Reactive oxygen species stimulate Paneth cell plasticity and diminish antimicrobial function
The gut epithelium faces constant environmental oxidative stresses. How it responds to pathological reactive oxygen species (ROS) is not fully understood. Using Paneth cell (PC) lineage reporters and genetic tracing, we show that as PC progenitors mature, a decline in their oxidative phosphorylation (OXPHOS) activity coincides with an increased capacity to produce antimicrobial peptides (AMPs). Direct stimulation by elevated extracellular ROS, often found during gut infection and inflammation, can drive a subset of PCs into mitotic cell division. Increasing mitochondrial superoxide production via impairment or uncoupling of the respiratory electron transport chain similarly stimulated PC cell-cycle entry and dedifferentiation into various intestinal epithelial cell types. Using gain- and loss-of-function approaches, we found that the Rho-GTPase CDC42 in PCs regulates the balance of ROS and antimicrobial peptide production, influencing the outcome of pathogenic infection. CDC42 deficiency impairs mitochondrial respiration in PCs, elevating cellular ROS, plasticity, and inflammation. Together, ROS directly suppress the mature PC phenotypes, contributing to the widely observed PC pathology in inflammatory diseases. Our findings suggest that molecular defects affecting OXPHOS balance and antimicrobial peptide production in PCs will likely impair innate defense and drive inflammatory progression in the intestine.
Authors
- Zhi Wei (ORCID: https://orcid.org/0000-0001-6059-4267)
- Jagannatham Naidu Bhupana (ORCID: https://orcid.org/0009-0009-3304-5831)
- Y Chen
- Sheila Bandyopadhyay (ORCID: https://orcid.org/0000-0002-1827-9324)
- Jared Bianchi‐Smak
- Oscar Pellón-Cárdenas (ORCID: https://orcid.org/0000-0003-3085-1618)
- H Park
- Michael P. Verzi (ORCID: https://orcid.org/0000-0003-4082-4330)
- Nan Gao (ORCID: https://orcid.org/0000-0003-4264-7438)
- Iyshwarya Balasubramanian
- Edward M. Bonder (ORCID: https://orcid.org/0000-0001-6463-9143)
- Jean‐Pierre Etchegaray (ORCID: https://orcid.org/0000-0002-6663-8870)
- Xiao Zhang (ORCID: https://orcid.org/0000-0002-8213-6686)
- Jiaxing Yang (ORCID: https://orcid.org/0009-0005-8439-1428)
- Dahui Wang (ORCID: https://orcid.org/0009-0002-4345-104X)
- Edward Gonzalez
Institutions
- Rutgers, The State University of New Jersey (US)
- New Jersey Institute of Technology (US)
- Cooper Medical School of Rowan University (US)
- Cooper University Health Care (US)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-07-18
- DOI
- https://doi.org/10.1038/s44318-026-00869-y
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Division of Cancer Prevention, National Cancer Institute
- New Jersey Commission on Brain Injury Research
- Crohn's and Colitis Foundation
- National Human Genome Research Institute
- NIH Office of the Director
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Complementary and Integrative Health
- New Jersey Commission on Cancer Research