Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

Klepsch, Victoria; Moschen, Alexander R.; Tilg, Herbert; Baier, Gottfried; Hermann-Kleiter, Natascha

doi:10.3389/fimmu.2019.01070

Cited by 54 publications

(40 citation statements)

References 198 publications

(271 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are consistent with finding that pharmacologic inhibition of ROR-γt provides therapeutic benefits in mouse models of intestinal inflammation and reduces the frequencies of Th17 cells but not ILC3s [118]. Studies in patients with IBD have shown that Th17 lymphocytes are involved in the pathogenesis of both CD and UC [119][120][121][122][123]. IL-17 expression in the mucosa and serum is increased in Five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function Fine mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the GPBAR1 single-nucleotide polymorphism rs11554825 and PSC (p = 0.010) and UC (p = 8.5 × 10(−7) [106] IBD patients and correlates with an increase in the expression of RORγt and the number of Th17 cells [124][125][126].…”

Section: Rorγt and Ibdsupporting

confidence: 89%

Section: Bile Acid-activated Receptors In Ibdmentioning

confidence: 99%

See 1 more Smart Citation

Bile Acid Signaling in Inflammatory Bowel Diseases

et al. 2020

View full text Add to dashboard Cite

Bile acids are a group of chemically different steroids generated at the host/microbial interface. Indeed, while primary bile acids are the end-product of cholesterol breakdown in the host liver, secondary bile acids are the products of microbial metabolism. Primary and secondary bile acids along with their oxo derivatives have been identified as signaling molecules acting on a family of cell membrane and nuclear receptors collectively known as “bile acid-activated receptors.” Members of this group of receptors are highly expressed throughout the gastrointestinal tract and mediate the bilateral communications of the intestinal microbiota with the host immune system. The expression and function of bile acid-activated receptors FXR, GPBAR1, PXR, VDR, and RORγt are highly dependent on the structure of the intestinal microbiota and negatively regulated by intestinal inflammation. Studies from gene ablated mice have demonstrated that FXR and GPBAR1 are essential to maintain a tolerogenic phenotype in the intestine, and their ablation promotes the polarization of intestinal T cells and macrophages toward a pro-inflammatory phenotype. RORγt inhibition by oxo -bile acids is essential to constrain Th17 polarization of intestinal lymphocytes. Gene-wide association studies and functional characterizations suggest a potential role for impaired bile acid signaling in development inflammatory bowel diseases (IBD). In this review, we will focus on how bile acids and their receptors mediate communications of intestinal microbiota with the intestinal immune system, describing dynamic changes of bile acid metabolism in IBD and the potential therapeutic application of targeting bile acid signaling in these disorders.

show abstract

Section: Rorγt and Ibdsupporting

confidence: 89%

Section: Bile Acid-activated Receptors In Ibdmentioning

confidence: 99%

Bile Acid Signaling in Inflammatory Bowel Diseases

et al. 2020

View full text Add to dashboard Cite

show abstract

“…When directly comparing fat-1 EtOH + LPS vs. WT EtOH + LPS-treated mice, we found an increase in the expression of xenobiotic metabolism genes in fat-1 mice, including Cyp2b10 , Cyp3a11 , and Nr1i3 . Cyp2b10 and Cyp3a11 , both of which are target genes for Nr1i3 , are decreased in expression in ulcerative colitis [ 35 ]. Enrichment of n-3 PUFAs may increase the expression and transcriptional activity of Nr1i3 , providing a robust xenobiotic metabolism response during EtOH and LPS-induced injury and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Hardesty

Warner

Song

et al. 2021

IJMS

View full text Add to dashboard Cite

Chronic alcohol consumption leads to disturbances in intestinal function which can be exacerbated by inflammation and modulated by different factors, e.g., polyunsaturated fatty acids (PUFAs). The mechanisms underlying these alterations are not well understood. In this study, RNA-seq analysis was performed on ileum tissue from WT and fat-1 transgenic mice (which have elevated endogenous n-3 PUFAs). Mice were chronically fed ethanol (EtOH) and challenged with a single lipopolysaccharide (LPS) dose to induce acute systemic inflammation. Both WT and fat-1 mice exhibited significant ileum transcriptome changes following EtOH + LPS treatment. Compared to WT, fat-1 mice had upregulated expression of genes associated with cell cycle and xenobiotic metabolism, while the expression of pro-inflammatory cytokines and pro-fibrotic genes was decreased. In response to EtOH + LPS, fat-1 mice had an increased expression of genes related to antibacterial B cells (APRIL and IgA), as well as an elevation in markers of pro-restorative macrophages and γδ T cells that was not observed in WT mice. Our study significantly expands the knowledge of regulatory mechanisms underlying intestinal alterations due to EtOH consumption and inflammation and identifies the beneficial transcriptional effects of n-3 PUFAs, which may serve as a viable nutritional intervention for intestinal damage resulting from excessive alcohol consumption.

show abstract

“…Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug‐induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as well as its emerging roles in other physiologic and pathologic processes such as energy metabolism and metabolic diseases, infectious diseases, cancer, and inflammatory bowel disease (IBD), as briefly discussed in Sections to , PXR has become an attractive therapeutic target . However, PXR is notorious for promiscuously binding structurally diverse chemicals, including clinical drugs, environmental toxins, and endogenous metabolites, making it a challenging therapeutic target partly because of the perceived difficulty of studying its structure‐activity relationship .…”

Section: Introductionmentioning

confidence: 99%

“…The results of recent clinical and preclinical studies suggest that PXR agonists can be used to treat IBD in a PXR‐dependent way . IBD is characterized by an immune response‐driven inflammation of the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

show abstract

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

Cited by 54 publications

References 198 publications

Bile Acid Signaling in Inflammatory Bowel Diseases

Bile Acid Signaling in Inflammatory Bowel Diseases

Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Contact Info

Product

Resources

About