2. Academic Validation
  3. Disruption of bile acid homeostasis potentiates Paneth cell ablation by activating the intestinal Farnesoid X receptor in necrotizing enterocolitis

Disruption of bile acid homeostasis potentiates Paneth cell ablation by activating the intestinal Farnesoid X receptor in necrotizing enterocolitis

  • NPJ Biofilms Microbiomes. 2026 Jan 8;12(1):38. doi: 10.1038/s41522-025-00904-6.
Jing Xiong # 1,  Ting Guo # 1,  Tingting Gao 1,  Yeerfan Aierken 1,  Qingqi Chong 1,  Zhibao Lv 2,  Li Lu 3
Affiliations

Affiliations

  • 1 Department of General Surgery, Shanghai Children's Hospital, School of medicine, Shanghai Jiao tong University, Shanghai, China.
  • 2 Department of General Surgery, Shanghai Children's Hospital, School of medicine, Shanghai Jiao tong University, Shanghai, China. [email protected].
  • 3 Department of General Surgery, Shanghai Children's Hospital, School of medicine, Shanghai Jiao tong University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41507219 DOI: 10.1038/s41522-025-00904-6
Abstract

Although disrupted bile acid (BA) homeostasis is implicated in necrotizing enterocolitis (NEC), its role in NEC pathogenesis remains unclear. We revealed that secondary BA accumulation in the ileum with severe NEC induced Paneth cell (PC) loss via the activation of the intestinal farnesoid X receptor (FXR). Single-cell RNA Sequencing (scRNA-seq) showed that high FXR expression was associated with the differentiation of intestinal stem cells (ISCs) in NEC. Mechanistically, intestinal FXR upregulation induced PC loss by inhibiting Wnt/planar cell polarity (PCP) signaling, which regulates ISC lineage priming toward PCs. Furthermore, disrupting the gut-liver axis by downregulating FGF receptor 4 (FGFR4) abrogated the suppression of the BA synthesis induced by elevated FXR levels in severe NEC, leading to improved outcomes, including a restored Firmicutes/Bacteroidetes ratio and a normalized butyrate concentration. Interestingly, FGFR4 inhibition restored the PC population in a butyrate-dependent manner. Our findings demonstrate that FXR regulated PC generation directly or indirectly via the gut-liver axis.

Figures
Products