cytolysin is transferred from the intestine to the liver, causing corresponding disease symptoms (Figure 1a) .

Considering that the current treatment options for alcoholic hepatitis are limited, the researchers further explored the possibility of bacterial phages (referred to as phage) — This virus is known to target specific bacteria. Compared with antibiotics, phages are more specific and can avoid killing beneficial bacteria. In addition, due to the large difference between the surface of human cells and the surface of bacterial cells, generally do not think that phages will infect animal or human cells. [9] .

Bacteriophage is used to treat human intestinal Salmonella (Salmonella) and Shiga (Shigella) has been infected for nearly 100 years. (Clostridium difficile) [11,12] . EverIt has been proposed that bacteriophages may be used in the future to reshape human or animal intestinal microbial communities. (ie, the microbiome) Bacteria, less pathogenic bacteria [13] . The feasibility of Enterococcus faecalis phage in treating human diseases has also been discussed in the literature. [7] , phage can kill human bone infections and wounds [14,15] and drug-resistant Enterococcus faecalis in dental cavity infections [16]. In addition, phages for the food industry are also under development. People hope to remove faecal enterococci from cheese medium and reduce the production of toxic waste. [17] .

To test whether there is a method for targeted removal of cytolysin-producing Enterococcus faecalis in mice, the researchers identified some phages specifically targeting Enterococcus faecalis. (Figure 1b) , and these phages do not affect other intestinal bacteria. The researchers transplanted human feces into the intestines of mice and fed a high-alcohol diet. Then some mice received enterococcus faecalis-specific phages at the same time, and the remaining mice received phages against a rare bacteria. It was found that mice receiving Enterococcus faecalis-specific phage had significantly less liver damage than the other group.

Research has proved the superiority of using phage to explore the relationship between microorganisms and disease incidence. Researchers have shown that phages can be used not only to find bacteria associated with disease development, but also to provide more options for treatment. However, to evaluate whether the phage method can be used in humans, further experiments, including clinical trials, are needed. For example, could phage therapy help target Enterococcus faecalis in the gut before patients undergoing a liver transplant.

Duan Yi and colleagues used bacteriophage to treat a group of diseases caused by intestinal bacteria, but the symptoms occur outside the intestine. Most of the research on phages revolves around the treatment of drug-resistant bacteria, and the research by Duan Yi et al. proved the broader clinical possibilities of phages.


1.Marshall, BJ, Armstrong, JA, McGechie, DB & Glancy, RJ Med. J. Aust. 142, 436– 439 (1985).

2.Duan, Y. et al. Nature 575, 505–511 (2019).

3.Llorente, C. et al. Nature Commun. 8, 837 (2017).

4. Van Tyne, D. & Gilmore, MS Annu. Rev. Microbiol. 68, 337–356 (2014). < / span>

5. Lebreton, F. et al. Cell 169, 849–861 (2017).

6. Ubeda, C. et al.J. Clin. Invest. 120, 4332–4341 (2010).

7.Bolocan, A. S. et al. Viruses 11, 366 (2019).

8. Arias, CA & Murray, BE Nature Rev. Microbiol. 10, 266–278 (2012).

9.Nguyen, S. et al. mBio 8, e01874–17 (2017).

10.Abedon, ST, Kuhl, SJ, Blasdel, BG & Kutter, EM Bacteriophage 1, 66-85 (2011).

11.Nale, JY, Chutia, M., Carr, P., Hickenbotham, PT & Clokie, MRJ Front. Microbiol. 7, 1383 (2016).

12.Nale, JY, Redgwell, TA, Millard, A. & Clokie, MRJ Antibiotics 7, 13 (2018). < / span>

13.Whiteson,K. L. mSystems 3, 00166-17 (2018).

14. Melo, LDR, Ferreira, R., Costa, AR, Oliveira, H. & Azeredo, J. Sci. Rep . 9, 6643 (2019).

15.Barros, J. et al. Int. J. Antimicrob. Agents 54, 329–337 (2019).

16.Al-Zubidi, M. et al. Infect Immun. 87, e00512-19 (2019).

17.del Rio, B. et al. Front. Microbiol. 10, 566 (2019).

Microbial clues to a liver disease Title published on “Natural” News and Perspectives on November 13, 2019

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