The Duodenal Microenvironment in Functional Dyspepsia

Abstract

Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.

Keywords: Duodenum; Dyspepsia; Eosinophils; Intestinal mucosa; Mast cells.

Figure 1

General overview of the duodenal mucosa. The epithelial cell layer separates the mucosal and luminal part. In the crypts, the stem cell niche is found, from which all other epithelial cell types can differentiate. Enterocytes are the most prominent epithelial cell type. Goblet cells and Paneth cells secrete mucus and anti-microbial products, creating a mucus layer on top of the epithelium that is difficult to permeate by pathogens. The other epithelial cells, enteroendocrine cells and tuft cells are both chemosensory cells, secreting hormones and neuropeptides, and immune- and neuromodulators, respectively. These epithelial cells form intra- and extracellular connections to maintain the integrity of the barrier. MUC2, mucin 2; ZO, zonula occludens; α-cat, α-Catenin; β-cat, β-Catenin.

Figure 2

Graphical overview of alterations in the duodenal epithelial barrier of patients with functional dyspepsia. Several reports have shown increased duodenal permeability in functional dyspepsia (FD) patients, which might be attributed to changes in cell-cell adhesion proteins. The gene expression of tight junction proteins, like zonula occludens (ZO)-1 and claudins were reported to be decreased in FD, whereas the alteration of expression of other cell-cell adhesion proteins has only been shown in single studies. Additionally, goblet cells, a mucus-secreting epithelial cell, were also decreased in patients with FD, while mucin 2 (MUC2), the most common mucin in the mucus layer, expression was increased. α-cat, α-Catenin; β-cat, β-Catenin.

Figure 3

Graphical overview of alterations in the duodenal mucosa of patients with functional dyspepsia. Duodenal eosinophils and mast cells have been implicated in the immune activation observed in functional dyspepsia (FD) patients. Most consistent reports are on the increased activation status of eosinophils, whereas more contradicting results are found for the numbers of eosinophils and mast cells. The implication of both immune cells in FD, leads to the assumption that an eosinophil-mast cell axis might be at play. Both eosinophils and mast cells release specific mediators upon activation, that can damage the epithelial barrier and might activate the other cell type. In addition, patients with FD experience more perceived stress. Chronic stress has been shown to stimulate the release of corticotropin releasing hormone (CRH) from eosinophils, which is mediated by substance P (SP). Gut-homing lymphocytes were increased in patients with FD compared to healthy controls (HC). In addition, an increased T helper (Th)2/Th17 signature was observed in patients compared to HC. Intraepithelial lymphocytes are increased in patients that developed FD after an infection. Lastly, submucosal gliosis was observed in the duodenum of patients with FD. MBP, major basic protein; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin.