Uranium-bearing dust disrupts the colonic mucus layer leading to goblet cell hyperplasia and upregulation in mucin expression

Background: Across the Western United States, there are thousands of abandoned uranium mines (AUMs) which leach heavy metals into the surrounding soil, water, and air. This leads to elevated levels of heavy metal exposure in communities residing near AUMs and poses a major public health concern. Inhalation and ingestion are the primary routes of heavy metal exposure, and the gastrointestinal tract is one of the first organs to encounter these toxins. There is little known on how heavy metals, such as uranium, may impact the gastrointestinal epithelium. The mucus layer of the gut is a physical barrier that protects the epithelium from microbes and ingested toxins. Goblet cells (GCs) are specialized secretory cells which secrete MUC2, the primary protein of the mucus layer. GC function and mucus layer barrier integrity are crucial for gut homeostasis. Objective: Using human derived intestinal organoids (HIOs), we aim to determine how uranium-bearing dust (UBD) impacts the colonic mucus layer and GC physiology. Hypothesis: UBD degrades the colonic mucus layer leading to GC hyperplasia and upregulation of secreted and adherent mucins. Methods: HIOs derived from healthy adult colonic biopsies (UNM IRB 18-626 and 18-171) were established and shown to physiologically model the intestinal epithelia. HIOs were grown in monolayers to determine the impact of UBD on the secreted mucus layer. HIOs grown in 3D form were used to assess GC cellular composition and functional consequences of UBD exposure. UBD was collected near the Jackpile Paguate Uranium Mine, one of the largest open-pit uranium mines in the United States located outside of the Pueblo of Laguna. For controls, we used cell culture media and aluminum silicate, the predominant clay component found in the area. HIOs were exposed to UBD at 20μg/ml (monolayers) and 50μg/ml (3D form) for 24h. Results: UBD exposure in HIOs monolayers degraded the mucus layer to 5μm thickness compared to a 15μm thickness in control. Immunoblotting further confirmed a reduction in the mucus layer in UBD treatment (64%) compared to control (100%) and aluminum silicate (96.6%). To characterize transcriptomic changes, control and UBD-exposed 3D HIOs (n=3 unique donors) were processed for droplet-based single cell sequencing. UBD exposure led to an expansion in secretory cells. Specifically, we found upregulation in cells expressing ATOH1 (0.29% - control to 3.6% - UBD), a master transcription factor essential for intestinal secretory cell differentiation and MUC2 (8.7% - control to 51.7% - UBD). This was further confirmed with immunostaining of Trefoil factor 3, a GC marker. Additionally, there was an upregulation in cells expressing adherent mucins MUC1 (6.8% - control to 31% - UBD), MUC13 (6.5% to 32.2% - UBD, and MUC17 (0.2% - control to 1.6% - UBD). Conclusion: Our results indicate that UBD exposure degrades the gastrointestinal mucus layer resulting in GC hyperplasia and upregulation of cells expressing mucins to restore barrier integrity. Funding: R01ES034400, P42ES025589, and 5T32GM144834-04. 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.