Dataset Information

VGLL4 modulates Paneth cells and sustains intestinal homeostasis.

ABSTRACT: Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 expression. Loss of VGLL4 in the intestinal epithelium decreases Paneth cell numbers and AMPs production, and triggers gut microbiota dysbiosis, impairing intestinal regenerative capacity. Mechanistically, VGLL4 forms a complex with TEAD4 and ATOH1, stimulating GFI1 expression and promoting Paneth cell differentiation. Furthermore, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining microbiota composition. Collectively, our findings uncover novel roles for VGLL4 in intestinal homeostasis.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS10456 | MetaboLights | 2026-03-12

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	a_MTBLS10456_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS10456_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS10456_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS10456_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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VGLL4 modulates Paneth cells and sustains intestinal homeostasis.

Zhang Haoen H Wang Zuoyun Z Wang Xiaodong X Yu Wentao W Zhang Guoying G Zhang Haijiao H Lu Yi Y Sun Yang Y Lu Tiantian T Li Xiaoyu X Yang Ruizeng R Sun Jiaqi J Xu Jinjin J Huang Shuo S Ma Xueyan X Ren Jiale J Tang Nan N Cheng Zhonghua Z Yu Jing J Wei Fang F Zhou Hu H Li Jinsong J Qin Jun J Jin Yunyun Y Zhang Lei L

EMBO reports 20260202

Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 ...[more]

PMID: 41629625

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Project description:BACKGROUND & AIMS: Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our overarching goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis and to identify novel signal transduction pathways that become dysregulated in IBD. METHODS: We have applied a multi-scale systems biology approach to a mouse model of chronic colitis. We combined quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intra-cellular signaling molecules in order to generate a tissue level model of the inflamed disease state. We utilized the computational model to identify signaling pathways that were dysregulated in the context of colitis and then validated model predictions by measuring the effect of small molecule pathway inhibitors on colitis. RESULTS: Our data-driven computational model identified mTOR signaling as a potential driver of inflammation and mTOR inhibition reversed the molecular, immunological, and epithelial manifestations of colitis. Inhibition of Notch signaling, which induces epithelial differentiation, had the same effect, suggesting that the epithelial proliferation/differentiation state plays a key role in maintaining homeostasis of the colon. Confirming this, we found that colonic organoids grown ex vivo showed a similar relationship between proliferation and cytokine expression, even in the absence of gut bacteria and immune cells. CONCLUSIONS: Our study provides a tissue-level systems biology perspective of murine colitis and suggests that mTOR plays a key role in regulating colonic homeostasis by controlling epithelial proliferation/differentiation state. We used microarrays to examine changes in global gene expression patterns associated with chronic inflammation induced by the T cell transfer model of Inflammatory Bowel Disease.

Dataset Information

VGLL4 modulates Paneth cells and sustains intestinal homeostasis.

Dataset's files

Publications

VGLL4 modulates Paneth cells and sustains intestinal homeostasis.

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