Abstract
Inflammatory bowel disease (IBD) is a complex, multifactorial inflammatory disorder of the gut characterized by an imbalance in host–microbiota interactions. Here, we review how early events of IBD are shaped by gene–environment interactions, especially those involving microbial perturbations. Those perturbations eventually lead to chronic inflammation and tissue damage of the gastrointestinal tract. IBD is a multi-hit process in which infectious and noninfectious agents initiate a cascade of immune activation in genetically susceptible individuals. Ultimately the process results in irreversible immunological and physical scarring. These interactions are host specific, with genetic variants influencing the threshold for immune activation and the degree of damage, thus leading to variability in disease progression and therapeutic outcomes. Finally, we discuss challenges, including addressing health disparities and potential strategies for more personalized and effective therapies that target host–microbiota interactions during the preclinical phase of IBD.
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Acknowledgements
This work was supported by National Institutes of Health (NIH) grant DK093668 (to K.C.) and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH (to P.L.).
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K.C. and P.L. wrote and edited the manuscript.
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K.C. has received research support from Pfizer, Takeda, Genentech and AbbVie. K.C. has consulted for or received an honorarium from PureTech Health, Genentech and AbbVie. K.C. is an inventor on US patents 10,722,600 and provisional patent 62/935,035 and 63/157,225. P.L. declares no competing interests.
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Cadwell, K., Loke, P. Gene–environment interactions shape the host–microbial interface in inflammatory bowel disease. Nat Immunol 26, 1023–1035 (2025). https://doi.org/10.1038/s41590-025-02197-5
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DOI: https://doi.org/10.1038/s41590-025-02197-5
