Table 1.

Summary of studies describing ISC-specific modulatory effectors and their association with Human IBD and/or DSS-colitis

ISC-modulating effector/factor	ISC modulation and/or underlying mechanism(s)	Association with Human IBD and/or DSS-colitis
Sirtuin 2 (SIRT2)16	SIRT2- deficient mice show reduced ileal enterocyte and GC differentiation and increased IEC proliferation. SIRT2 inhibits Wnt/β-catenin signaling.	SIRT2 expression markedly reduced in IBD.
SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1)14,15	IEC-specific Setdb1 deletion show reduced GCs and EECs in SI, along with mis-positioning of PCs.	Reduced SETDB1 expression in human IBD and in DSS mice model of colitis; Over-representation of rare missense variants of SETDB1 in human IBD.
Liver Receptor Homolog-1 (LRH-1)18	LRH-1 KO mice show reduced Notch signaling, increased crypt cell death, distortion in epithelial cellular composition. LRH-1 potentiates Wnt/β-catenin signaling and epithelial renewal.	GWAS have implicated LRH-1 in IBD. Human LRH-1 (hLRH-1) rescues epithelial integrity and when overexpressed, mitigates inflammatory damage in murine and human intestinal organoids.
CD4720	CD47 inhibits IEC proliferation and migration by suppressing four Yamanaka transcriptional factors (OSKM – Oct4, Sox2, Klf4 and c-Myc)	CD47 expression enhances in UC and CD as well as in mouse experimental colitis models.
X-box–binding protein 1 (XBP1)21	Hypomorphic variants of XBP1 drive Ire1α–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells.	Hypomorphic variants of ER stress response mediators, such as XBP1, confer genetic risk for IBD

GCs, Goblet cells; IECs, Intestinal epithelial cells; EECs, Enteroendocrine cells; SI, Small Intestine; PCs, Paneth cells; DSS, Dextran Sodium Sulfate; KO mice, Knockout mice