13 Oct Disruption of Intestinal Clock Genes May Be Associated with Obesity and Inflammatory Disorders
MedicalResearch.com Interview with:
Marco Colonna, MD
Robert Rock Belliveau MD Professor
Pathology & Immunology
Washington University School of Medicine
Qianli Wang MD-PhD Student
Washington University School of Medicine
MedicalResearch.com: What is the background for this study?
Response: Many aspects of the mammalian digestive system including gut motility, nutrient absorption, and microbiota follow a daily rhythm. This circadian rhythm is generated by the cyclic expressions of molecular clock genes thought to be present in most cells. Group 3 innate lymphoid cells (ILC3) are lymphocytes residing in the intestinal mucosa that respond rapidly to activation in both homeostatic and inflammatory settings. Namely, ILC3s help maintain the mucosal barrier, regulate epithelial lipid transport, and protect against bacterial enteric infections. As tissue resident cells within the highly dynamic and rhythmic environment of the intestine, it may be advantageous for ILC3s to also be synchronized with the circadian rhythm.
MedicalResearch.com: What are the main findings?
Response: In this study, we found that ILC3 express multiple circadian and cytokine genes in a rhythmic manner. In addition, disruption of circadian rhythm using a model that mimics shift work resulted in altered ILC3 functions. Furthermore, Nr1d1, a key circadian gene, is required for normal ILC3 development and function. Mice with genetic deletions of Nr1d1 failed to develop a subset of ILC3s and produced aberrant levels of cytokines. Together, our study shows ILC3s are attuned to the circadian rhythm and require certain clock genes for normal development and functions.
MedicalResearch.com: What should readers take away from your report?
Response: Circadian disruptions are increasingly prevalent in modern life and have been associated with increased risks of obesity, cardiovascular diseases, metabolic syndromes, and inflammatory bowel disease. The exact mechanism of this correlation is not well understood. While circadian disorders likely results in defects across multiple cell types, given ILC3s’ roles in regulating lipid absorption and intestinal barrier integrity, ILC3 dysfunction during circadian disruption may help explain the associated metabolic and inflammatory pathologies/
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The exact mechanism and effect of circadian regulated ILC3 function on physiology and pathology require more in depth examination. Furthermore, circadian regulation of the tissue resident ILC3s may be particularly advantageous as it enables anticipation of environmental changes and synchronization with the rest of the digestive system. This raises the possibility that other tissue resident immune cells in different organs may also undergo circadian regulation. Thus, it would be important to consider the effects of biological rhythm on immune cells in our understanding and treatment of diseases.
Qianli Wang, Michelle L. Robinette, Cyrielle Billon, Patrick L. Collins, Jennifer K. Bando, José Luís Fachi, Cristiane Sécca, Sofia I. Porter, Ankita Saini, Susan Gilfillan, Laura A. Solt, Erik S. Musiek, Eugene M. Oltz, Thomas P. Burris, Marco Colonna. Circadian rhythm–dependent and circadian rhythm–independent impacts of the molecular clock on type 3 innate lymphoid cells. Science Immunology, 2019; 4 (40): eaay7501 DOI: 10.1126/sciimmunol.aay7501
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