Host Nuclear Receptor Activation in the Colon: Consequences for Inflammatory Bowel Diseases and Colorectal Carcinogenesis
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Date
2020-10-28
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Abstract
Inflammatory Bowel Diseases (IBDs) and Colorectal Cancers (CRC) are a complex collection of diseases with limited and invasive treatment options. Therefore, prevention is key but effective methods of doing so are elusive. While it is increasingly accepted that host genetics, the gut microbiota, and environmental exposures including diet can impact disease development and progression, exact mechanisms are still being investigated and results are sometimes conflicting. Host nuclear receptor (NR) activation, including that of the estrogen receptors (ER) and the aryl hydrocarbon receptor (AhR), has been linked to both exacerbation and prevention of these diseases.
One ER ligand present in the diet, bisphenol-A (BPA), has been shown to exert estrogenic activity, but the mechanisms by which it may exacerbate IBDs are unclear. Therefore, the ability of BPA to exacerbate colitis and alter microbial derived metabolites (MDMs) was investigated in mice. BPA not only worsened disease activity, but exposure also slowed recovery, increased inflammation, and reduced levels of several metabolites associated with decreased inflammation. Furthermore, this activity was attributed to the ability of BPA to reduce cell number similarly to 17β-Estradiol in vitro.
Diets high in saturated fat (HFD) have been linked to increased risk for IBDs and CRC, and AhR activation by colonic metabolites has been associated with preventing both diseases. However, the interaction of HFD and AhR in intestinal epithelial cells (IECs) has yet to be established. Therefore, a chemically-induced CRC mouse model lacking AhR in IECs (AhrΔIEC) and fed a HFD was employed to investigate this interaction, and though colon mass incidence was not increased compared to low fat diet (LFD) fed control animals, colon mass multiplicity as well as β-catenin intensity and nuclear localization all increased.
To investigate the impact of the dysbiotic feces observed in AhrΔIEC mice, a fecal transplant model was used. Wild-type mice were treated with antibiotics, then dosed with AhrΔIEC donor feces depleted in Akkermansia muciniphila. A. muciniphila was then gavaged in an attempt to rescue decreased gut barrier integrity associated with AhrΔIEC donors and fecal transplant recipients. While A. muciniphila was not significantly increased in any group that received it compared to respective vehicle controls, antibiotic treated animals without fecal transplant had a significant increase in the relative abundance of A. muciniphila that corresponded with improved gut barrier integrity and an increase in MDMs that act as AhR ligands.
These results demonstrate the complex interactions and varied effects of environmental exposures through diet, the gut microbiome and MDMs, and host NR activation in the colon on the development and progression of IBDs and CRC. Findings such as these will allow the advancement of therapeutics in the prevention of these diseases.
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Nuclear Receptors, Intestinal Epithelial Cell, Inflammatory Bowel Disease, Colorectal Cancer, Microbiome, Metabolites, Bisphenol-A, Estrogen Receptor, Aryl Hydrocarbon Receptor, High Fat Diet, Fecal Transplant, Akkermansia muciniphila