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

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

doi:10.11131/2016/101199

Cited by 34 publications

(36 citation statements)

References 215 publications

(234 reference statements)

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“…However, these receptors can also act as important regulators of inflammation and immunity, especially in the intestine. 27,[39][40][41] The PXR, a master regulator of the human drug metabolism enzyme CYP3A4 (CYP3A11 in mice), is expressed throughout the intestine and liver where it can "sense" endogenous and exogenous substances. At these sites, activation of the PXR can also exert anti-inflammatory and pro-healing effects.…”

Section: Discussionmentioning

confidence: 99%

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

et al. 2019

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Clostridioides difficile (formerly Clostridium difficile; C difficile), the leading cause of nosocomial antibiotic-associated colitis and diarrhea in the industrialized world, triggers colonic disease through the release two toxins, toxin A (TcdA) and toxin B (TcdB), glucosyltransferases that modulate monomeric G-protein function and alter cytoskeletal function. The initial degree of the host immune response to C difficile and its pathogenic toxins is a common indicator of disease severity and infection recurrence. Thus, targeting the intestinal inflammatory response during infection could significantly decrease disease morbidity and mortality. In the current study, we sought to interrogate the influence of the pregnane X receptor (PXR), a modulator of xenobiotic and detoxification responses, which can sense and respond to microbial metabolites and modulates inflammatory activity, during exposure to TcdA and TcdB. Following intrarectal exposure to TcdA/B, PXR-deficient mice (Nr1i2 −/− ) exhibited reduced survival, an effect that was associated with increased levels of innate immune cell influx. This exacerbated response was associated with a twofold increase in the expression of Tlr4. Furthermore, while broad-spectrum antibiotic treatment (to deplete the intestinal microbiota) did not alter the responses in Nr1i2 −/− mice, blocking TLR4 signaling significantly reduced TcdA/B-induced disease severity and immune responses in these mice. Lastly, to assess the therapeutic potential of targeting the PXR, we activated the PXR with pregnenolone 16α-carbonitrile (PCN) in wild-type mice, which greatly reduced the severity of TcdA/B-induced damage and intestinal inflammation. Taken together, these data suggest that the PXR plays a role in the host's response to TcdA/B and may provide a novel target to dampen the inflammatory tissue damage in C difficile infections. K E Y W O R D SClostridioides difficile, eosinophils, neutrophils, Nr1i2, pregnane X receptor, toxinThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionmentioning

confidence: 99%

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

et al. 2019

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“…IPA and IAA are proposed as beneficial indole derivatives produced by desirable genera within the gut microbiome (40,53). Studies have correlated IPA and IAA levels with better prognosis for individuals with type 2 diabetes, Crohn's disease, and inflammatory bowel disease (49,(52)(53)(54)(55). IPA was also in clinical trials for its effect against Alzheimer's disease (56,57).…”

Section: Discussionmentioning

confidence: 99%

“…Curiously, these same derivatives act, via an unknown mechanism, as antibacterials against Legionella pneumophila (44)(45)(46) and Mycobacterium tuberculosis (47,48), and possess antiinflammatory properties (40,(49)(50)(51). High levels of these indole derivatives in peripheral circulation correlate with protection against inflammatory bowel disease, Crohn's disease, and type 2 diabetes (49,(52)(53)(54)(55); one of them was in clinical trials as an antiinflammatory that reduces Alzheimer's disease progression (56,57).…”

Section: Significancementioning

confidence: 99%

Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates

Sherchand

Aiyar

2019

Proc. Natl. Acad. Sci. U.S.A.

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A striking difference between genital and ocular clinical isolates of Chlamydia trachomatis is that only the former express a functional tryptophan synthase and therefore can synthesize tryptophan by indole salvage. Ocular isolates uniformly cannot use indole due to inactivating mutations within tryptophan synthase, indicating a selection against maintaining this enzyme in the ocular environment. Here, we demonstrate that this selection occurs in two steps. First, specific indole derivatives, produced by the human gut microbiome and present in serum, rapidly induce expression of C. trachomatis tryptophan synthase, even under conditions of tryptophan sufficiency. We demonstrate that these indole derivatives function by acting as de-repressors of C. trachomatis TrpR. Second, trp operon derepression is profoundly deleterious when infected cells are in an indoledeficient environment, because in the absence of indole, tryptophan synthase deaminates serine to pyruvate and ammonia. We have used biochemical and genetic approaches to demonstrate that expression of wild-type tryptophan synthase is required for the bactericidal production of ammonia. Pertinently, although these indole derivatives de-repress the trpRBA operon of C. trachomatis strains with trpA or trpB mutations, no ammonia is produced, and no deleterious effects are observed. Our studies demonstrate that tryptophan synthase can catalyze the ammonia-generating β-elimination reaction within any live bacterium. Our results also likely explain previous observations demonstrating that the same indole derivatives inhibit the growth of other pathogenic bacterial species, and why high serum levels of these indole derivatives are favorable for the prognosis of diseased conditions associated with bacterial dysbiosis.Chlamydia trachomatis | genital and ocular serovars | tryptophan synthase β-elimination | serine deamination | trp operon de-repression

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“…We have previously shown that PXR activation down-regulates TLR4 mRNA expression leading to inhibition of NF-κB signaling 2,35,36 . We have also shown that FKK5 and FKK6 interact directly with PXR LBD and result in its activation.…”

Section: Characterization Of Fkk5 and Fkk6 On Pxr-tlr4 And Nf-κb Signmentioning

confidence: 99%

“…We have also shown that FKK5 and FKK6 interact directly with PXR LBD and result in its activation. Thus, to determine the effect of FKK5 and FKK6 on the PXR-TLR4-NF-κB signaling pathway, we used PXR-transfected Caco-2 cells and exposed these cells to FKK5 and 6 since undifferentiated Caco-2 cells inherently have low PXR expression (not detected) but relatively higher TLR4 expression and are excellent in vitro models for the study of enterocyte function [36][37][38][39] . FKK5 and FKK6 down-regulates TLR4 (0.39-fold and 0.49-fold, respectively) but up-regulates CYP3A4 (3.7-fold and 3.29-fold, respectively) and MDR1 (5.12-fold and 6.45-fold, respectively) mRNA expression ( Fig.…”

Section: Characterization Of Fkk5 and Fkk6 On Pxr-tlr4 And Nf-κb Signmentioning

confidence: 99%

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

Dvořák

Kopp

Costello

et al. 2019

Preprint

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The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as firstin-class PXR selective non-cytotoxic agonists, as a proof-of-concept for microbial metabolite mimicry.The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in humanized mice. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

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

Cited by 34 publications

References 215 publications

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

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