Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

Qiu, Zhijuan; Cervantes, Jorge; Cicek, Basak B.; Mukherjee, Subhajit; Venkatesh, Madhukumar; Maher, Leigh; Salazar, Juan C.; Mani, Sridhar; Khanna, Kamal M.

doi:10.1038/srep31936

Cited by 39 publications

(36 citation statements)

References 21 publications

(32 reference statements)

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“…[128][129][130] The CAR, which is primarily expressed in the liver and small intestine, 131 shares some common ligands with PXR and has overlapping target genes and functions. 137 The decreased intestinal expression of PXR and PXR-target genes was found in IBD patients, and PXR locus may be associated with susceptibility to IBD. [132][133][134][135] PXR is an integral part of maintaining commensalism between gut microbiota and intestinal mucosal homeostasis.…”

Section: Bile Acids-activated Receptorsmentioning

confidence: 99%

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

Song

Khan

et al. 2019

Intl Journal of Cancer

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The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids–microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids–microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.

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Section: Bile Acids-activated Receptorsmentioning

confidence: 99%

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

Song

Khan

et al. 2019

Intl Journal of Cancer

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“…21 In the present study, we observed an increase in Ly6C hi monocyte infiltration into the colonic LP following TcdA/B exposure, an effect that was exaggerated in mice lacking the PXR and correlated with increased levels of inflammation and tissue damage in these mice. Other studies have also shown changes in monocyte responses during enteric infections, 26 suggesting the PXR may play a role somewhere in the inflammatory cascade controlling the dynamics of monocyte responses.…”

Section: Discussionmentioning

confidence: 99%

“…29 This TLR4-PXR signaling axis is not only important in maintaining the integrity of the intestinal epithelium, but can modulate immune responses during enteric infections, 26,61 and thus drove the rationale behind examining the role of the PXR and targeting the TLR4-PXR axis during C difficile toxin-induced inflammation and tissue damage. [26][27][28] This assertation was supported by our finding of increased expression of Tlr4 in the colon of Nr1i2 −/− mice following TcdA/B exposure. Furthermore, blocking TLR4 was able to return the exacerbated immune cell responses and cytokine expression (including G-CSF and IL-6) in Nr1i2 −/− mice to levels similar to WT mice following TcdA/B exposure.…”

Section: Discussionmentioning

confidence: 99%

“…The PXR is highly expressed in the liver and intestine where it can regulate nuclear factor κ-light-chain-enhancer of B cells (NFκB) activation and the expression of a number of inflammatory mediators. 25,26 Importantly, PXR signaling in the intestine can dampen TLR4 signaling to promote intestinal barrier function and prevent inflammation in the GI tract. 25,27 The influence of the PXR in the modulation of enteric infections has also emerged with evidence for the involvement of a PXR-TLR4-driven mechanism.…”

Section: Introductionmentioning

confidence: 99%

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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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“…In human tissues and in a mouse model, PXR activation has been shown to reduce the effect of RIF . Several pathways leading to inflammatory processes have been shown to be controlled by PXR, thus potentially being variable among individuals in terms of appropriate immune response and microbe killing . The high heterogeneity in causes of death did not allow for exploring the association for specific unfavorable outcomes.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Calcagno

Cusato

Sekaggya-Wiltshire

et al. 2019

Clin Pharma and Therapeutics

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Unsatisfactory treatment outcomes have been reported in patients coinfected with HIV/tuberculosis (TB). The aim of this study was to assess the influence of single‐nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis was performed. The impact of SNPs on antitubercular drug exposure, adverse events, and treatment outcomes was evaluated in patients coinfected with HIV/TB receiving treatments for both conditions. In 221 participants, N‐acetyltransferase 2 (NAT2; rs1799930), solute carrier organic anion transporter family member 1B1 (SLCO1B1; rs4149032), and pregnane X receptor (PXR; rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163; 73.8%), yet PXR 63396TT carriers had a higher probability of death (P = 0.007) and of worsening peripheral neuropathy (P = 0.018). In this exploratory study in Ugandan patients coinfected with HIV/TB, genetic variants in PXR, SLCO1B1, and NAT2 were moderately associated with isoniazid exposure, whereas PXR 63396TT carriers showed worse outcomes.

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Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

Cited by 39 publications

References 21 publications

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

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

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

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