Beyond Eosinophilic Esophagitis: Eosinophils in Gastrointestinal Disease-New Insights, "New" Diseases

Abstract

Functional dyspepsia (FD) is a highly prevalent disorder. Upper endoscopy is normal, and according to the Rome IV criteria, there is no established pathology. Data accumulated over the last 15 years has challenged the notion FD is free of relevant pathology, and in particular, increased duodenal eosinophils have been observed. Intestinal eosinophils play important roles in microbial defence, immune regulation, tissue regeneration and remodelling, and maintaining tissue homeostasis and metabolism; degranulation of eosinophils releases toxic granule products (e.g., major basic protein, eosinophil-derived neurotoxin) which can damage nerves. Normal cut-offs for eosinophil infiltration into the duodenum histologically are less than five eosinophils per high power field (<25 per five high power fields). In clinical practice there is evidence that pathologically increased intestinal eosinophils may often be overlooked. In a meta-analysis duodenal eosinophils were significantly increased in FD although there was substantial heterogeneity; degranulation of duodenal eosinophils was also significantly higher in FD without significant heterogeneity. In addition, increased duodenal permeability, systemic immune activation, and an altered mucosa-associated duodenal microbiome have been identified that may help explain why symptoms arise, often occur after food with exposure to food antigens, and typically fluctuate. Several potentially reversible risk factors for FD have now been identified. We evaluate the current evidence linking duodenal microinflammation and immune activation with FD and disorders of gut-brain interactions that overlap with FD. We propose a two-hit disease model for eosinophilic functional dyspepsia (EoFD) with management implications.

Keywords: Eosinophils; food antigens; functional dyspepsia; mast cells; microbiome.

Fig. 1.

Increased duodenal eosinophils in functional dyspepsia (FD) versus healthy controls. Biopsies were collected from the second portion of the duodenum (D2) of FD patients and controls and stained with (A) haematoxylin and eosin (40× magnification, arrows indicate eosinophils, circles indicate intra-epithelial lymphocytes (IELs) scale bar = 50μm). (B) Average duodenal eosinophil counts per five high powered fields were examined between controls and FD. (C) Average duodenal eosinophil counts within the FD subtypes. (D) Duodenal intra-epithelial lymphocytes (IELs) were counted across groups using H&E-stained sections and were not increased. (E) Immunohistochemical staining of CD117+ mast cells performed (20× magnification, arrows indicate CD117+ cells, scale bar = 50μm). (F) Mast cells were counted based on CD117+ positively stained cells (brown) in all groups. Mast cells based on immunohistochemical staining of CD117+ were not increased. n = 15–22 for controls, n = 38–67 for FD, n = 24 postprandial distress syndrome (PDS), n = 43 epigastric pain syndrome (EPS) ± PDS. Data presented as mean ± SEM. From Burns G. et al. Front Immunol. 6, no. 13 (January 2023): 1051632. doi: 10.3389/fimmu.2022.1051632.

Fig. 2.

Duodenal mucosa-associated microbiome in functional dyspepsia versus controls by 16S rRNA gene sequencing. Differences in relative abundance of bacterial genera between patients with functional dyspepsia (FD) and controls were established using the Mann–Whitney U test, with false discovery rate (FDR) correction for multiple comparisons. The dominant phylum are Firmicutes, genus Streptococci. From Zhong L, Shanahan ER, Raj A, Koloski NA, Fletcher L, Morrison M, Walker MM, Talley NJ, and Holtmann G. “Dyspepsia and the Microbiome: Time to Focus on the Small Intestine.” Gut 66, no. 6 (June 2017):1168–1169. Copyright 2017 by GUT. Figure reproduced with permission of GUT in the format of a figure via Copyright Clearance Center.

Fig. 3.

Pathogenesis of eosinophilic functional dyspepsia (EoFD): two-hit hypothesis. 1. The duodenal barrier is breached after infection, exposure to cigarettes or drugs, or in acute stress. 2. In a genetically primed individual, antigen presentation to the small intestinal mucosa then occurs (food macromolecules and/or microbial antigens). 3. Activation of eosinophils and mast cells through an immune cascade. 4. Local nerve sensitization and systemic immune activation leading to symptomatology. 5. Maintenance of a low-grade state of inflammation through bidirectional gut–brain and brain–gut pathways resulting in fluctuating symptoms [Image created in BioRender].