Highlight Publication October 2011

Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M.
Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.
Cell. 2011 Oct 28;147(3):629-40
http://dx.doi.org/10.1016/j.cell.2011.09.025

Lay description
Leafy greens, widely recognised as containing essential ingredients for ensuring optimum health and wellbeing, have been shown to influence our intestinal health by delivering a protective factor to certain cells of the immune system. These findings, reported 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 Dr Marc Veldhoen at the Babraham Institute and Dr Brigitta Stockinger, Head of Division of Molecular Immunology at the MRC 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. After feeding otherwise healthy mice a vegetable-poor diet for two to three weeks, 70 to 80% of these [protective] cells disappeared; a surprising finding since the new diet contained all other known essential ingredients such as minerals and vitamins.

IELs are involved in maintaining the integrity of the intestinal surface by preventing bacteria from entering and by stimulating epithelial cell growth. 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; when the intestinal surface was mildly damaged in animals eating a diet lacking in vegetables, the mice were not as quick to repair that damage.

The implications to human intestinal immunity are currently not known. However, it is hoped that 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.

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.

Press release relating to this publication

About the lead author

Marc Veldhoen studied Medical Biology at the Faculty of Medicine, Utrecht University, and continued his career in the Stockinger-lab at the National Institute for Medical Research (Mill Hill) where he obtained his PhD in 2003. During his post-doctoral work at the NIMR he was the first to describe the de novo differentiation of the new Th17 and Th9 subsets of T helper cells. He went on to show the importance of Th17 cells in the initiation of autoimmune responses, their plasticity, and, via the identification of the Aryl Hydrocarbon Receptor in Th17 and IL-17 producing TCRγδ cells, established a link between the environment and auto-immunity. In 2010 he moved to the Babraham Institute to take up a position as group leader. He continued  his work on the AhR and discovered a direct link between dietary phytochemicals and the maintenance of epithelial immune cells. He was awarded a prestigious 2010 ERC Staring Independent Research grant, and selected into the esteemed EMBO young investigator programme in 2011.