These findings, reported online in the journal Cell, have implications for better understanding the basis of intestinal inflammatory disorders such as inflammatory bowel disease (IBD) and may offer new opportunities for therapeutic intervention.
The collaboration between UK-based researchers at the Babraham Institute, which receives strategic funding from the BBSRC, and the Medical Research Council’s National Institute for Medical Research provides new insight into how one chemical component found in cruciferous vegetables like broccoli, governs the survival of a special type of white blood cell, part of the body’s front line defence against infections and important in wound repair.
The cells in question, known as intra-epithelial lymphocytes (IELs), exist as a network just beneath the epithelial cells that form the barrier along the body’s surfaces. They play a critical role in monitoring the large number of micro-organisms present in the intestine, keeping infections at bay and maintaining a healthy gut. The research shows for the first time that mice fed a diet low in vegetables rapidly lose these specialised immune cells (IELs) lining the intestinal tract, but not other immune cells.
“This was surprising, since the new diet contained all other known essential ingredients such as minerals and vitamins,” said Dr Marc Veldhoen, senior author of the paper who conducted a large part of these studies in Dr Brigitta Stockinger’s department at the MRC National Institute for Medical Research prior to taking up a position as Group Leader at the Babraham Institute. “I would have expected that cells at the surface would play some role in the interaction with the outside world, but such a clear cut interaction with the diet was unexpected. After feeding otherwise healthy mice a vegetable-poor diet for two to three weeks, I was amazed to see that 70 to 80% of these [protective] cells disappeared.”
IELs are involved in maintaining the integrity of the intestinal surface by preventing bacteria from entering and by stimulating epithelial cell growth. Dr Veldhoen explained, “The consequences of losing these immune cells are two-fold. There is a failure to control the tightly regulated make-up of the intestinal bacteria, normally composed of beneficial species that aid digestive processes but which now contains more opportunistic, potentially harmful bacteria. It also results in a more fragile intestinal lining, elevating the risk of intestinal inflammation.”
The team discovered that a particular receptor molecule present at high levels on IELs – the aryl hydrocarbon receptor (AhR) – is central to understanding the connection between diet, numbers of IELs and a healthy gut. Earlier studies showed that the receptor’s activity can be triggered by dietary ingredients found at high levels in vegetables from the mustard or cabbage families; indole-3-carbinol (I3C) for instance can activate AhR, especially after contact with stomach acid.
Mice fed a purified synthetic diet almost completely devoid of vegetables showed a significant decrease in AhR activity and a loss of IELs, compared to those fed a normal diet, while supplementation of the low vegetable diet with I3C only maintained the intestinal IELs. Mice genetically lacking the AhR receptor were found to have no IELs and to lose control over the microbes living on the intestinal surface, both in terms of their numbers and composition. While the presence of AhR on IELs is directly important for their survival in the intestine, it is not needed for their generation or positioning in the intestine.
Animals lacking AhR activity for either genetic or dietary reasons showed lower levels of antimicrobial proteins, heightened immune activation and greater susceptibility to injury. And when the researchers mildly damaged the intestinal surface in animals eating a diet lacking in vegetables, the mice were not as quick to repair that damage.
Dr Brigitta Stockinger, Head of Division of Molecular Immunology at the National Institute for Medical Research added: “The food we eat plays a crucial role in influencing our immune system and we have been looking at the intricate biology that determines how cells in our intestines maintain an intrinsic protection against microbes. This study in mice is an important step towards increasing our understanding of how environmental signals shape immune responses at barrier sites such as the intestine. Marc Veldhoen’s continuing studies at the Babraham institute will no doubt take this onto the next step.”
The implications to human intestinal immunity are currently not known. However, as an immunologist, Veldhoen says he hopes the findings will generate interest in the medical community, since some of the characteristics observed in the mice, on either a low vegetable diet or lacking AhR, are consistent with some clinical observations seen in patients with inflammatory bowel disease. These include increased levels of immune inflammation, increased susceptibility to intestinal damage, an altered composition and number of the intestinal bacteria and changes in the production of bactericidal factors. Interestingly, epidemiological studies have correlated a diet low in fruit and vegetables with an increased risk of IBD.
“It’s tempting to extrapolate to humans,” he said. “The problem is that there are many other factors that might play a role. It’s already known to be a good idea to eat your greens. Our results provide a molecular basis for the importance of cruciferous vegetable-derived phyto-nutrients as part of a healthy diet.”
The discovery will also enable scientists to ask fundamental questions about the frequent interactions of cells of the immune system with external environmental factors. This was highlighted with the additional finding that IELs present in the mouse skin also crucially depend on the activation of AhR. While the nature of the interactions preserving skin IELs is currently unknown, it may provide a rationale for the reported association between some intestinal and skin disorders, the most frequent of which is psoriasis, as well as diet choices.
The research was funded initially by MRC and also by BBSRC at the Babraham Institute, which undertakes world-leading life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health.
Professor Michael Wakelam, Director of the Babraham Institute said, “This research, in collaboration with the National Institute for Medical Research, is giving important insight into how dietary insufficiencies can adversely impact the immune system. This is also providing a greater understanding of the mechanisms behind intestinal inflammation, which is of direct relevance to promoting a healthier lifespan, supporting BBSRC’s mission to drive advances in fundamental bioscience for better health and wellbeing.”
Notes to editors
Publication details: Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E., Wilhelm, C., and Veldhoen, M. (2011). Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell doi:. 10.1016/j.cell.2011.09.025
About the Babraham Institute
The Babraham Institute undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute receives a total of £22.4M (in 2010-11) in strategic programme grants from BBSRC, The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. For more information see: www.babraham.ac.uk.
For almost 100 years the Medical Research Council (MRC) has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. For more information see www.mrc.ac.uk.
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