You AhR What You Eat: Linking Diet and Immunity
The fact that AhR is required for normal intestinal immune function raises the intriguing question of what compounds trigger intestinal AhR signaling under physiological conditions. Prior work revealed that AhR signaling is triggered by certain tryptophan derivatives that are specific to plants (Ito et al., 2007). These include compounds such as indole-3-carbinol (I3C), which is found at especially high levels in cruciferous vegetables such as broccoli, cabbage, and cauliflower and is converted into high-affinity AhR ligands after encountering the acid environment of the stomach. To test for a dietary origin for the intestinal AhR ligand, Li et al. manipulated the diets of their mice, switching them to a synthetic feed that lacks ingredients of vegetable origin. Remarkably, the altered diet produced a phenotype that mimicked the situation in Ahr−/− mice, including a decline in IEL numbers, enhanced susceptibility to epithelial damage, and increased numbers of intestinal Bacteroides, and these alterations could be mitigated by adding back I3C to the diet. Thus, plant-derived dietary compounds, such as I3C, act through AhR to maintain IELs in the intestinal epithelium and promote normal intestinal immune function.
The Li et al. study significantly expands our understanding of how diet impacts immunity and health by showing that a plant-derived nutrient profoundly shapes the capacity for intestinal immune defense. However, a number of intriguing questions remain. First, how does AhR signaling lead to IEL maintenance in the epithelium? Identification of AhR-regulated pathways within IELs should provide insight into this question and could also potentially identify AhR target genes. Second, are there other dietary ligands for AhR that derive from noncruciferous plant foods, or from animal-derived foods? Given the variety and flexibility of most mammalian diets, a specific dependence on cruciferous vegetables for optimal intestinal immune function would seem overly restrictive. Rather, it seems likely that many other foods contain compounds with similar immunostimulatory properties.
A broader question raised by these studies is why the intestinal immune system has evolved a requirement for exposure to dietary compounds. In most animals, including humans, feeding is accompanied by the ingestion of environmental bacteria, many of which are likely to be pathogenic. Thus, linking heightened intestinal immune activation to food intake could serve to bolster immunity precisely when it is needed. At the same time, this would allow energy to be conserved in times of food scarcity. In many mammals, feeding is also linked to day-night cycles of light and dark, and thus it would be interesting to learn whether stimulation of intestinal AhR occurs in a circadian manner to coincide with food intake.