Microbial signals trigger the release of neutrophil extracellular traps (NETs) through peptidyl arginine deiminase 4 (PADI4). In turn, NETosis can propagate inflammation to distant tissues. We hypothesize that PADI4 mediates the interactions between diet-modified microbiota and host metabolism. We report that in the adipose tissue of individuals with obesity, NETosis was associated with dysglycemia. In mice, high-fat diet (HFD) induced not only dysmetabolism and metainflammation but also local and systemic signs of NETosis. Deleting Padi4 in hematopoietic cells (Padi4KO) blunted liver and adipose inflammation and improved metabolism under HFD. While NETs were able to disrupt gut epithelial integrity, abrogating NETosis preserved intestinal barrier function and mitigated metabolic endotoxemia due to HFD. Padi4 deletion did not prevent diet-induced dysbiosis, but Padi4KO mice were protected from intestinal hyperpermeability and metabolic impairment due to the transfer of HFD-modified microbiota. As Padi4KO did not blunt the dysmetabolic effects of lipopolysaccharide, we concluded that NETosis operates at the microbiota-intestinal interface, inducing hyperpermeability and the systemic spillover of bacterial-derived products, paving the way to the metabolic consequences of HFD. Finally, pharmacologic PADI4 inhibition recapitulated findings obtained in Padi4KO mice on metabolism and liver steatosis, thereby uncovering a druggable role for PADI4 in mediating the metabolic effects of unhealthy microbiota.
Article Highlights
- Obesity and diabetes collide and drive serious health problems.
- Peptidyl arginine deiminase 4 (PADI4) is the key enzyme in neutrophil extracellular trap (NET)osis, a candidate link between overfeeding and dysmetabolism. We explored the role of NETosis in the induction of type 2 diabetes due to high-fat diet (HFD).
- Blocking HFD-induced NETosis prevented intestinal hyperpermeability caused by diet-modified microbiota; metabolic endotoxemia; glucose intolerance; insulin resistance; systemic, adipose, and liver inflammation; and liver steatosis.
- Blunting NETosis by blocking PADI4 emerges as druggable target to prevent the metabolic consequences of unhealthy microbiota.
