Tag Archives: Cirrhosis

Genetically-engineered probiotic could be a new way to reduce alcohol-induced health problems

Excessive alcohol consumption leads to painful hangovers and accompanying headaches, fatigue, and nausea. Drinking alcohol has also been linked to a raft of health problems in the human body, including heart disease, cirrhosis, and immune deficiency. One way to avoid those consequences would be to drink less, but researchers in China have introduced another way to mitigate hangovers and other adverse outcomes -; a genetically-engineered probiotic.

In a paper published this week in Microbiology Spectrum, the researchers described their approach and reported that in experiments on mice, the treatment reduced alcohol absorption, prolonged alcohol tolerance, and shortened the animals’ recovery time after exposure to alcohol. The probiotic hasn’t yet been tested on humans, but the authors predicted that if it confers the same benefits, it could present a new way to reduce alcohol-induced health problems, and liver problems in general.

Meng Dong, Ph.D, at the Chinese Academy of Science’s Institute of Zoology, who worked on the study, noted that clinical applications may extend beyond alcohol-related conditions. “We believe that genetically engineered probiotics will provide new ideas for the treatment of liver diseases,” she said.

The human body primarily uses forms of an enzyme called alcohol dehydrogenase, or ADH, to metabolize alcohol. But some variants are more effective than others: Some studies have found that a form called ADH1B, found primarily in East Asian and Polynesian populations, is 100 times more active than other variants. Previous studies on mice have shown that viral vectors genetically engineered to express ADH1B can accelerate the breakdown of alcohol, but that approach hasn’t been shown to be safe in humans.

Motivated by those findings, Dong and her colleagues looked for a safer delivery method, focusing on the probiotic Lactococcus lactis, a bacterium often used in fermentation. They used molecular cloning to introduce the gene for human ADH1B into a bacterial plasmid, which was then introduced into a strain of L. lactis. Lab tests confirmed that the probiotic secreted the enzyme. The researchers encapsulated the probiotic to ensure it would survive against stomach acid, then tested it on 3 groups of 5 mice, each exposed to different levels of alcohol.

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Untreated mice showed signs of drunkenness 20 minutes after exposure to alcohol. When the mice were placed on their backs, for example, they were unable to get back on their feet. But in the group that received a probiotic that expressed human ADH1B, half the mice were still able to turn themselves over an hour after alcohol exposure. A quarter never lost their ability to turn themselves over.

Further tests showed that 2 hours after exposure, blood alcohol levels in the control group continued to rise, while those in the probiotic-treated mice had begun to fall. In addition, the researchers found that treated mice showed lower levels of lipids and triglycerides in their livers, suggesting that the probiotic could alleviate alcohol-related damage to that organ.

The next step, Dong said, is to investigate whether the potential therapeutic effect of the modified probiotic extends to humans.

We are excited about the improvement of recombinant probiotics in acute alcohol-induced liver and intestinal damage.”

Meng Dong, Ph.D, Chinese Academy of Science’s Institute of Zoology

Source:
Journal reference:

Jiang, X., et al. (2023) Oral Probiotic Expressing Human Ethanol Dehydrogenase Attenuates Damage Caused by Acute Alcohol Consumption in Mice. Microbiology Spectrum. doi.org/10.1128/spectrum.04294-22.

Research identifies western diet-induced microbial and metabolic contributors to liver disease

New research from the University of Missouri School of Medicine has established a link between western diets high in fat and sugar and the development of non-alcoholic fatty liver disease, the leading cause of chronic liver disease.

The research, based in the Roy Blunt NextGen Precision Health Building at MU, has identified the western diet-induced microbial and metabolic contributors to liver disease, advancing our understanding of the gut-liver axis, and in turn the development of dietary and microbial interventions for this global health threat.

We’re just beginning to understand how food and gut microbiota interact to produce metabolites that contribute to the development of liver disease. However, the specific bacteria and metabolites, as well as the underlying mechanisms were not well understood until now. This research is unlocking the how and why.”

Guangfu Li, PhD, DVM, co-principal investigator, associate professor in the department of surgery and Department of Molecular Microbiology and Immunology

The gut and liver have a close anatomical and functional connection via the portal vein. Unhealthy diets change the gut microbiota, resulting in the production of pathogenic factors that impact the liver. By feeding mice foods high in fat and sugar, the research team discovered that the mice developed a gut bacteria called Blautia producta and a lipid that caused liver inflammation and fibrosis. That, in turn, caused the mice to develop non-alcoholic steatohepatitis or fatty liver disease, with similar features to the human disease.

“Fatty liver disease is a global health epidemic,” said Kevin Staveley-O’Carroll, MD, PhD, professor in the department of surgery, one of the lead researchers. “Not only is it becoming the leading cause of liver cancer and cirrhosis, but many patients I see with other cancers have fatty liver disease and don’t even know it. Often, this makes it impossible for them to undergo potentially curative surgery for their other cancers.”

As part of this study, the researchers tested treating the mice with an antibiotic cocktail administered via drinking water. They found that the antibiotic treatment reduced liver inflammation and lipid accumulation, resulting in a reduction in fatty liver disease. These results suggest that antibiotic-induced changes in the gut microbiota can suppress inflammatory responses and liver fibrosis.

Li, Staveley-O’Carroll and fellow co-principal investigator R. Scott Rector, PhD, Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research -; are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society. The team recently received a $1.2 million grant from the National Institutes of Health to fund this ongoing research into the link between gut bacteria and liver disease.

Source:
Journal reference:

Yang, M., et al. (2023). Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nature Communications. doi.org/10.1038/s41467-023-35861-1.

The cell sentinel that neutralizes hepatitis B

The hepatitis B virus (HBV) is responsible for one of the most serious and common infectious diseases. Transmitted through biological fluids, it attacks the liver cells. The chronic form of the disease can lead to serious complications, including cirrhosis and liver cancer. There is no effective treatment for the chronic form of the disease, which can only be prevented by vaccination. After identifying a key protein complex that is active when our body is infected by the virus, a team from the University of Geneva (UNIGE) has deciphered the precise functioning of this protective mechanism, opening the way to new therapeutic targets. These results can be read in the journal Nature Structural and Molecular Biology.

Hepatitis B is the most common form of hepatitis. It is a viral disease caused by the hepatitis B virus. It is mainly blood or sexually transmitted. It is up to 100 times more contagious than HIV. By infecting the liver cells, this virus causes a transitory inflammation of this organ that can also evolve towards a chronic infection. This can then lead to serious pathologies, such as cirrhosis or liver cancer. It is estimated that nearly one million people die each year from this disease worldwide. There is no definitive treatment for chronic hepatitis B. The only way to prevent it is to be vaccinated before the disease appears.

In 2016, a UNIGE team led by Michel Strubin, an associate professor in the Department of Microbiology and Molecular Medicine and in the Geneva Centre for Inflammation Research at the UNIGE Faculty of Medicine, revealed a mechanism that is crucial for understanding this disease: when our immune system defends itself against it, a complex — i.e. an interdependent set — of six proteins called SMC5/6, present in our cells, detects the viral DNA and blocks it. The virus then strikes back and produces a specific protein, the X protein. This protein enters the cell and degrades SMC5/6, which is no longer able to play its sentinel role.

A three-step mechanism

Before this discovery, the antiviral function of SMC5/6 was unknown. It was only identified as a key complex for the structural maintenance of our chromosomes. Today, Michel Strubin’s team has made a new breakthrough. In a recent study, conducted in collaboration with the American pharmaceutical company Gilead Sciences, the UNIGE researchers identified the three steps and the specific proteins required for SMC5/6 to play its antiviral role.

”In the first step, a protein of the SMC5/6 complex detects the virus’ DNA and traps it”, explains Fabien Abdul, a senior research and teaching assistant in the Department of Microbiology and Molecular Medicine at the UNIGE Faculty of Medicine and first author of the study. ”Then, a second protein of the complex — SLF2 — takes the trapped DNA of the virus into a sub-compartment of the nucleus of the attacked cell, called the PML body. A third protein — Nse2 — then comes into play and inhibits the virus’ chromosome.”

As SMC is a large family of protein complexes, the researchers also wanted to know whether other ‘members’ of this family were able to bind to hepatitis B viral DNA. ”We discovered that this competence was unique to SMC5/6”, says Fabien Abdul.

Towards new therapeutic targets

To achieve these results, the research team worked on in vitro cell cultures. ”We used molecular biology techniques and more specifically genetic scissors called CRISPR-Cas9. This tool allowed us to cut the DNA strands within the cells and thus delete or modify the gene coding for each protein constituting the SMC5/6 complex. Thanks to this technique, we were able to make one or other of the proteins disappear and thus understand their respective functions within the complex”, explains Michel Strubin, the study’s last author. Based on these observations, the three steps of the antiviral mechanism could be established.

This discovery provides a better understanding of how the complex functions during its antiviral action. It could thus pave the way for the identification of new therapeutic targets to combat the hepatitis B virus. ”The next stage of research will consist of better deciphering the mechanism of inhibition of the virus in the sub-compartment of the cell nucleus”, indicates Aurélie Diman, a postdoctoral researcher in Michel Strubin’s laboratory. Work will also have to be carried out on the X protein, whose role was identified by the UNIGE researchers in 2016, in order to better understand the counter-attack mechanism of hepatitis B against the antiviral activity of the cellular SMC5/6.

Story Source:

Materials provided by Université de Genève. Note: Content may be edited for style and length.

Journal Reference:

  • Fabien Abdul, Aurélie Diman, Bastien Baechler, Dhivya Ramakrishnan, Dmytro Kornyeyev, Rudolf K. Beran, Simon P. Fletcher, Michel Strubin. Smc5/6 silences episomal transcription by a three-step function. Nature Structural & Molecular Biology, 2022; 29 (9): 922 DOI: 10.1038/s41594-022-00829-0
  • Université de Genève