Introduction
Gastric visceral hypersensitivity (VH) is a key pathophysiological feature of functional dyspepsia (FD), characterized by enhanced perception of gastric distension and postprandial pain. Recent studies suggest that dietary gluten may act as a pro-nociceptive factor in FD, particularly in individuals without celiac disease but with dyspeptic symptoms. However, mechanisms linking gluten to VH remain elusive.
Aims & Methods
In the clinical arm, multiple linear regression assessed associations between gluten intake and symptom frequency/severity (postprandial fullness, epigastric pain, early satiety), adjusting for age, sex, and BMI. In the experimental arm, Sprague-Dawley rats received either a 20% gluten diet or gluten-free diet for 8 weeks; an iodoacetamide-induced FD model served as a positive control. Gastric sensitivity was evaluated by abdominal withdrawal reflex (AWR) and electromyography (EMG) following surgical placement of a gastric balloon and electrodes. Duodenal and fecal samples were collected for 16S rRNA microbiota profiling and RNA-seq. Histological and molecular analyses included H&E staining, intraepithelial lymphocyte (IEL) counts, RT-qPCR of cytokines, and quantification of GFAP, Substance P, and MAPK components by RT-qPCR, Western blot, or immunofluorescence. Aprepitant (10 mg/kg/day) was administered during the final 2 weeks to assess its therapeutic effect.
Results
A total of 74 patients diagnosed with FD based on Rome IV criteria (EPS (epigastric pain syndrome)+PDS (postprandial distress syndrome): 29, EPS: 12, PDS: 33) and 29 healthy controls were included. FD patients, particularly EPS subtypes, exhibited significantly higher gluten intake than healthy controls (P＜0.001). Multiple linear regression revealed that gluten intake was a significant positive predictor of symptom frequency and severity in FD patients (frequency: β = 0.0407, 95% CI: 0.0197–0.0617, P ＜0.001; severity: β = 0.0230, 95% CI: 0.0091–0.0368, P＜0.01).
In rats, gastric sensitivity in the 20% gluten group was comparable to the iodoacetamide-induced FD model and significantly greater than the gluten-free control group, exhibited by slower weight gain, increased AWR score, higher area under the curve (AUC) of electromyograph and reduced 24-hour food intake. Compared to controls, gluten-fed rats showed reduced fecal abundance of Lactobacillus and Lactococcus, increased Lachnoclostridium, and decreased Lactococcus in duodenal mucosa. Duodenal tissues also exhibited elevated intraepithelial lymphocyte (IEL) counts, increased expression of IL-1β, IL-4, and IL-5, and upregulation of inflammation-related genes Reg1α and Reg3β, indicating low-grade mucosal inflammation. In addition, gluten exposure significantly increased duodenal expression of Substance P (SP), GFAP, and phosphorylated MAPK pathway proteins.
At week 8, rats in the gluten group were treated with either the NK1R antagonist aprepitant or saline. Aprepitant administration significantly attenuated VH, as shown by reduced AWR scores and EMG AUC compared with the gluten+saline group. Aprepitant also suppressed the expression of IL-1β, IL-4, Reg1α, Reg3β, and MAPK-related genes, suggesting a key role of SP-mediated neuroimmune activation in gluten-induced VH.
Conclusion
Long-term high gluten intake induces gastric hypersensitivity, accompanied by gut dysbiosis, mucosal inflammation, and SP-mediated MAPK signaling. Targeting neuroimmune pathways may offer novel therapeutic strategies for gluten-induced epigastric symptom management.
References
POMENTI S, DEVINSKY J, JODORKOVSKY D. Diet for Functional Gastrointestinal Disorders/Disorders of Gut-Brain Interaction [J]. The Medical clinics of North America, 2022, 106(5): 899-912.
SHAH A, KANG S, TALLEY N J, et al. The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity [J]. Gut microbes, 2022, 14(1): 2132078.