Mast cells, eosinophils, and intestinal permeability in gastrointestinal disorders

Disorders of gut-brain interaction (DGBI) are related to a range of factors including unbalanced gut microbiota, low-grade immune activation, neural hyperexcitability, visceral hypersensitivity, and intestinal barrier dysfunction. Regarding the involvement of neuroimmune interactions in abdominal pain, Javier Aguilera-Lizarraga from the University of Cambridge reviewed mechanistic evidence that mast cells can be activated by the microbiota (e.g. intestinal fungi). Subsequent release of histamine then causes pain by afferent activation. Recent evidence also suggested that the intestinal microbiome itself can be a source of histamine that contributes to visceral pain. Furthermore, it appears that gut infections can trigger localized dietary antigen specific immune responses that cause foods to be perceived as harmful, leading to persistent abdominal pain.

Identification of a mechanism in the gut that underlies food-induced abdominal pain. Source: Aguilera-Lizarraga’ talk at NeuroGASTRO 2023.

 

Beyond mast cells, eosinophils are also emerging as relevant players in gastrointestinal disorders. Edoardo Savarino from the University of Padova updated factors involved in eosinophilic esophagitis (EoE) pathogenesis, which is one of the most common eosinophilic gastrointestinal disorders. It is a chronic inflammatory disease which is likely to be primarily activated by food antigens. Altered esophageal and salivary microbiota composition was reported, even independent of disease activity. The latter may help discriminate between patients with EOE and non-EOE subjects.

It is noteworthy that eosinophils can also be involved in persistent gastrointestinal symptoms beyond the esophagus. Lucas Wauters from the KU Leuven University shared data involving duodenal eosinophilic infiltration in functional dyspepsia. Along with reduced clinical symptoms, proton pump inhibitor (PPI) treatment also diminished barrier dysfunction as well as mast cell and eosinophil counts. Wauters also showed the decrease in mucus-associated Neisseria and Porphyromonas in functional dyspepsia correlated with symptoms and duodenal eosinophils and Streptococcus abundance remained higher in patients with functional dyspepsia that stopped PPI. Based on these and other findings a randomized control trial with probiotics was conducted. Probiotics were efficacious and clinical response associated with changes in immune and microbiota parameters. Overall, these findings suggest that the duodenal microenvironment should no longer be overlooked in DGBI.

 

Duodenal eosinophilia emerges as a pathophysiological mechanism and therapeutic target in functional dyspepsia. Source: Wauters’ talk at NeuroGASTRO 2023.

 

Intestinal permeability is also key in neurogastroenterology, and a specific session was focused on ongoing translational research in the field. Ricard Farré from the KU Leuven showed that paracellular and transcellular intestinal permeability is increased in patients with functional dyspepsia, active ulcerative colitis, ulcerative in remission, IBS with mixture pattern, and celiac disease. Whether barrier dysfunction is a primary or secondary events is not known, but indications are that increased permeability may lead to enhanced translocation of microbiota members or components that play a role in the pathogenesis of the aforementioned diseases and disorders.

Giovanni Barbara from the University of Bologna presented new findings on the alteration of the intestinal and vascular barrier in patients with IBS, which correlate with gastrointestinal (e.g., abdominal pain severity and frequency) and extra-gastrointestinal symptoms (e.g., anxiety and depression score). Importantly, patients also showed enhanced presence of bacterial genetic material in blood, suggesting that the observed epithelial and vascular alterations lead to microbiome translocation events.  Interestingly, based on findings from the DISCOVERIE project, Alice Rustichelli from the KU showed that patients with IBS with and without comorbidities have a reduced small intestinal permeability but a normal colonic permeability, compared to healthy controls. The latter contradicts the Bologna findings and needs further investigation.

 

An altered intestinal and vascular barrier is associated with increased microbiome translocation in patients with IBS. Source: Barbara’s talk at NeuroGASTRO 2023.

 

The role of food and diet in the management of bowel disorders

Up to 60-80% of patients report that food triggers or exacerbates abdominal symptoms which means a poor food-related quality of life (enjoyment, frustration and achieving adequate nutrition through eating and drinking). This situation drives patients to change their eating habits based on their belief of how food impacts symptoms. Mechanisms through which food can trigger IBS symptoms include immune activation (food hypersensitivity), the presence of bioactive compounds (e.g., capsaicin of chili peppers) and FODMAP components that are fermented by the colonic microbiota. Diet is also known to change microbiome composition and function.

Specific foods such as fat, carbohydrates, dairy, fruit and vegetables are those that most commonly resulted in symptoms in patients with IBS, with the number of food items avoided correlated with the severity of symptoms.

Sanna Nybacka from the University of Gothenburg updated the lights and shadows of common restrictive dietary approaches in IBS: low FODMAP diet, gluten free diet and low carbohydrate diet. The low FODMAP diet has an established treatment algorithm consisting in three phases (restriction for 4-8 weeks, reintroduction for 6-10 weeks and FODMAP personalization), and is the most researched restrictive diet for IBS. Some caveats of the low FODMAP diet are unknown long-term effectiveness, mechanisms, and educational delivery. When it comes to gluten-free diet and low carbohydrate diet, today we have insufficient evidence to recommend them.

Overall, the downsides of restrictive diets, as acknowledged by Nybacka, include that they can negatively impact nutrient intake, they can negatively impact food-related quality of life, and they can lead to disordered eating. In particular, 6% of patients undergoing neurogastro examination met full criteria for avoidant/restrictive food intake disorder motivated by concerns about fear of consequences, sensory issues, and lack of interest in food. Healthcare professionals should thus consider screening for disordered eating behaviors in patients undergoing neurogastroenterology or motility examinations, particularly when providers consider dietary interventions.

Working flow for dietary management of patients with abdominal pain associated with diarrhea and/or constipation according to the American Gastroenterology Association. Source: Nybacka’s talk at Neuro GASTRO 2023.

 

Further reading:

Duodenal eosinophilia, mast cells, and permeability in patients with functional dyspepsia:

 

Food and diet in DGBI: