# Obesity-Associated Metabolomic and Functional Reprogramming in Neutrophils from Horses with Asthma

## TL;DR

Obesity in horses with asthma changes neutrophil metabolism and increases inflammation, suggesting that managing weight could improve treatment outcomes.

## Contribution

The study reveals how obesity alters neutrophil function and metabolism in equine asthma, offering new insights into potential therapeutic strategies.

## Key findings

- Obese asthmatic horses have higher IL-1β levels and increased neutrophil activity compared to non-obese horses.
- Neutrophils from obese horses show elevated production of reactive oxygen species and altered fatty acid and amino acid metabolism.
- Metabolomic changes include increased itaconate and citraconic acid, indicating metabolic reprogramming linked to inflammation.

## Abstract

Equine asthma is a chronic lung disease that causes breathing problems and involves inflammation driven by neutrophils. Obesity is becoming more common in horses and may worsen inflammatory conditions. This study compared obese and non-obese horses with asthma to understand how obesity affects neutrophil function. Obese horses showed higher levels of the inflammatory marker IL-1β and increased neutrophil activity. Their neutrophils also produced more reactive oxygen species and had an elevated expression of inflammatory genes. Metabolomic analysis revealed changes in how these immune cells process fats and amino acids, with increased levels of key molecules like itaconate and citraconic acid. These results suggest that obesity alters neutrophil metabolism, making them more reactive and possibly contributing to more severe airway inflammation. Managing obesity may therefore be important in treating equine asthma, and targeting neutrophil metabolism could offer new therapeutic opportunities.

Equine asthma is a chronic respiratory disease characterised by neutrophilic inflammation, airway hyperresponsiveness, and impaired pulmonary function. Obesity, increasingly prevalent among domestic horses, has been identified as a potential risk factor for exacerbating inflammatory conditions. This study aimed to explore whether obesity modifies neutrophil metabolism and inflammatory responses in horses affected by asthma. Six asthmatic horses in clinical remission were categorised into two groups: obese and non-obese, based on body condition score. Serum levels of interleukin-1β (IL-1β) and peripheral blood neutrophil counts were significantly higher in obese horses, indicating a heightened systemic inflammatory state. Neutrophils from obese horses displayed a stronger oxidative burst following zymosan stimulation and elevated IL-1β gene expression in response to lipopolysaccharide, suggesting a hyperinflammatory phenotype. Metabolomic profiling of neutrophils identified 139 metabolites, with notable differences in fatty acids, branched-chain amino acids, and tricarboxylic acid (TCA) cycle intermediates. Pathway enrichment analysis revealed significant alterations in fatty acid biosynthesis, amino acid metabolism, and glutathione-related pathways. Elevated levels of itaconate, citraconic acid, and citrate in obese horses indicate profound metabolic reprogramming within neutrophils. These results suggest that obesity promotes a distinct neutrophil phenotype marked by increased metabolic activity and heightened responsiveness to inflammatory stimuli. This altered profile may contribute to the persistence or worsening of airway inflammation in asthmatic horses. The findings underscore the importance of addressing obesity in the clinical management of equine asthma and open avenues for further research into metabolic-targeted therapies in veterinary medicine.