Glucagon-Like Peptide 1 Receptor (Glp1r) Deficiency Does Not Appreciably Alter Airway Inflammation or Gut-Lung Microbiome Axis in a Mouse Model of Obese Allergic Airways Disease and Bariatric Surgery

Purpose: High body mass index (>= 30 kg/m2) is associated with asthma severity, and nearly 40% of asthma patients exhibit obesity. Furthermore, over 40% of patients with obesity and asthma that receive bariatric surgery no longer require asthma medication. Increased levels of glucagon-like peptide 1 (GLP-1) occur after bariatric surgery, and recent studies suggest that GLP-1 receptor (GLP1R) signaling may regulate the gut microbiome and have anti-inflammatory properties in the lung. Thus, we hypothesized that increased GLP-1R signaling following metabolic surgery in obese and allergen-challenged mice leads to gut/lung microbiome alterations, which together contribute to improved features of allergic airways disease. Methods: Male and female Glp1r-deficient (Glp1r-/-) and replete (Glp1r+/+) mice were administered high fat diet (HFD) to induce obesity with simultaneous intranasal challenge with house dust mite (HDM) allergen to model allergic airway disease with appropriate controls. Mice on HFD received either no surgery, sham surgery, or vertical sleeve gastrectomy (VSG) on week 10 and were sacrificed on week 13. Data were collected with regard to fecal and lung tissue microbiome, lung histology, metabolic markers, and respiratory inflammation. Results: HFD led to metabolic imbalance characterized by lower GLP-1 and higher leptin levels, increased glucose intolerance, and alterations in gut microbiome composition. Prevalence of bacteria associated with short chain fatty acid (SCFA) production, namely Bifidobacterium, Lachnospiraceae UCG-001, and Parasutterella, was reduced in mice fed HFD and positively associated with serum GLP-1 levels. Intranasal HDM exposure induced airway inflammation. While Glp1r-/-genotype affected fecal microbiome beta diversity metrics, its effect was limited. Conclusion: Herein, GLP-1R deficiency had surprisingly little effect on host gut and lung microbiomes and health, despite recent studies suggesting that GLP-1 receptor agonists are protective against lung inflammation. Plain Language Summary: Asthma is a chronic lung disease that affects over 20 million Americans. In addition, obesity is a major worldwide healthcare problem whose impact is increasing each year. Asthma patients with obesity have worse symptoms, use more medications and have reduced asthma control than lean patients. Also, both asthma and obesity are linked to changes in the normal bacteria that live in the gut and the airways. Weight loss, either through bariatric surgery or through diet and exercise, improves asthma symptoms, through unknown mechanisms. One way that bariatric surgery may impact asthma is through the increase in beneficial gut hormones (GLP-1) and restoration of altered bacteria in the gut and airways. Our study shows that overall, obese mice experience changes in hormones involved in weight gain and glucose metabolism as well as gut bacteria, particularly those that may produce important factors that could improve health. We did not find any links between changes in the bacteria in the gut or lung and features of airway disease or effects from bariatric surgery in the mice. Mice that lacked GLP-1 activity did not differ from normal mice for weight, glucose tolerance, or prevalence of bacteria in the lung. Future studies will explore the timeline of these bacterial changes and the role of the gut and lung microbiomes in human obesity-associated asthma.