Introduction

Celiac disease (CeD) is triggered by gluten peptides that bind to HLA-DQ2 or -DQ8 in the small intestinal lamina propria which leads to gluten specific TH1 T cell activation and expansion, small intestinal inflammation, villous atrophy and intraepithelial lymphocytosis (IEL) (1, 2). With emphasis on the gut-brain axis we analyzed the consequences of active CeD inflammation on immune cell activation in the brain.

Aims & Methods

CeD is associated with symptoms of foggy mind, chronic fatigue and depression (3, 4). The immunological communication between the gut and brain axis has not been studied in-depth in CeD, including the relation of behavior and mental functioning with intestinal immune activation and resultant inflammatory changes in the blood and the brain.
NOD-DQ8 mice were sensitized to gliadin and fed a gluten-containing or gluten-free diet for 2 weeks. Key transcripts in the small intestine and brain were analyzed using qPCR and compared to FACS data of both organs.

Results

The brain is an active site of induced inflammation subsequent to CeD induction of the gut, with a highly significant upregulation of cerebral IL17a, IL23a, IL22b, IL6, IL33, Nlrp3 and COX2. Moreover, the brain dopamine/noradrenaline and neuroactive tryptophane metabolism was upregulated by enhanced production of dopamine beta hydroxylase, kynurenine-3-monooxigenase (KMO) and quinolinate phosphoribosyl transferase (Qprt).

Conclusion

The significant proinflammatory cytokine production in the brain of humanized NOD DQ8 mice with active CeD confirms a gut-brain immune communication in CeD. This is accompanied by elevated transcript levels of inflammation-induced mediators. Importantly, enzymes encoding neurotransmitter synthesis are upregulated, which may explain fatigue and mental dysfunction in patients with active CeD.

References

(1) Lindfors, K., Ciacci, C., Kurppa, K., Lundin, K. E. A., Makharia, G. K., Mearin, M. L., Murray, J. A., Verdu, E. F., & Kaukinen, K. (2019). Coeliac disease. Nature reviews. Disease primers, 5(1), 3. https://doi.org/10.1038/s41572-018-0054-z
(2) Verdu, E. F., & Schuppan, D. (2021). Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. Gastroenterology, 161(5), 1395–1411.e4. https://doi.org/10.1053/j.gastro.2021.08.016
(3) Belpınar, A., Dağ, Y. S., Arıcıoğlu Sülün, A., Yayan, E. H., & Varol, F. İ. (2023). The effect of anxiety and depression levels of children with celiac disease on quality of life. Journal of pediatric nursing, 73, e260–e265. https://doi.org/10.1016/j.pedn.2023.09.019
(4) Sharma, N., Singh, K., & Senapati, S. (2021). Celiac disease poses significant risk in developing depression, anxiety, headache, epilepsy, panic disorder, dysthymia: A meta-analysis. Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology, 40(5), 453–462. https://doi.org/10.1007/s12664-021-01215-2

Introduction

Emerging evidence suggests that poor oral health may play a role in gastrointestinal carcinogenesis through inflammatory and microbiome-mediated mechanisms. However, its association with esophageal cancer remains insufficiently explored.

Aims & Methods

We aimed to assess the association of oral health indicators and oral hygiene behaviors with esophageal cancer risk using both dental health screening and claims-based data. We conducted a population-based case-control study using the Korean National Health Insurance Service (NHIS) database and the National Health Screening (NHS) records. To enhance the reliability of our study, we examined oral hygiene from two complementary perspectives: (1) oral health assessed through dental examinations and questionnaires in the NHS database and (2) periodontal disease status determined based on a claim-based analysis of the NHIS database. Individuals newly diagnosed with esophageal cancer were identified and matched at a 1:4 ratio to cancer-free controls through rigorous propensity score (PS) matching based on sociodemographic factors, comorbidities, lifestyle behaviors, and laboratory parameters. Oral health variables were assessed using national dental screening program data (status of decayed, missing, and filled teeth; gingivitis severity; dental calculus; and self-reported oral hygiene practices) and NHIS claims data identifying periodontal disease using ICD-10 codes and procedure codes. Multivariable-adjusted conditional logistic regression analyses were performed to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs).

Results

After PS matching, the oral health analysis included 4,238 cancer cases and 16,904 controls, while the claim-based periodontal disease analysis comprised 18,905 cancer cases and 75,604 matched controls in the final analysis. In multivariable analysis, missing teeth (adjusted OR, 1.16; 95% CI, 1.08–1.25) and inadequate oral hygiene behaviors—including brushing fewer than three times daily (aOR, 1.14; 95% CI, 1.07–1.23), infrequent toothbrushing before bedtime (aOR, 1.08; 95% CI, 1.00–1.16), infrequent use interdental cleaning tools (aOR, 1.10; 95% CI, 1.01–1.19), and dental visits in the past year (aOR, 1.09; 95% CI, 1.02–1.16)—were significantly associated with an increased risk of esophageal cancer. Additionally, claim-based periodontal disease was independently associated with elevated risk (aOR, 1.05; 95% CI, 1.01–1.09). Subgroup analyses revealed consistent associations across smoking and obesity strata, while sex-, age-, and alcohol-stratified analyses demonstrated differential patterns.

Conclusion

This study provides comprehensive, population-based evidence that both clinically assessed dental health indicators and behavioral oral hygiene practices are associated with esophageal cancer risk. The integration of screening-based and claims-based data enhances the validity of the findings and highlights oral health as a potential modifiable risk factor for esophageal cancer prevention.