Abstract
Duodenal adenomas have malignant potential, yet the drivers of duodenal tumorigenesis remain unclear. Duodenal adenomas robustly develop in villin-TLR4 mice, a transgenic mouse model of increased innate immune signaling in the intestinal epithelium. Here, we sought to test the contributions of the microbiota and bile acids to duodenal adenoma development.
Duodenal tissue was analyzed for proliferation rate and histology in villin-TLR4 versus WT mice. Mice were rederived into germ-free conditions and administered a diet containing the bile acid sequestering resin cholestyramine or treated with the NADPH oxidase inhibitor apocynin. Chemokine expression and myeloid cell recruitment were measured. Findings from mouse studies were corroborated by RNA sequencing and tissue microarray analyses of human duodenal adenomas.
Constitutive activation of epithelial TLR signaling in the duodenum led to adenomas with an intestinal phenotype. Non-adenomatous duodenal tissue showed increased expression of Cxcl1 and Cxcl2 by intestinal epithelial cells and recruitment of S100A8+ and myeloperoxidase (MPO)+ myeloid cells. Re-deriving villin-TLR4 mice in germ-free conditions or feeding them a cholestyramine-supplemented diet prevented tumor initiation, epithelial expression of CXCR2 ligands, and myeloid cell recruitment. Apocynin supplementation slowed tumor progression without affecting chemokine expression or myeloid cell recruitment. In humans, duodenal adenomas had enriched neutrophil activation pathways, increased chemokine expression, and infiltration of S100A8+ and MPO+ myeloid cells.
Bile acids and the microbiota are necessary for duodenal adenoma development and are potentially modifiable risk factors in humans at risk of duodenal adenomas. The recruitment of myeloid cells may promote tumor progression via the release of reactive oxygen species.
[Display omitted]