Unipd study. Discovered link between diet, gut microbiota, and systemic inflammation in metabolic diseases

14.02.2025

A research team from the University of Padua and the Veneto Institute of Molecular Medicine (VIMM) has discovered a new mechanism by which a high-fat diet alters the intestinal barrier and triggers systemic inflammation, increasing the risk of metabolic diseases such as type 2 diabetes. The study titled “Padi4-dependent NETosis enables diet-induced gut hyperpermeability, translating dysbiosis into systemic inflammation and dysmetabolism,” published in the journal «Diabetes», identifies a key role for the enzyme PADI4 and a process known as NETosis.

Type 2 diabetes is one of the major global health emergencies, affecting over half a billion people worldwide and about 4 million in Italy. Obesity is one of the main risk factors for the development of diabetes and other metabolic disorders, such as fatty liver disease, a condition characterized by fat accumulation in the liver that can progress to more serious diseases like cirrhosis and liver cancer.
The publication emphasizes the importance of understanding the mechanisms underlying these interactions to develop new preventive and therapeutic strategies. The implications of this research are highly significant for understanding metabolic diseases and suggest a potential therapeutic target to counteract the negative effects of overeating and obesity.

"We observed that a typical Western diet, rich in fats, induces an immune response in neutrophils, which are white blood cells that function to defend the body against bacterial and fungal infections,” explains Mattia Albiero, the first author of the study and a researcher at the Department of Surgical, Oncological and Gastroenterological Sciences at the University of Padua and VIMM. "Neutrophils release structures called NETs: these, in turn, compromise the intestinal barrier, facilitating the spread of bacterial components into the bloodstream and promoting systemic inflammation."

The researchers conducted experiments on animal models and human adipose tissue samples, demonstrating that diet-induced NETosis leads to increased intestinal permeability, resulting in the propagation of inflammatory signals throughout the body. In particular, mice lacking the PADI4 enzyme or in which the enzyme was inhibited by a drug were protected from the negative effects of a high-fat diet.
"This discovery paves the way for new therapeutic strategies," emphasizes Gian Paolo Fadini, Full Professor of Endocrinology at the Department of Medicine at the University, Director of the Metabolic Diseases and Diabetology Unit at the University Hospital, and Head of the Experimental Diabetology Laboratory at VIMM. "Pharmacological inhibition of PADI4 could represent a new approach to prevent metabolic complications related to obesity, such as type 2 diabetes and fatty liver disease."