Scientists from the Babraham Institute near Cambridge in collaboration with colleagues from Brazil and Italy have discovered a way that good bacteria in the gut can control genes in our cells. The work, published today (9th January) in Nature Communications, shows that chemical messages from bacteria can change the location of key chemical markers throughout the human genome. By communicating in this way, the bacteria may help to fight infections and to prevent cancer.
This work, led by Dr Patrick Varga-Weisz shows how chemicals produced by bacteria in the gut from the digestion of fruit and vegetables can affect genes in the cells of the gut lining. These molecules, called short chain fatty acids, can move from the bacteria and into our own cells. Inside our cells, they can trigger processes that change gene activity and that ultimately affect how our cells behave.
This new research shows that the short chain fatty acids increase the number of chemical markers on our genes. These markers, called crotonylations, were only discovered recently and are a new addition to the chemical annotations in the genome that are collectively called epigenetic markers. The team showed that short chain fatty acids increase the number of crotonylations by shutting down a protein called HDAC2. Scientists think that changes in crotonylation can alter gene activity by turning genes on or off.
The team studied mice that had lost most of the bacteria in their gut and showed that their cells contained more of the HDAC2 protein than normal. Other research has shown that an increase in HDAC2 can be linked to an increased risk of colorectal cancer. This could mean that regulating crotonylation in the genome of gut cells is important for preventing cancer. It also highlights the important role of good bacteria and a healthy diet in this process.
This research was made possible by support from the bilateral BBSRC-Brazil fund established as part of an agreement between Research Councils UK (RCUK) and the State of Säo Paulo Research Foundation (FAPESP) to welcome, encourage and support collaborative research between the UK and Brazil.
First author, Rachel Fellows, said: “Short chain fatty acids are a key energy source for cells in the gut but we’ve also shown they affect crotonylation of the genome. Crotonylation is found in many cells but it’s particularly common in the gut. Our study reveals why this is the case by identifying a new role for HDAC2. This, in turn, has been implicated in cancer and offers an interesting new drug target to be studied further.”
Lead scientist Dr Patrick Varga-Weisz, said: “Our intestine is the home of countless bacteria that help in the digestion of foods such as plant fibres. They also act as a barrier to harmful bacteria and educate our immune system. How these bugs affect our cells is a key part of these processes. Our work illuminates how short chain fatty acids contribute to the regulation of proteins that package the genome and, thus, they affect gene activity.”
Rachel Fellows, Jérémy Denizot, Claudia Stellato, Alessandro Cuomo, Payal Jain, Elena Stoyanova, Szabina Balázsi, Zoltán Hajnády, Anke Liebert, Juri Kazakevych, Hector Blackburn, Renan Oliveira Corrêa, José Luís Fachi, Fabio Takeo Sato, Willian R. Ribeiro, Caroline Marcantonio Ferreira, Hélène Perée, Mariangela Spagnuolo, Raphaël Mattiuz, Csaba Matolcsi, Joana Guedes, Jonathan Clark, Marc Veldhoen, Tiziana Bonaldi, Marco Aurélio Ramirez Vinolo, and Patrick Varga-Weisz; Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases; Nature Communications (2018) DOI: 10.1038/s41467-017-02651-5
Work at the Babraham Institute is possible thanks to the Biotechnology and Biological Sciences Research Council (BBSRC). This work included funding from the Medical Research Council, São Paulo Research Foundation (FAPESP), Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health.
Dr Juri Kazakevych, cells in the lining of the mouse large intestine showing DNA in red and crotonylation in green.
Affiliated Authors (in author order):
Rachel Fellows, Jérémy Denizot, Claudia Stellato, Payal Jain, Elena Stoyanova, Szabina Balázsi, Zoltán Hajnády, Anke Liebert, Juri Kazakevych, Hector Blackburn, Hélène Perée, Mariangela Spagnuolo, Raphaël Mattiuz, Csaba Matolcsi - Nuclear Dynamics Laboratory, Babraham Institute
Joana Guedes, Marc Veldhoen - Lymphocyte Signalling & Development Laboratory, Babraham Institute
Jonathan Clark - Facility Head, Biological Chemistry Facility, Babraham Institute
Patrick Varga-Weisz - Group Leader, Nuclear Dynamics Laboratory, Babraham Institute
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.
All experimental protocols in this publication that were performed at the Babraham Institute were approved by the Babraham Research Campus Animal Welfare and Ethical Review Body (AWERB) and the Home Office (PPL 80/2488 and 70/8994).
The antibiotics treatment experiments were performed at the University of Campinas. Male C57BL/6 mice at age 8-12 weeks were provided by the Multidisciplinary Centre for Biological Investigation (CEIMB) and all the experimental procedures were approved by the Ethics Committee on Animal Use of the Institute of Biology, University of Campinas (protocol number 3742-1). Number of animals used was kept to a minimum. Mice of equivalent age and breed were randomly put in experimental groups.
Some experiments were performed using gut organoid cultures, which is an important step towards implementing ‘The 3Rs’ as it represents an approach that replaces some of the need for animal experiments.
Please follow the link for further details of the Institute’s animal research and our animal welfare practices: http://www.babraham.ac.uk/about-us/animal-research.
About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.
09 January 2018