Recent understanding of the pathophysiology of functional dyspepsia: role of the duodenum as the pathogenic center

Abstract

Over almost 30 years since functional dyspepsia (FD) was defined, researchers have endeavored to elucidate the pathophysiology of functional gastrointestinal disorders. Now a consensus is emerging that the gastric symptoms of FD are caused mainly by gastric motility abnormalities and gastric hypersensitivity. The involvement of other causative factors including acid, Helicobacter pylori, psychological factors, and diet has been debated, but how they are involved in the manifestation of dyspeptic symptoms remains unclear. We believe that most of those factors cause FD symptoms by inducing gastric motility abnormalities and gastric hypersensitivity via the duodenum. Here, we discuss 2 possible reasons why patients with FD experience chronic upper abdominal symptoms: (1) the possibility that the contents of the duodenum of patients with FD differ from those of healthy persons and the different contents stimulate the duodenum, and (2) the possibility that the duodenum of patients with FD is more sensitive to noxious stimuli because of low-grade inflammation and increased mucosal permeability.

Keywords: Duodenum; Dyspepsia; Microinflammation; Pathophysiology; Permeability.

Fig. 1

Although excessive response to stress is thought to underlie the pathophysiology of functional gastrointestinal (GI) disorders, there are factors that cause the excessive response. As we previously proposed, we think that the factors that contribute to manifestation of symptoms by patients with functional dyspepsia (FD) can be broadly divided into 3 categories. Zone A includes genetics, GI infections, and the environment early in life, especially stressful events; Zone C consists of the physiological abnormalities that directly cause FD symptoms, namely gastric motility abnormalities and gastric hypersensitivity; and Zone B includes numerous other factors—such as Helicobacter pylori infection, gastric acid, and diet—that modify the Zone C factors by acting on the duodenum. In this model, the duodenum can be thought of as the pathogenic center of FD

Fig. 2

Duodenal events that may be occurring in patients with FD are shown schematically. Dyspepsia is caused by gastric motility abnormalities and gastric hypersensitivity that result from transmission of noxious stimuli from the duodenum by afferent nerves. The duodenums of patients with FD are thought to be susceptible to such stimulation. Associated with that susceptibility are two key pathogenic features—increased mucosal permeability and low-grade inflammation—which really are two sides of the same coin. The duodenal lumen has a wide variety of contents including acid, bile acids, lipids, food-derived substances, and enteric bacteria. Increased mucosal permeability would allow these contents to penetrate the mucosa, where they would be recognized by immune cells and then targeted by inflammatory cells. Such contents also might be able to stimulate submucosal afferent nerves and thereby cause physiological abnormalities in the stomach that result in dyspeptic symptoms. Duodenal contents also might directly stimulate duodenal mucosal cells, which as a result would then release inflammatory mediators that excite afferent nerves. Priming of the duodenum by low-grade inflammation caused by psychological stress or remaining after severe gastrointestinal infection (salmonellosis, dysentery, etc.) may be another important factor in FD pathogenesis. Because of the inflammation, sensory nerves would be sensitized by inflammatory mediators and cytokines released by eosinophils, mast cells, macrophages, and other inflammatory and immune cells, and mucosal permeability would be increased, making the duodenum more susceptible to effects from its contents. Thus, sensitization and priming of duodenal mucosa as a result of low-grade inflammation and increased mucosal permeability may be related to chronic FD symptoms