Macrophages treated with the short-chain fatty acid butyrate – a by-product of dietary fiber breakdown – are better equipped to fight bacteria in the gut, report researchers from the Kennedy Institute and the Translational Gastroenterology Unit. These findings could lead to new strategies to restore gut health in inflammatory bowel disease (IBD).
The research, published in Immunity, shows that macrophages produce more bacteria-busting antimicrobial peptides and clear bacteria faster if treated with butyrate during their development. And when mice were fed butyrate, the animals became more resistant to intestinal infection.
Butyrate is a naturally occurring short-chain fatty acid produced by gut microbes as they break down dietary fiber. Although previous studies have linked butyrate to gut health, this is the first report to show that butyrate can increase immunity against harmful bacteria in the intestine.
“Importantly, butyrate bolsters macrophage antimicrobial activity without inducing inflammation.” says Kennedy Director Professor Fiona Powrie, who co-led the study together with Professor Holm Uhlig, a Principal Investigator at the Translational Gastroenterology Unit, Oxford.
Fiona adds, “This is particularly exciting in the context of IBD where the butyrate pathway could be targeted to promote beneficial macrophage responses and re-establish homeostasis”.
IBD are chronic painful diseases, which include conditions such as Crohn’s disease and ulcerative colitis, affecting approximately 5 million people worldwide. Defective antimicrobial responses are thought to contribute to IBD, and high numbers of inflammation-promoting macrophages in the gut are linked to severe disease.
Speaking of the research, Holm said “Since the level of butyrate in the gut of patients depends on diet as well as specific members of the microbiota that can metabolise plant fibers into butyrate, this study is potentially not only relevant for treatment but also for understanding how prevention or maintenance of remission can be achieved”.
The team found that butyrate re-wired the metabolism of developing macrophages and activated a distinct set of genes to drive the accumulation of non-inflammatory antimicrobial macrophages. They went on to show that butyrate mediates these effects by restraining the activity of enzyme histone deacetylase 3 (HDAC3).
The researchers are now examining intestinal macrophages isolated from IBD patients to understand whether defects in metabolic signaling contribute to the development of disease.
The ongoing collaboration between the Powrie and Uhlig laboratories is part of a wider partnership between the Kennedy Institute, the Translational Gastroenterology Unit and the MRC Weatherall Institute of Molecular Medicine within the NIHR Oxford Biomedical Research Centre (BRC) Gastroenterology and Mucosal Immunity Theme, which ultimately seeks to drive new therapies and personalised medicine approaches for inflammatory gastrointestinal and skin diseases into the clinic.
The work was funded by the Wellcome Trust, the BBSRC, the Helmsley Charitable Trust, and the Crohn’s & Colitis Foundation, with contribution from the BRC Gastrointestinal biobank supported by the NIHR BRC.