Uranium-bearing dust induces differentiation and expansion of enteroendocrine cells In human colonoids

Chronic exposure to environmental toxins and heavy metals has been tenuously linked to intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer, all of which have been steadily increasing in prevalence for the past 40 years. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. Uranium exposure remains an important legacy environmental and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. Human colonoids were used to define the molecular and cellular changes that occur in response to uranium bearing dust (UBD) exposure. Here, we use single cell RNA sequencing to characterize the molecular changes that occur to proliferative and differentiated intestinal epithelial cells exposed to UBD. We demonstrate that this environmental toxicant disrupts proliferation and induces hyperplastic differentiation of secretory lineage cells, specifically enteroendocrine cells (EEC). These cell types show increased differentiation into de novo EEC sub-types not found in control colonoids. These findings highlight the significance of epithelial differentiation as major colonic responses to heavy metal-induced injury.