PAD2 Deficiency Reveals Sex-Divergent Colonic Homeostasis, β-Catenin Remodeling, and Antibiotic-Sensitive Phenotypes
4 affiliations
- 1Department of Surgery, Division of Surgical Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
- 2Experimental Pathology, Biomedical Sciences Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
- 3Comparative Pathology and Veterinary Diagnostics, University of Virginia, Charlottesville, VA 22908, USA
- 4Department of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USA
Abstract
Peptidylarginine deiminase 2 (PAD2) catalyzes protein citrullination and is implicated in inflammatory bowel disease and colorectal cancer. However, its role in regulating the intestinal epithelium and the influence of biological sex and the microbiome remain poorly defined. This study investigated the relationships among PAD2 deficiency, sex-divergent epithelial states, β-catenin regulation, and the intestinal microbiome. Global PAD2 knockout and wild-type littermate mice of both sexes were characterized under basal conditions and following dextran sodium sulfate-induced colitis. Intestinal epithelial phenotypes were assessed by histology, immunofluorescence, immunoblotting, quantitative RT-PCR, and immunoprecipitation. Gut microbial communities were evaluated by shotgun metagenomics, while broad-spectrum antibiotic treatment, fecal protein immunoblotting, and recombinant human PAD2 exposure in vitro were used to examine relationships among antibiotic-sensitive factors, β-catenin regulation, and epithelial phenotypes. PAD2 deficiency was associated with distinct epithelial states in male and female colons before injury. Male KO mice displayed increased β-catenin phosphorylation and increased susceptibility to DSS colitis, whereas female KO mice demonstrated increased total β-catenin abundance and preservation of structural epithelial features following injury. Female KO microbiota exhibited genotype-associated differences in microbial community composition by exploratory Bray-Curtis PERMANOVA. Broad-spectrum antibiotic treatment altered the female epithelial phenotype, reduced active β-catenin, and progressively depleted luminal PAD2-immunoreactive proteins. Exogenous recombinant human PAD2 increased epithelial protein citrullination and altered active β-catenin abundance in HT29 cells. Collectively, these findings demonstrate both sex-specific and sex-divergent colonic phenotypes while supporting a framework connecting PAD2 biology, epithelial architecture, and the microbial environment during intestinal maintenance and injury.
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BibTeX
@article{dawson2026pad2,
title = {{PAD2 Deficiency Reveals Sex-Divergent Colonic Homeostasis, β-Catenin Remodeling, and Antibiotic-Sensitive Phenotypes}},
author = {Zachary D. Dawson and Tamriage Martin and Eunhye Ji and Kyung Eun Lee and Xi Chen and Xinyu Zhou and Samantha St. Jean and Yongqing Li and Jianjie Ma},
journal = {Biomolecules},
year = {2026},
month = sep,
doi = {10.3390/biom16101415},
url = {https://www.mdpi.com/2218-273X/16/10/1415},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PAD2 Deficiency Reveals Sex-Divergent Colonic Homeostasis, β-Catenin Remodeling, and Antibiotic-Sensitive Phenotypes
AU - Zachary D. Dawson
AU - Tamriage Martin
AU - Eunhye Ji
AU - Kyung Eun Lee
AU - Xi Chen
AU - Xinyu Zhou
AU - Samantha St. Jean
AU - Yongqing Li
AU - Jianjie Ma
PY - 2026
DA - 2026/09/30
JO - Biomolecules
DO - 10.3390/biom16101415
UR - https://www.mdpi.com/2218-273X/16/10/1415
AB - Peptidylarginine deiminase 2 (PAD2) catalyzes protein citrullination and is implicated in inflammatory bowel disease and colorectal cancer. However, its role in regulating the intestinal epithelium and the influence of biological sex and the microbiome remain poorly defined. This study investigated the relationships among PAD2 deficiency, sex-divergent epithelial states, β-catenin regulation, and the intestinal microbiome. Global PAD2 knockout and wild-type littermate mice of both sexes were characterized under basal conditions and following dextran sodium sulfate-induced colitis. Intestinal epithelial phenotypes were assessed by histology, immunofluorescence, immunoblotting, quantitative RT-PCR, and immunoprecipitation. Gut microbial communities were evaluated by shotgun metagenomics, while broad-spectrum antibiotic treatment, fecal protein immunoblotting, and recombinant human PAD2 exposure in vitro were used to examine relationships among antibiotic-sensitive factors, β-catenin regulation, and epithelial phenotypes. PAD2 deficiency was associated with distinct epithelial states in male and female colons before injury. Male KO mice displayed increased β-catenin phosphorylation and increased susceptibility to DSS colitis, whereas female KO mice demonstrated increased total β-catenin abundance and preservation of structural epithelial features following injury. Female KO microbiota exhibited genotype-associated differences in microbial community composition by exploratory Bray-Curtis PERMANOVA. Broad-spectrum antibiotic treatment altered the female epithelial phenotype, reduced active β-catenin, and progressively depleted luminal PAD2-immunoreactive proteins. Exogenous recombinant human PAD2 increased epithelial protein citrullination and altered active β-catenin abundance in HT29 cells. Collectively, these findings demonstrate both sex-specific and sex-divergent colonic phenotypes while supporting a framework connecting PAD2 biology, epithelial architecture, and the microbial environment during intestinal maintenance and injury.
SN - 2218-273X
ER -