Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes – published online 28/01/2025

Jason L. Floyd, Ram Prasad, Mariana D. Dupont, Yvonne Adu‑Rutledge, Shambhavi Anshumali, Sarbodeep Paul, Sergio Li Calzi, Xiaoping Qi, Akanksha Malepati, Emory Johnson, Patricia Jumbo‑Lucioni, Jason N. Crosson, John O. Mason III, Michael E. Boulton, Robert S. Welner, Maria B. Grant

In recent years, it has been increasingly recognised that the gut influences disease throughout the body. In diabetes, a hyperpermeable gut barrier allows for systemic endotoxaemia and the exacerbation of inflammatory cascades in a multitude of tissues, especially microvascular beds. In this issue, Floyd et al (https://doi.org/10.1007/s00125-024-06349-4) explored the influence of a hyperpermeable gut barrier in the pathogenesis of diabetic retinopathy in humans and rodents. The authors provide evidence that a hyperpermeable gut barrier and subsequent endotoxaemia are exclusive to type 2 diabetes and promote neutrophilia. In the human participants, gut barrier permeability and endotoxaemia were associated with the severity of diabetic retinopathy. In rodents, gut barrier dysfunction was shown to promote intestinal neutrophil activation and the generation of neutrophil extracellular traps (NETs). Inhibition of NET formation strengthened the gut barrier and prevented the development of diabetic retinopathy in a rodent model of diabetes. The authors conclude that assessment of peripheral neutrophilia and gut barrier dysfunction in individuals with diabetes may help to predict endotoxaemia and the development of microvascular complications.