Bifidobacterium Infantis Promotes FOSL1-Mediated Transcriptional Repression of VDR to Accelerate Autoimmune Pancreatitis Progression Through Activation of Oxidative Stress.

Abstract

Even though colonization by Bifidobacterium spp. is a prominent feature of the gut microbial community in autoimmune pancreatitis (AIP), the detailed mechanism remains to be explored. The purpose of this study is to determine whether Bifidobacterium infantis (B. infantis) accelerates the progression of AIP through the activation of plasmacytoid dendritic cells (pDCs) and the molecular mechanism. Mild and severe AIP mice were developed. B. infantis was gavaged into mild AIP mice, and transcriptome sequencing was conducted to analyze transcriptomic differences of pDCs in the pancreas after B. infantis colonization. FOSL1 was upregulated, and VDR was downregulated within the pancreatic pDCs of AIP mice. B. infantis accelerated pancreatitis in mice with mild AIP by activating pDCs, which was rescued by a neutralizing antibody to pDCs (BST2) or Fos-like antigen 1 (FOSL1) knockdown. AIP progression, mitigated by FOSL1 knockdown after B. infantis colonization in mice, was exacerbated by combined vitamin D3 receptor (VDR) knockdown. B. infantis-stimulated activation of pDCs was mediated by FOSL1-inhibited VDR transcription, which promoted oxidative stress. These data collectively suggest that B. infantis activates FOSL1 and inhibits VDR transcription, leading to an imbalance in the oxidative status and activation of pDCs, thereby exacerbating AIP.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10753-025-02368-4.

Keywords: Bifidobacterium Infantis 35624; Autoimmune pancreatitis; FOSL1; Plasmacytoid dendritic cells; VDR.