Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease

Table 1

Representative animal studies examining the potential roles of NRs in colitis.

NRs	Study type	Functions and effects	Ref.
PPARγ	Agonist: 5-ASA; PPARγ KO mice	PPARγ is a target of 5-ASA underlying anti-inflammatory effects	[33]
	Agonist: rosiglitazone; IEC-specific PPARγ KO mice	PPARγ expressed in the IEC has an endogenous role in protection against colitis	[34]
	CD4+ T cell-specific PPARγ KO mice	PPARγ in T cells is involved in preventing gut inflammation by regulating adhesion molecules and inflammatory mediators	[37]
	Agonist: pioglitazone; Macrophage-specific PPARγ KO mice	Macrophage-specific PPARγ KO exacerbated colitis, impaired Treg compartment, and increased LP CD8+ T cells	[35]
VDR	Agonist: 1,25(OH)2 D-3; VDR KO mice	VDR preserves the integrity of junction complexes and the healing of the IEC	[58]
	Agonist: 1,25(OH)2 D-3; hVDR Tg and VDR KO mice	VDR signaling attenuates PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis	[60]
	IEC-specific VDR KO mice	Absence of intestinal epithelial VDR affects microbial assemblage and autophagy	[61]
PXR	Agonist: pregnenolone-16alpha-carbonitrile; PXR KO mice	PXR agonist decrease mRNA expression of several NF-κB target genes in a PXR-dependent manner	[74]
	Agonist: rifaximin, rifampicin SR12813, and PCN	Agonists enhanced intestinal epithelial repair by p38 MAP kinase-dependent way	[76]
	Agonist: rifaximin and SR12813	PXR regulates the IEC barrier by modulating cytokine-induced MLCK expression and JNK1/2 activation	[81]
FXR	Agonist: 6E-CDCA, INT-747; FXR KO mice	Colitis was exacerbated in FXR KO mice. FXR activation stabilizes corepressor NCoR on the NF-κB responsive element	[88]
	Agonist: INT-747; FXR KO mice	FXR downregulates the expression of key proinflammatory cytokines and preserves epithelial barrier function	[90]
	Agonist: GW4064	FXR activation attenuated apical Cl (-) currents by inhibiting the expression of CFTR and Na (+)/K (+)-ATPase activity	[94]
RORγt	Inhibitor: digoxin	Digoxin downregulated Th17 cytokines	[102]
	Inhibitor: GSK805	GSK805 provided therapeutic benefit in intestinal inflammation and reduced the frequency of Th17 cells but not ILCs	[103]

NRs, nuclear receptors; PPARγ, proliferator-activated receptor-γ; IEC, intestinal epithelial cells; KO, knockout; LP, lamina propria; VDR, vitamin D receptor; PXR, pregnane X receptor; FXR, farnesoid X receptor; RORγt, retinoid-related orphan receptor gammat; ILCs, innate lymphoid cells.