Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

Abstract

Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.

Research trends in the field of the gut-brain interaction: Functional dyspepsia in the spotlight – An integrated bibliometric and science mapping approach

“…In contrast, few studies have demonstrated changes in stomach immune cell profiles, none of which are associated with symptoms of FD ( Futagami et al, 2010 ; Li et al, 2010 ; Pasricha et al, 2021 ), confirming that dyspeptic symptoms do not directly correlate with gastric pathophysiology. Accordingly, this further strengthens the notion that the duodenum is likely to be the key pathogenic organ for FD in that impaired duodenogastric communication is induced by duodenal abnormalities therefore generating FD symptoms ( Vanheel and Farré, 2013 ; Wauters et al, 2020a ; Ceulemans et al, 2022 ). Furthermore, increased mast cells and degranulation was found in the duodenum of FD patients in addition to the eosinophilic infiltration ( Vanheel et al, 2014 ; Cirillo et al, 2015 ; Taki et al, 2019 ), although these findings were not always consistent ( Tanaka et al, 2016 ; Puthanmadhom Narayanan et al, 2021 ), nevertheless substantiating the concept of an eosinophil-mast-cell axis ( Wechsler et al, 2021 ).…”

Understanding neuroimmune interactions in disorders of gut–brain interaction: from functional to immune-mediated disorders

“…Since then, several groups reported similar findings and a meta-analysis confirmed increased T-cells in the lamina propria of the rectosigmoid 57. In contrast, gastroduodenal lymphocyte infiltration, including intra-epithelial lymphocyte counts, does not come up as a consistent feature of FD,58 59 even if two small studies reported elevated CD8+T cell counts and aggregates in postinfectious FD 60 61. Peripheral blood lymphocytes expressing gut-homing markers were increased in FD40 and IBS 62–64.…”

“…Moreover, as discussed above, IBS supernatant-induced hyperreactivity of neurons which could be blocked by histamine receptor H1 antagonists and protease inhibitors, underscoring the importance of mast cell derived soluble mediators in neuronal hyperreactivity 32 33 47. The role of mast cells in FD is less established, although a few studies have shown increased duodenal mast cell counts 59 69. Mast cell activation in FD is suggested by a study using electron microscopy showing more heterogeneous granules in duodenal mast cells in FD and evidence of increased release of histamine and tryptase from gastric biopsies 36 70.…”

“…In FD, however, a more prominent role has been attributed to duodenal eosinophil infiltration which has been reported by multiple groups (figure 4). 69 Duodenal eosinophils as well as their activation and degranulation were often also linked to symptoms, although only based on statistical correlations and mechanistic evidence is still largely lacking 59 69. In the initial reports, it was suggested that duodenal eosinophilia was a feature of PDS,72 but a recent meta-analysis showed similar counts in the FD subgroups 69.…”

“…Nevertheless, in none of the mentioned studies, a link between symptom pattern or severity and the immune phenotype could be established. Similarly, large studies are lacking in FD and even if mildly elevated IL-1 and IL6 expression in the duodenal and gastric mucosa have been reported, the findings are limited to single studies with a small sample size 59. One small study found a higher production of the Th2 related cytokines IL-5 and IL-13 by stimulated PBMCs, which is of interest based on the eosinophil-predominant immune signal in FD, although confirmatory data are needed 84.…”