Targeted communication between the environment and immune cells is a key determinant of intestinal and organismal homeostasis, yet the precise regulation of these processes in health and disease remains incompletely understood. A recent Nature paper shows that communication via one of such conduits, goblet cell-associated antigen passages (GAPs), is perturbed in two common diseases that were largely conceptualized as liver diseases, alcohol-associated liver disease and metabolic dysfunction-associated steatohepatitis.
Over the last decades, it has become evident that successful homeostasis at border surfaces relies on regulated and controlled "communication" between components of the environment (e.g., microbiota, nutrients), epithelial cells and immune cells. These communication strands have important roles beyond the barrier organ itself by conditioning processes in other organs (e.g., gut-liver axis, gut-brain axis). In the intestines, interactions between components of the environment and immune cells are to a large extent facilitated by distinct anatomical structures such as Peyer's patches and solitary intestinal lymphoid tissues. Recently, a novel conduit system termed goblet cell-associated antigen passages (GAPs) has been identified. Goblet cells via GAPs facilitate the delivery of metabolites from the intestinal lumen to underlying CD103 lamina propria dendritic cells (DCs) that have tolerogenic properties and may promote intestinal homeostasis. Goblet cells rapidly form GAPs in response to acetylcholine (ACh) acting on the muscarinic ACh receptor 4 (mAChR4) (Fig. 1, left). It is an important question of how GAP opening and closure is regulated during homeostatic adaptation, how these pathways become dysregulated or co-opted in diseases and whether they can be leveraged for therapeutic intervention or disease prevention.