Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes

Severity of diabetic retinopathy and DME were associated with peripheral neutrophilia, gut barrier dysfunction and endotoxaemia in the human participants. db/db mice exhibited intestinal neutrophilia, specifically stem-like pre-neutrophils, which was associated with elevated NETosis and decreased levels of vascular reparative cells. Chronic inhibition of NETosis in db/db mice reduced intestinal senescence and NETs in the retina. These changes were associated with reduced endotoxaemia and an anti-inflammatory bone marrow milieu with retention of pre-neutrophils in the bone marrow and increased gut infiltration of myeloid angiogenic cells. Collectively, PAD-4i treatment decreased gut barrier dysfunction, restoring physiological haematopoiesis and levels of haematopoietic vascular reparative cells.