Environmental influences on gut homeostasis
The integrity of the intestinal barrier has implications for health even beyond the gut. Numerous genetic loci are involved in inflammatory disorders of the gut such as Crohn’s disease or ulcerative colitis and the genetic susceptibility for disease is well documented. However, environmental factors, including smoking, diet, use of antibiotics also play a significant role is development of intestinal diseases. One of the mediators of environmental stimuli is the aryl hydrocarbon receptor, (AHR) a member of the basic helix loop helix PAS domain family of transcription factors, which function as environmental sensors of light, oxygen or in the case of AHR environmental pollutions such as TCDD. It has recently become clear that physiological AHR ligands such as dietary components and tryptophan metabolites, partly generated by bacteria from the microbiota, serve to drive beneficial functions of AHR in the immune system as well as in non-haematopoietic cells. An important aspect of AHR activation is the necessity for tight regulation as prolonged stimulation has detrimental effects.
For this purpose, several feedback mechanisms are in place that curtail AHR activation, notably the AHR induced Cyp1a1 that metabolises AHR ligands and thereby terminates signalling. We have shown that dysregulation of this feedback in intestinal epithelial cells causes a loss of AHR stimulation and phenocopies AHR deficiency with resulting loss of ILC3 and IL-22 production and extreme susceptibility to intestinal infections. This can however be corrected by supplementation of the diet with plant derived substances that increase AHR ligands and provide Cyp1a1 inhibitors. Organoid cultures from mice with dysregulated AHR pathway show hyperproliferation of stem cells and defective differentiation and AHR mutant mice are highly susceptible to colon tumorigenesis. Both can be prevented by dietary supplementation, emphasising the requirement for a functional, regulated AHR pathway in intestinal homeostasis.
PhD, FRS, FMedSci, Group leader
The Francis Crick Institute, London, UK