234 Supplementary Results Box 1. Individual mucosal gene–bacteria associations and their potential biological implications in IBD. Mucosal bifidobacteria positively associate with aryl hydrocarbon receptor (AHR) and ABCtransporter (ABCC1) expression levels The positive association between AHR expression and bifidobacteria could be explained by the fact that Bifidobacterium spp. can produce aromatic lactic acids such as indole-3-lactic acid (out of aromatic amino acids like tryptophan) via aromatic lactate dehydrogenase, which in turn activates the host aryl hydrocarbon receptor.1,2 Activation of the aryl hydrocarbon receptor, a crucial regulator of intestinal homeostasis and immune responses, leads to a reduction of inflammation in intestinal epithelial cells3 and confers immunoprotective effects.4 Another intriguing observation is the positive association between bifidobacteria and host expression of the ABCC1 gene. ABCC1 is a member of the ATP-binding cassette transporters (ABC transporters, and also known as multidrug resistance-associated protein 1, MRP1) that has multiple physiological functions, but it may also confer pathophysiological sequelae, especially in the context of cancer.5 Under physiological circumstances, it detoxifies endogenously generated toxic substances (as well as xenobiotics), protects against oxidative stress, transports leukotrienes and lipids and may facilitate the cellular export and body distribution of vitamin B12. 6 Interestingly, several Bifidobacterium species (e.g. B. animalis, B. longum and B. infantis) can synthesize vitamin B12, which is subsequently absorbed in the large intestine via unknown mechanisms. 7-9 Mucosal bifidobacteria associate with FOSL1, a subunit of the AP-1 transcription factor Associations between mucosal Bifidobacterium bacteria and expression of FOSL1 genes were amongst the top significant individual gene–bacteria interactions. Fos-related antigen 1 (FRA1), encoded by FOSL1, is a subunit of the activator protein 1 (AP-1) transcription factor. In the intestine, the AP-1 transcription factor is commonly activated in response to inflammatory stimuli and has been implicated in IBD.10 More specifically, an interaction may exist between AP-1 activity and the glucocorticoid receptor, which may be part of the anti-inflammatory effects of steroid treatment.11 In steroid-resistant patients with CD, AP-1 activation was primarily observed in the nuclei of intestinal epithelial cells, whereas this activation was restricted to lamina propria macrophages in steroid-sensitive patients.10 This suggests a differing cellular activation pattern of AP-1 activation in steroid-resistant patients where the expression of this transcription factor may interfere with the activity of the glucocorticoid response. In an experimental study in which pregnant mice were supplemented with butyrate, FOS genes, including Fosl1, were observed to be downregulated in the colon and associated with protection against experimentally-induced colitis.12 Although there are currently no reports of potential immune-modulating effects for Fosl1, it has 85% homology with Fosl2, another AP-1 transcription factor. A recent study demonstrated that Fosl2 is important in T-reg development and control of autoimmunity. Interestingly, several GWASs have reported associations of a SNP located in the promoter region of FOSL2 with IBD,1315 and the presence of this SNP was also shown to correlate with FOSL2 expression in blood Chapter 6
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