From stomach tissue to cellular mechanisms: unraveling the role of mononuclear phagocytes in the pathophysiology of gastroparesis

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ABSTRACT Gastroparesis is a chronic gastrointestinal motility disorder characterized by delayed gastric emptying, chronic abdominal pain, nausea and vomiting. Its incidence has increased 3-fold in the last decade, which has increased healthcare costs by 10-fold. It is suggested that immune dysregulation plays a role in the pathophysiology of the disease; however, the immune cellular mechanisms remain largely unknown, especially in humans. This is largely in part because of limited knowledge on the types and functions of immune cells present in the human stomach. This gap in knowledge presents a significant barrier to understanding the cellular mechanisms of disease, and for the rational design of novel therapeutic strategies. Our preliminary data using mass cytometry (CyTOF) shows that the human stomach harbors mononuclear phagocyte populations that are more diverse than previously appreciated. Our studies also point, for the first time, to a disease that affects not only the stomach muscularis as previously suggested, but also the stomach mucosa. Importantly, mononuclear phagocytes in the mucosa of gastroparesis patients are dysregulated in numbers and function, which correlates with delayed stomach emptying. Based on these data, our central hypothesis is that gastroparesis patients harbor dysregulated mucosa and muscularis mononuclear phagocytes that contribute to the pathophysiology of the disease. In three specific aims, we propose to resolve the identity and dysregulation of stomach mucosa and muscularis mononuclear phagocytes in gastroparesis patients at a resolution that has not been done until now. We will also explore the role of a neuronal peptide in modulating stomach mononuclear phagocyte function during gastroparesis. To achieve these aims, we will take advantage of approaches that allow for the identification of mononuclear phagocytes in an unbiased fashion. These approaches will be combined with ex vivo functional assays and a mouse model of stomach emptying with the goal of unraveling cellular mechanisms of disease. Our rationale is that by investigating the identity, i.e., phenotype and function, of human stomach mononuclear phagocytes, we can elucidate the cellular mechanisms underpinning delayed stomach emptying in gastroparesis. This proposal has the potential to impact the rational design of therapeutic strategies for gastroparesis.