Telomere dysfunction impairs intestinal differentiation and predisposes to diet-induced colitis
Year: 2022
Type: preprint
Abstract: Intestinal epithelium dysfunction causes barrier defects, malabsorption and dysbiosis, predicting local and systemic disease, morbidity and mortality in humans. However, the underlying causes are not well understood. Here we show that telomere shortening is a host intrinsic factor that impairs enterocyte differentiation. The presence of such undifferentiated enterocytes is associated with barrier disruption and malabsorption of nutrients, such as fructose. A fructose-rich diet causes increased fructose spillover to the colon and induces colitis in a microbiome-dependent manner. The microbiome uses fructose to synthesize essential metabolites, including NAD precursors, that complement the host’s low NAD pool in the inflamed colon. Thus, telomere shortening drives enterocyte dysfunction and predisposes to diet-induced colitis through barrier disruption, increased nutrient flux to the colon and modulation of the microbiome. This differerentiation defect expands the canonical stem cell failure-centered view of how telomere shortening impacts the intestine and predisposes to intestinal disease in conditions associated with short telomeres.
Authors: Mindy Engevik, Lei Guo, Won-Suk Song, Christopher G Chronowski, Viktor Akhanov, Navish Bosquez, Amy C. Engevik, Numan Oezguen, Cristian Coarfa, Nagireddy Putluri, Andre Catic, Joseph A. Baur, Milton Finegold, Noah Shroyer, Jianhua Gu, Ronaldo P. Ferraris, Jennifer A Halliday, Christophe Herman, Simona Colla, Herman Dierick, Cholsoon Jang, Ergun Sahin
Institutions: Medical University of South Carolina, Baylor College of Medicine, The University of Texas Southwestern Medical Center, University of California, Irvine, Texas Children's Hospital, Dan L Duncan Comprehensive Cancer Center, University of Pennsylvania, Houston Methodist, Rutgers, The State University of New Jersey, Rutgers New Jersey Medical School, The University of Texas MD Anderson Cancer Center
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Cancer Prevention and Research Institute of Texas, American Association for the Study of Liver Diseases, Dan L. Duncan Cancer Center, Baylor College of Medicine, Edward Mallinckrodt, Jr. Foundation, John S. Dunn Gulf Coast Consortium for Chemical Genomics, Ted Nash Long Life Foundation, Korea Health Industry Development Institute, National Institutes of Health, National Institute on Aging, National Cancer Institute
Awards: Cell differentiation regulates intestinal tight junctions, G1133087115, G2471611692, G274084553, G2859315832, G3102002109, G3326864172, G3643660333, G3859611914, G418187648, G4523668814, G4558765985, The Combinatorial Drug Discovery Program (CDDP), G4819929959, Proteomics and Metabolomics Core Facility, G5248451359, G5465708471, G5508324684, G5520316217, G5843987319, G7022586960, G7185013638, GCC Center for Advanced Microscopy and Image Informatics, G7275029977, G7514240623, Advanced Multiparameter Cytometry and Cell Sorting Core, G7557813972, G7722306932, G7837447426, G8153776008, G8271546232, G8413015676, G871071120, G9000012617, G9000012702, G9000014417, G9000052874, G9000069527, G9000154030, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4285590780