Chronic inflammation in the colon is a known risk factor for colorectal cancer, but how the intestinal epithelium maintains mucosal immune homeostasis remains poorly understood. To address this gap, we investigated how loss of the RNA-binding protein heterogeneous nuclear ribonucleoprotein I (hnRNP I) in intestinal epithelial cells (IEC) impacts colonic epithelial physiology and host–microbe defense. We hypothesized that loss of epithelial hnRNP I would impair mucosal innate immune defenses and promote chronic inflammation-driven epithelial hyperproliferation. In a mouse model with an IEC-specific knockout of hnRNP I, we profiled epithelial changes using single-cell RNA sequencing (scRNA-seq) alongside various molecular and histological analyses. KO mice spontaneously developed colitis—evidenced by shortened colons, elongated crypts, and goblet cell loss. Single-cell transcriptomic analysis revealed a broad downregulation of epithelial innate defense programs in KO colonocytes. Antimicrobial peptide genes and reactive oxygen species generators were markedly reduced, along with goblet cell mucin factors, indicating a compromised mucosal barrier. Consequently, KO colons exhibited signs of epithelial stress and inflammation, including widespread crypt hyperproliferation, emergence of metaplastic colonocytes, and expansion of mucosal lymphoid follicles. Collectively, our findings demonstrate that epithelial hnRNP I is indispensable for maintaining mucosal innate immune defenses. Its loss compromises the antimicrobial barrier, leading to chronic inflammation and epithelial stress that are linked to colitis-associated colorectal cancer in humans and mouse models. This research is supported by grants from the USDA Cooperative State Research, Education and Extension Service (Hatch project numbers #ILLU-971-344, ILLU-698-992, and ILLU-698-989), Division of Nutritional Sciences Vision 20/20 Research program, and the Office of the Vice Chancellor for Research and Innovation at the University of Illinois at Urbana-Champaign. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Zhang et al. (Fri,) studied this question.