The dietary emulsifier polysorbate-80 induces cell death in intestinal epithelial cells via ferroptosis

The microbiota and westernised diet are suggested to contribute to the development of chronic diseases such as obesity, inflammatory bowel disease, metabolic syndrome. Recent studies demonstrated that certain dietary emulsifiers negatively impacted both the intestinal microbiota (bacteria) and the subsequent host response resulting in worsening of these conditions in rodents. However, mechanistic understanding of how these dietary emulsifiers affect the host response are largely unknown. Preliminary studies revealed that the dietary emulsifier polysorbate 80 (p80) was toxic to human intestinal epithelial cells (IECs), while another dietary emulsifier carboxymethyl cellulose (CMC) was not. The aim of this study was to unravel what mechanism(s) are regulated by p80 to induce cell death on epithelial cells. We identified alterations in mitochondria metabolism, reduced proliferation, and increased cell death, without heighten inflammatory response in p80-treated human IECs and murine organoids (mini 3D-guts). Using small molecule inhibitors targeting different cell death mechanisms, we showed that p80 causes an early structural damage on the mitochondria, an increase in reactive oxygen species (ROS), an accumulation in iron and lipid peroxidation resulting in an increased ferroptotic (iron-dependent) cell death over time. These structural findings were validated by alterations in ferroptosis markers in p80-treated cells. In conclusion, our data suggest that dietary emulsifying agents such as p80 can contribute to the increased incidence of chronic intestinal conditions and metabolic syndrome by altering host responses such as induction of cell death in conjunction with microbial alterations.