Pseudomonas instigates neutrophil accumulation in adipose tissue and insulin resistance in obesity 2309070

Introduction Obesity is a global pandemic, with over 75% of the U.S. population classified as overweight or obese. Adipose tissue inflammation is a major driver of metabolic complications associated with obesity. Previous studies have shown that obesity promotes neutrophil recruitment to visceral adipose tissue (VAT), which correlates with increased intestinal permeability and insulin resistance. The microbiome in obese VAT differs from that in lean VAT and is shaped by high-fat diet consumption. Whether specific microbes drive VAT neutrophil accumulation to cause obesity-related complications remains unknown. Methods To address this question, we developed a mouse model in which fecal microbiota from obese human donors were administered to mice pretreated with antibiotics and an antifungal (avatar mice). Using three-dimensional whole-mount imaging of VAT, 16S sequencing, flow cytometry, and molecular analyses, we investigated gut microbiome-driven mechanisms underlying VAT inflammation. Results Our study revealed that: (1) Proteobacteria were enriched in the VAT of mice gavaged with fecal microbiota from obese humans; (2) oral gavage with Pseudomonas aeruginosa (PAO1), a member of the Proteobacteria phylum, led to its detection in VAT and caused an increase in VAT neutrophils and Cxcr2 expression in the avatar mice; (3) the increase in VAT neutrophils was strictly dependent on PAO1, as heat-killed PAO1, other bacteria, or PAO1 mutants lacking essential structural components (e.g., flagella or O-antigen) were unable to recapitulate the obese phenotype; and (4) gavage with PAO1 was sufficient to trigger insulin resistance in recipient avatar mice. Conclusion Together, these findings reveal potential mechanisms by which bacteria in the human intestinal microbiome trigger adipose tissue inflammation and metabolic dysfunction in obesity. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)