Altered gut flora can have a significant impact on the risk of alcohol-related liver disease and cancer

August 27, 2020: Two studies presented at the Digital International Liver Congress™ 2020 demonstrate the importance of gut microbiota in alcohol-related liver disease and cancer. A major role of intestinal microbial biodiversity is fecal microbial transplantation, a technique that demonstrates promise as an intervention to improve some aspects of alcohol-related liver disease. In a second study, we used a mouse model to correlate changes in gut microbiota with the actions of key signaling molecules and mediate the risk of hepatocarcinogenesis.

In recent years, imbalance of intestinal flora or enterotoxemia has been thought to contribute to alcoholic liver disease. In the case of chronic use of alcohol, the reactive oxygen species generated by alcohol metabolism cause chronic intestinal inflammation, increase intestinal permeability and alter the composition of the microflora. This includes the spread of inflammation-related bacteria such as Proteobacteria and the reduction of protected species such as Fecalobacteria. Increased intestinal permeability is thought to lead to the transfer of enterobacterial DNA and endotoxin to the liver. In particular, the latter is believed to induce the proinflammatory Toll-like receptor 4 (TLR4) signaling pathway associated with liver carcinogenesis.

The importance of gut microbiota raises the possibility of exploiting its manipulation to improve patient outcomes. In a first study, whether fecal microbial transplantation (FMT), the transfer of fecal bacteria from healthy subjects to patients, could reduce alcohol craving as the first step in subsequent large-scale trials Tested A pilot, double-blind, placebo-controlled, randomized clinical trial attempted several options to discontinue use of alcohol, but failed 20 patients with alcohol use disorder (AUD) and cirrhosis Alcohol cravings shown to reduce FMT when given FMT or placebo, and the impact profile of global and psychosocial illness at day 15 post treatment. A corresponding significant increase in microbiota diversity was seen in FMT patients compared to baseline (p = 0.02). Aristipes and rosebria were also abundant in patients receiving FMT compared to placebo on Day 15.

“FMT has been shown to be safe and to reduce short-term alcohol cravings and improve psychosocial quality of life in patients with cirrhosis and AUD,” said research presenter McGuire VA Medical. Dr. Jasmohan S Bajaj, Center, USA added. “Relative Abundance of Short-Chain Fatty Acid-Producing Bacteria Identified in Highly Diverse Patients After FMT Shows Alteration of the Intestinal Brain Axis as a Potential Tool to Alleviate AUD in Patients with Cirrhosis”

The second study uses mice genetically engineered to develop steatohepatitis (NEMO?hepa mice) to investigate how intestinal flora influences the process of hepatocellular carcinoma development. did. By crossing these mice with other mice that carry other genes involved in the inflammatory response to inactivated bacteria, and altering the gut microbial balance with broad spectrum antibiotics, the NLRP6 receptor (colon homeostasis Research team has shown that deficiency can lead to intestinal bacterial disease), more severe steatohepatitis and higher tumor burden. The degree of intestinal barrier permeability was highly correlated with some indicators of tumor burden and liver inflammation. Importantly, this immunophenotype can be transferred to other mice by FMT, provided it has functional TLR4 signaling, and reverts when the transplanted microbiota is depleted with broad spectrum antibiotics. can do.

“Remarkably, we also found that replacing the depleted Ackermansia muciniphila in the gut of these mice could help improve inflammation and steatohepatitis,” said Dr. Kaimarx Schneider of RWTH Aachen University Hospital in Germany. It was done.” “This knowledge of how short-term changes to the microbiota remodel the liver tumor microenvironment may reveal new therapeutic options for the prevention and treatment of cancer.”

Luca Valenti, a member of the EASL Scientific Committee at the University of Milan, said: “Understanding the interactions between the human and microbiome genomes (metagenomics) in health and disease has been one of the major areas of progress in the last few years,” Italy. “These studies laid the foundation for harnessing this new knowledge for the treatment of liver disease.”

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This annual meeting is an EASL flagship event that brings together scientific and medical professionals from around the world to learn about the latest liver research and exchange clinical experience. The attending experts will present, share, debate, and conclude with the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year’s conference is held entirely in digital format due to global health conditions. Digital International Liver Congress™ 2020 will take place August 27-29, 2020. For more information on attendance and registration, visit https://ILC Congress.I/..

Founded in 1966, the non-profit organization has grown to over 4,500 members worldwide, including many of Europe’s and other major hematologists. EASL is one of Europe’s leading liver associations, developing into a major European association with international influence, in promoting research on liver diseases, supporting broader education, and promoting changes in European liver policy. It has an impressive track record.

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Session title: General Session I

Session Date: Thursday 27th August 2020, 14.00-14.15

Presenter: Kai Markus Schneider

Summary: Gut flora promotes hepatocarcinogenesis by promoting TLR4-dependent proliferation of suppressor cells from monocytic bone marrow

Session title: Alcohol-related liver disease

Session date and time: Thursday, August 27, 2020, 11.30-11.45

Presenter: Jasmohan S Bajaj

Summary: Fecal microbial transplantation reduces short-term cravings and improves quality of life and microbial diversity in cirrhosis and alcohol use disorders: a randomized, placebo-controlled clinical trial

Jasmohan S Bajaj and Kai Markus Schneider have no relevant disclosures.

1. Meloni M, etc. Alcohol or gut flora: who is guilty? Int J Mol Sci. 2019; 20 (18): 4568.

2. Engen, PA etc. Gastrointestinal microbiota: The effect of alcohol on the composition of intestinal microbiota. Alcohol resolution. 2015;37(2):223-36.

3. Bjørkhaug ST etc. Characteristics of composition and function of intestinal flora in patients with chronic alcohol overdose. Gut microbes. 2019; 10 (6): 663-75.

4. Li F et al. Microbiota and alcoholic liver disease. Liver Resolution 2019; 3 (3-4): 218-26.

5. Wan MLY, El-Nezami H. Targeting the intestinal microbiota of hepatocellular carcinoma: probiotics as a novel treatment. Hepatobiliary surgery Nutr. 2018; 7 (1): 11-20.

6. Microbiota-modulating metabolites such as Levy M form the intestinal microenvironment by regulating NLRP6 inflammasome signaling. cell. 2015; 163(6): 1428-43.