Within the framework of the RTG1743, it was demonstrated that diet overrides genetic lupus susceptibility (Nat Commun, 10:4097). In the first funding period of RTG2633, an in-depth characterization of the metabolic and immunological alterations imposed by diet in non-autoimmune prone-C57Bl6/J mice was performed. The results already demonstrate that Western-Diet promotes the transition from health to autoimmune pre-disease, evidenced by significantly elevated levels of anti-nuclear antibodies and infiltration of the exocrine pancreas with CD3+ T cells. 

In addition, using large-scale real-world data, it has been shown that obesity is a risk factor for several autoimmune diseases (Front Endocrinol,16:1516433).

Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are a class of medications that mimic the effect of the natural hormone GLP-1 to lower blood sugar, promote weight loss, and reduce appetite, making them an effective treatment for type 2 diabetes and obesity. Recently, we completed a study demonstrating that GLP1-RA treatment improves treatment outcomes in psoriasis. Taken together, obesity is a major driver of autoimmune pre-disease across two species. We will now investigate if weight-loss interventions in a population-at-risk (overweight persons) can reverse this autoimmune pre-disease risk imposed by overweight and obesity.

Our hypothesis is that effective weight loss, whether achieved through bariatric surgery or GLP-1 receptor agonist medication, will reverse the pre-autoimmune state. This hypothesis will be challenged by performing retrospective cohort studies in the TriNetX database to assess the impact of bariatric surgery or GLP-1 receptor agonist treatment in overweight and obese persons on autoimmune disease risk. In parallel, we will analyse the impact of bariatric surgery or GLP-1 receptor agonist treatment by an in-depth characterization of circulating B- and T cell responses using single cell RNA-sequencing and Cytek. Finally, we will use prospectively collected data on autoantibody levels before and after weight loss interventions to infer causality in the retrospective cohort studies.