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.

Introduction

Functional dyspepsia (FD) is associated with duodenal eosinophilia and gut microbiota dysbiosis. Proton pump inhibitors (PPIs), as a first-line therapy, can suppress duodenal eosinophilic inflammation to ameliorate symptoms, yet the symptom relief rate is low. Rifaximin (RIF), an antibiotic known to modulate the gut microbiota, may offer an alternative therapeutic avenue. It is hypothesized that combining RIF with PPIs could more effectively alleviate FD symptoms and duodenal inflammation by targeting the gut microbiota.

Aims & Methods

A single-center, open-label, randomized controlled clinical trial was conducted on subjects who met the inclusion and exclusion criteria (Trial registration: ChiCTR2300069313). Ninety-six patients were randomly assigned in a 1:1 ratio to either the PPI+RIF group or the PPI group. The follow-up period extended to 4 weeks post-treatment cessation. The primary endpoint was the symptom relief rate, while secondary endpoints included symptom response rate, duodenal eosinophil counts, and changes in the microbiota. The study hypothesis was that the clinical efficacy of PPI+RIF would be superior to that of PPI monotherapy.

Results

	PPI+RIF	PPI	Z value	P value	PPI+RIF	PPI	Z value	P value
Abbreviations: PPI+RIF: Proton Pump Inhibitor plus Rifaximin; PPI: Proton Pump Inhibitor; ITT: the intention-to-treat analysis;PP: the per-protocol analysis.
Symptom relief rate	ITT				PP
Week 2	54.2%（26/48）	54.2%（26/48）	0.000	0.500	53.7%（22/41）	53.3%（24/45）	0.030	0.488
Week 4	72.9%（35/48）	58.3%（28/48）	1.522	0.064	76.7%（33/43）	56.8%（25/44）	2.020	0.022
4 weeks post-treatment	77.1%（37/48）	47.9%（23/48）	3.095	0.001	78.6%（33/42）	48.9%（22/45）	3.036	0.001
Symptom response rate	ITT				PP
Week 2	70.8%（34/48）	72.9%（35/48）	-0.227	0.590	68.3%（28/41）	73.3%（33/45）	-0.514	0.696
Week 4	81.3%（39/48）	77.1%（37/48）	-0.503	0.307	83.7%（36/43）	75.0%（33/44）	1.012	0.156
4 weeks post-treatment	85.4%（41/48）	68.8%（33/48）	1.982	0.024	85.7%（36/42）	71.1%（32/45）	1.688	0.046

A total of 96 patients were enrolled in the randomized controlled study. There were no statistically significant differences in baseline demographic data and clinical characteristics between the two groups. According to the intention-to-treat (ITT) analysis, the PPI+RIF group showed significantly higher rates of symptom relief (P = 0.001) and symptom response (P = 0.024) at 4 weeks post-treatment. These findings were supported by the per-protocol (PP) analysis, which revealed a superior symptom relief rate for the combination group at both 4 weeks of treatment (P = 0.022) and 4 weeks post-treatment (P = 0.001), as well as a superior symptom response rate at 4 weeks post-treatment (P = 0.046). Combination therapy also led to a greater reduction in duodenal eosinophil infiltration (P = 0.036) and significantly decreased peak hydrogen sulfide (H₂S) levels (P < 0.001), indicating a reduction in small intestinal bacterial load. Oral microbiota analysis revealed that β-diversity of the oral flora increased following the PPI+RIF intervention, with an increased relative abundance of Enterococcus (P = 0.004). Conversely, the PPI intervention led to the enrichment of the potentially pathogenic bacterium Catonella (P = 0.006). Notably, treatment responders in the PPI+RIF group showed a specific enrichment of the Eubacterium_yurii_group (P = 0.037), an alteration associated with the amelioration of duodenal eosinophilic inflammation and the enhancement of pathways related to preventing bacterial invasion of the epithelium.

Conclusion

In patients with FD, combining a PPI with Rifaximin is superior to PPI monotherapy, improving both symptoms and duodenal eosinophil infiltration. This effect is linked to a reduction in H₂S-producing bacteria and a beneficial shift in the oral microbiota. The oral abundance of Eubacterium_yurii_group may serve as a biomarker for treatment response.

Disclosure

The authors declare that they have no conflicts of interest.