Changes in gut microbiota can greatly impact alcohol-related liver disease and cancer risk

27 August 2020: The importance of gut microbiota in alcohol-related liver disease and liver cancer has been demonstrated in two studies, presented at The Digital International Liver Congress™ 2020. The key role of microbial biodiversity in the gut was highlighted in a study of fecal microbial transplant, with the technique showing promise as an intervention to improve some aspects of alcohol-related liver disease. A second study used a mouse model to associate changes in gut microbiota with the action of key signalling molecules, mediating the risk of hepatocarcinogenesis.

In recent years, imbalances in gut microbiota, or dysbiosis, have been implicated as contributing to alcoholic liver disease. In cases of chronic alcohol use, reactive oxygen species produced by alcohol metabolism can lead to chronic intestinal inflammation, which in turn can increase gut permeability and alter microbiota composition. This includes expansion of inflammation-associated bacteria such as Proteobacteria, and reduction of protective species such as Faecalibacterium. Increased gut permeability is believed to lead to translocation of gut bacterial DNA and endotoxins to the liver. The latter, in particular, are thought to induce pro-inflammatory toll-like receptor 4 (TLR4) signalling pathways that are associated with hepatocarcinogenesis.

The importance of gut microbiota raises the possibility of exploiting its manipulation to improve patient outcomes. The first study tested whether fecal microbial transplant (FMT) – the transfer of fecal bacteria from a healthy individual to a patient – could reduce cravings for alcohol as the first step for use in subsequent larger trials. In a pilot, double-blind, placebo-controlled, randomized clinical trial, 20 patients with alcohol use disorder (AUD) and liver cirrhosis, who had tried several options to quit alcohol unsuccessfully, were given FMT or placebo, with FMT shown to reduce alcohol cravings as well as total and psychosocial sickness impact profile at Day 15 post-treatment. A corresponding significant increase in microbiota diversity was seen in FMT patients compared with baseline (p=0.02), including a higher relative abundance of Odoribacter. Alistipes and Roseburia were also more abundant in patients given FMT compared with placebo at Day 15.

‘FMT was safe and shown to have an impact on reducing short-term alcohol cravings and improving psychosocial quality of life in patients with cirrhosis and AUD’, added study presenter Dr Jasmohan S Bajaj of McGuire VA Medical Center, USA. ‘The relative abundance of short-chain fatty acid-producing bacteria identified in patients with higher diversity after FMT demonstrates that altering the gut-brain axis is a potential avenue to alleviating AUD in those with cirrhosis’.

A second study explored how gut microbiota may affect the process of developing hepatocellular carcinoma, using mice that have been genetically engineered to develop steatohepatitis (NEMO?hepa mice). By crossing these mice with others that have had other genes involved in the inflammatory response to bacteria inactivated, and then altering the gut microbial balance with broad-spectrum antibiotics, the research team showed that knocking out the NLRP6 receptor (a key mediator of colonic homeostasis that can cause intestinal dysbiosis if deficient) leads to more severe steatohepatitis and a higher tumour burden. The degree of intestinal barrier permeability was highly correlated with tumour burden as well as several indicators of inflammation in the liver. Crucially, this immune phenotype could be transferred to other mice by FMT, provided they had functional TLR4 signalling, and could be reversed if the transplanted microbiota were depleted with broad-spectrum antibiotics.

‘Strikingly, we also found that replacing depleted Akkermansia muciniphila bacteria in the guts of these mice helped ameliorate their inflammation and steatohepatitis’, said Dr Kai Markus Schneider of University Hospital RWTH Aachen, Germany. ‘This knowledge of how short-term changes to microbiota reshape the hepatic tumour microenvironment has the potential to reveal new therapeutic options for cancer prevention and therapy’.

‘The understanding of interactions between the human and microbiome genome (metagenome) in health and disease has represented one of the major areas of progress in the last few years’, said Professor Luca Valenti, an EASL Scientific Committee member from the University of Milan, Italy. ‘These studies lay the groundwork for exploiting this new knowledge for the treatment of liver disease’.

###

About The International Liver Congress™

This annual congress is EASL’s flagship event, attracting scientific and medical experts from around the world to learn about the latest in liver research and exchange clinical experience. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is being held entirely digitally due to the global health situation. The Digital International Liver Congress™ 2020 will take place from 27-29 August 2020. For more information on attendance and registration, please visit https://ilc-congress.eu/.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,500 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education, and promoting changes in European liver policy.

Contact

For more information or to speak to an expert, please contact Sean Deans in the ILC Press Office at:

* Email: [email protected]

* Telephone: +44 (0) 1444 811099

Session details

Session title: General session I

Date and time of session: Thursday 27 August 2020,14.00-14.15

Presenter: Kai Markus Schneider

Abstract: Gut microbiota drives hepatocarcinogenesis by promoting TLR4-dependent expansion of monocytic myeloid-derived suppressor cells

Session title: Alcohol-associated liver disease

Date and time of session: Thursday 27 August 2020, 11.30-11.45

Presenter: Jasmohan S Bajaj

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

Author disclosures

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

References

1. Meroni M, et al. Alcohol or gut microbiota: who is the guilty? Int J Mol Sci. 2019;20(18):4568.

2. Engen, PA, et al. The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol Res. 2015;37(2):223-36.

3. Bjørkhaug ST, et al. Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption. Gut Microbes. 2019;10(6):663-75.

4. Li F, et al. Microbiome dysbiosis and alcoholic liver disease. Liver Res. 2019;3(3-4):218-26.

5. Wan MLY, El-Nezami H. Targeting gut microbiota in hepatocellular carcinoma: probiotics as a novel therapy. Hepatobiliary Surg Nutr. 2018;7(1):11-20.

6. Levy M, et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signalling. Cell. 2015;163(6):1428-43.