Systemic Lupus Erythematosus Serum Stimulation of Human Intestinal Organoids Induces Changes in Goblet Cell Differentiation and Mitochondrial Fitness

Abstract

Human intestinal epithelial cells are the interface between potentially harmful luminal content and basally residing immune cells. Their role is not only nutrient absorption but also the formation of a tight monolayer that constantly secrets mucus creating a multi-layered protective barrier. Alterations in this barrier can lead to increased gut permeability which is frequently seen in individuals with chronic extraintestinal autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). Despite recent advances in identifying alterations in gut microbiota composition in SLE patients, not much attention has been given to the epithelial barrier itself. To date, it remains largely unexplored which role and function intestinal epithelial cells have in SLE pathology. Here, we present a unique near-physiologic in vitro model specifically designed to examine the effects of SLE on the epithelial cells. We utilize human colon organoids that are stimulated with serum obtained from SLE patients. Combining bulk and scRNA transcriptomic analysis with functional assays revealed that SLE serum stimulation induced a unique expression profile marked by a type I interferon gene signature. Additionally, organoids exhibited decreased mitochondrial fitness, alterations in mucus composition and imbalanced cellular composition. Similarly, transcriptomic analysis of SLE human colon biopsies revealed a downregulation of epithelial secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.