Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity

Harmit S Ranhotra,Subhajit Mukherjee,Martina Brave,Sridhar Mani,Kyle L Flannigan,Simon A Hirota,Dana J Lukin

doi:10.11131/2016/101199

Harmit S Ranhotra, Subhajit Mukherjee + Show 5 more

Open Access

https://doi.org/10.11131/2016/101199

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Abstract

The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.

Highlights

The alimentary canal is a site for a large population of different microbiota which contribute towards dietary digestion and absorption of nutrients, immunity and many other functions
AgiAl demonstrated that Farnesoid X receptor (FXR) activation has a positive influence on intestinal barrier structures and functions including a protective role in inflammatory bowel diseases (IBDs) mediated via antagonizing the Toll-like Receptor (TLR) 4/TNFα and NF-κB signaling in mice colonic mucosa and several types of immune cells [178,179,180]
There is a panoply of NRs (e.g., FXR, PPARγ, RORγt) [207,208,209,210], expressed in the intestinal epithelium as well as innate immune cells, that

Summary

Intestinal Barrier Function and IBD

The alimentary canal is a site for a large population of different microbiota (eukaryotes, archaea, bacteria and viruses) which contribute towards dietary digestion and absorption of nutrients, immunity and many other functions. But which needs to be proven by experiments is that the indole sensing pathway might get negatively regulated in the presence of “transient pathogens” or “indole-metabolizing bacteria”, which would result (based on our model) in a more permeable intestinal barrier due to loss of PXR signaling This could result in increased luminal sensing of these pathogens by sub-mucosal lymphoid cells and resulting inflammatory response could act to prevent invasion by these species. Using other AhR-responsive genes like Cyp1B1, the AhR repressor (Ahrr), and TCDD-inducible poly (ADP-ribose) polymerase (TiParp) showed complicated pattern of AhR agonist and antagonist activities of these metabolites that were both ligand and gene-dependent thereby acting as selective AhR modulators [158] This shows that tryptophan metabolites by modulating AhR transcriptional regulation might be selective and specific players in the control of intestinal epithelial cells interaction with the microbiota in the luminal environment.

Other Host Nuclear Receptors - Bridging With the Symbiotic Microbiota

Findings

Concluding Statements