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Inverse Association Between Poor Oral Health and Inflammatory Bowel Diseases

  • Weiyao Yin
    Correspondence
    Reprint requests Address requests for reprints to: Weiyao Yin, MD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden. fax: +46-8-31-4975.
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Reproductive Endocrinology, West China Second University Hospital, Sichuan University, Chengdu, China
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  • Jonas F. Ludvigsson
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
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  • Zhiwei Liu
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Ann Roosaar
    Affiliations
    Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Tony Axéll
    Affiliations
    Maxillofacial Unit, Halmstad Hospital Halland, Halmstad, Sweden
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  • Weimin Ye
    Correspondence
    Weimin Ye, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden. fax: +46-8-31-4975.
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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      Background & Aims

      The hygiene hypothesis (a lack of childhood exposure to microorganisms increases susceptibility to allergic diseases by altering immune development) has been proposed as an explanation for the increasing incidence of inflammatory bowel disease (IBD). However, there are few data on the relationship between oral hygiene and development of IBD, and study results have been inconsistent. We investigated the association between poor oral health and risks of IBD, ulcerative colitis (UC), and Crohn’s disease (CD).

      Methods

      We performed a population-based cohort study of 20,162 individuals followed for 40 years (from 1973 to 2012). Residents of 2 municipalities of Uppsala County, Sweden (N = 30,118), 15 years or older, were invited, and among them 20,333 were examined for tooth loss, dental plaques, and oral mucosal lesions at the time of study entry. Other exposure data were collected from questionnaires. Patients who later developed IBD (UC or CD) were identified by international classification codes from Swedish National Patient and Cause of Death Registers. Cox proportional hazards regression was used to estimate hazard ratios for IBD, UC, and CD.

      Results

      From National Patient and Cause of Death Registers, we identified 209 individuals who developed IBD (142 developed UC and 67 developed CD), with an incidence rate of 37.3 per 100,000 person-years. We found an inverse relationship between poor oral health and IBD, especially in individuals with severe oral problems. Loss of 5–6 teeth of the 6 teeth examined was associated with a lower risk of IBD (hazard ratio, 0.56; 95% confidence interval, 0.32–0.98). Having dental plaques that covered more than 33% of tooth surface was negatively associated with CD (hazard ratio, 0.32; 95% confidence interval, 0.10–0.97).

      Conclusions

      In a population-based cohort study of more than 20,000 people in Sweden, we associated poor oral health with reduced risk of future IBD.

      Keywords

      Abbreviations used in this paper:

      CD (Crohn’s disease), CI (confidence interval), HR (hazard ratio), IBD (inflammatory bowel disease), ICD (International Classification of Diseases), OML (oral mucosal lesion), PIN (Personal Identity Number), RAU (recurrent aphthous ulcer), UC (ulcerative colitis)
      See editorial on page 532.
      The incidence of inflammatory bowel disease (IBD), including the 2 subtypes ulcerative colitis (UC) and Crohn’s disease (CD), has increased worldwide in recent years.
      • M’Koma A.E.
      Inflammatory bowel disease: an expanding global health problem.
      The prevalence of IBD identified in the Swedish Patient Register in 2010 was 0.65%.
      • Busch K.
      • Ludvigsson J.F.
      • Ekstrom-Smedby K.
      • et al.
      Nationwide prevalence of inflammatory bowel disease in Sweden: a population-based register study.
      Environmental factors, such as westernization and modernization, are thought to be responsible for the rise of IBD.
      • Lakatos P.L.
      Environmental factors affecting inflammatory bowel disease: have we made progress?.
      Among various potential causes, the hygiene hypothesis is frequently pointed out. It suggests that absence of microbial exposure because of improved hygienic conditions causes an immunologic imbalance that predisposes to autoimmune diseases, such as IBD.
      • Singhal S.
      • Dian D.
      • Keshavarzian A.
      • et al.
      The role of oral hygiene in inflammatory bowel disease.
      The relationship between oral health and IBD has been debated because earlier studies show contradictory results. One study showed that patients with IBD reported more frequent tooth brushing, use of dental floss, and breath fresheners,
      • Singhal S.
      • Dian D.
      • Keshavarzian A.
      • et al.
      The role of oral hygiene in inflammatory bowel disease.
      whereas a Jordanian case-control study found no association between oral hygiene behaviors and IBD.
      • Habashneh R.A.
      • Khader Y.S.
      • Alhumouz M.K.
      • et al.
      The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study.
      Data on the number of teeth and oral infections in patients with IBD as compared with healthy control subjects are conflicting,
      • Singhal S.
      • Dian D.
      • Keshavarzian A.
      • et al.
      The role of oral hygiene in inflammatory bowel disease.
      • Habashneh R.A.
      • Khader Y.S.
      • Alhumouz M.K.
      • et al.
      The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study.
      • Vavricka S.R.
      • Manser C.N.
      • Hediger S.
      • et al.
      Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.
      • Brito F.
      • de Barros F.C.
      • Zaltman C.
      • et al.
      Prevalence of periodontitis and DMFT index in patients with Crohn's disease and ulcerative colitis.
      whereas oral diseases, such as periodontitis, gingivitis, or oral lesions, seem to be more common in patients with IBD.
      • Habashneh R.A.
      • Khader Y.S.
      • Alhumouz M.K.
      • et al.
      The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study.
      • Vavricka S.R.
      • Manser C.N.
      • Hediger S.
      • et al.
      Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.
      • Grossner-Schreiber B.
      • Fetter T.
      • Hedderich J.
      • et al.
      Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study.
      Frequently referred as an extraintestinal manifestation of IBD, to our knowledge the correlation of recurrent aphthous ulcer (RAU) and risk of IBD has not been studied.
      • Vavricka S.R.
      • Brun L.
      • Ballabeni P.
      • et al.
      Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort.
      This most common oral mucosal disease was thought to be initiated by oral microbiome changes in some studies.
      • Slebioda Z.
      • Szponar E.
      • Kowalska A.
      Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review.
      • Hijazi K.
      • Lowe T.
      • Meharg C.
      • et al.
      Mucosal microbiome in patients with recurrent aphthous stomatitis.
      To explore these uncertainties, we investigated the association between poor oral health and risk of IBD in a cohort of more than 20,000 individuals undergoing a baseline dental examination. To our knowledge, this is the first prospective cohort study exploring the association between oral health and IBD.

      Methods

       The Cohort and Follow-Up

      To evaluate the prevalence of oral mucosal lesions (OMLs) in the general population in Sweden, a population-based survey was carried out in the Uppsala county municipalities of Enköping or Håbo in 1973–1974.
      • Axell T.
      A prevalence study of oral mucosal lesions in an adult Swedish population.
      All residents (N = 30,118) aged 15 years or older were offered clinical oral examinations and asked to respond to questionnaires. In the first call, 18,659 individuals were examined. Among the nonparticipants, another 1674 joined in the second round out of 2292 randomly summoned individuals. Thus, a total of 20,333 individuals (68% of the initially invited residents) were enrolled and 20,212 made up the follow-up cohort after excluding missing or unreadable data.
      • Roosaar A.
      • Johansson AL.
      • Sandborgh-Englund G.
      • et al.
      Cancer and mortality among users and nonusers of snus.
      Among the excluded 121 individuals were 84 with incorrect Personal Identity Numbers (PINs), 14 with changed PINs during follow-up, 8 with illegible data, and 15 with more than 1 examination record (we only considered the first record). For the main analysis, the final study cohort comprised of 20,162 individuals after further exclusion of 9 individuals with missing data on covariates and 41 individuals with IBD diagnosed before study entry. Figure 1 shows the study recruitment.
      Figure thumbnail gr1
      Figure 1Flow chart of recruitment of the cohort. During 1973–1974, a population-based cohort in Uppsala County was created. All residents in 2 municipalities aged 15 years or older were invited. The final study cohort comprised of 20,162 individuals after ruling out individuals with missing data in covariates or an earlier IBD diagnosis.
      The cohort was followed up between January 1973 and December 2012. Through the individually unique PIN
      • Ludvigsson J.F.
      • Otterblad-Olausson P.
      • Pettersson B.U.
      • et al.
      The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.
      distributed to every Swedish resident, we were able to link oral health data with the Patient Register, Cause of Death Register, and Total Population Register, to ascertain incident IBD cases, deaths, and migrations.

       Oral Examination and Questionnaires

      Tooth number, dental plaque, and OMLs were examined at the time of entry. All clinical inspections were performed by a dentist with the study participants placed in a dental chair. Ramfjord index teeth (#16, #21, #24, #36, #41, and #44) were examined to assess baseline condition of dental losing. Because of a good correlation with full-mouth assessment for periodontal disease, Ramfjord teeth has become one of the most commonly used teeth subsets in epidemiologic study. Missing 0, 1–4, and 5–6 of the previously mentioned selected teeth was assumed to correlate with 21–32, 11–20, and 0–10 teeth at baseline.
      • Ramfjord S.P.
      The Periodontal Disease Index (PDI).
      Accurate measurement of dental plaque status could only be guaranteed when at least 2 teeth out of the 6 examined remained. Among people with 2 teeth or more, dental plaque status was categorized into 3 groups: (1) no dental plaque, (2) acceptable dental plaque (exposed tooth surface ≤33%), and (3) unacceptable dental plaque (exposed tooth surface >33%). OMLs were categorized into 3 types, which are closely related with oral hygiene: (1) fungal-associated OMLs (angular cheilitis, pseudomembranous candidiasis, chronic candidiasis, atrophic and nodular leukoplakia, median type of atrophy of tongue papillae, and unspecified glossitis), (2) denture-associated OMLs (localized, generalized, or papillomatous denture stomatitis; denture hyperplasia; traumatic ulcer; and flabby ridges), and (3) tongue lesions (lingua fissurata, plicated tongue, atrophy of tongue papillae, hairy tongue, coated tongue, median rhomboid glossitis, and unspecified glossitis).
      • Axell T.
      A prevalence study of oral mucosal lesions in an adult Swedish population.
      • Huang J.
      • Roosaar A.
      • Axell T.
      • et al.
      A prospective cohort study on poor oral hygiene and pancreatic cancer risk.
      The reference group here consisted of individuals without OMLs. Considering that most patients with RAU might not present active ulcers in the examination, we combined current RAU and history of RAU into 1 variable. Data on self-reported tobacco use (nonsmoker, ex-smoker, current smoker, non–smokeless moist snuff user, ever smokeless moist snuff user, or combined tobacco use) were obtained through questionnaires. Alcohol consumption data, including never or low consumption (less than once a week), moderate consumption (1–2 times a week), or high consumption (3 or more a week) were also from questionnaires. We also collected information of living areas (small town, rural, or small community) as a socioeconomic covariate.

       Inflammatory Bowel Disease Diagnosis

      The National Patient Register, established in the 1960s by the National Board of Health and Welfare, possesses information on inpatients with main and contributory diagnoses on the basis of the International Classification of Diseases (ICD). The coverage of the National Patient Register reached 100% for inpatients from 1987. Hospital-based outpatient care visits were included in 2001.
      • Ludvigsson J.F.
      • Andersson E.
      • Ekbom A.
      • et al.
      External review and validation of the Swedish national inpatient register.
      IBD was defined as having a main or contributory diagnosis either for UC (ICD7 572,20, 572,21, 578,03; ICD8 563,10, 569,02; ICD9 556; ICD10 K51) or for CD (ICD7 572,00, 572,09; ICD8 563,00; ICD9 555; ICD10 K50) according to the National Patient Register or an underlying cause of death according to Cause of Death Register.
      • Busch K.
      • Ludvigsson J.F.
      • Ekstrom-Smedby K.
      • et al.
      Nationwide prevalence of inflammatory bowel disease in Sweden: a population-based register study.
      Only the first diagnosis of IBD was considered. To ensure the specificity, sensitive analysis was carried out among patients having at least 2 visit records.

       Statistical Analysis

      We calculated person-time for each subject from the date entering the cohort until the date being censored. The exit date was determined by the date of IBD diagnosis, emigration out of Sweden, death, or end of follow-up (December 31, 2012), whichever occurred first. Differences in baseline characteristics among patients with IBD and normal population were compared by chi-square test for categorical variables and Student t test for continuous variables. Age-adjusted incidence rates, standardized by age distribution in 5-year-intervals, were computed by person-time experienced by the whole cohort. To evaluate relative risks of IBD, we estimated hazard ratios (HRs) using Cox proportional hazards regression models, with 95% confidence intervals (CIs). The model used attained age as the underlying time-scale, adjusted for sex, tobacco use, alcohol consumption, and residential areas. We also adjusted for attained calendar period in 10-year intervals (1973–1982, 1983–1992, 1993–2002, and 2003–2012). Assumption of proportional hazards was tested by the method of Schoenfeld residuals and none of the exposure variables and covariates showed violation of the assumption.
      Interactions between sex and exposure variables were checked by creating an interaction term (sex*oral health indicators) in the model. Sensitivity analyses were conducted by excluding the first 2 or 5 years of follow-up, to rule out the possibility of reverse causation. Two-sided P values set at 5% were considered statistically significant. SAS version 9.4 (SAS institute, Cary, NC) was used for all statistical analyses.

       Ethical Considerations

      Ethical approvals for original study and further cross-linkage to health and demographic registers were granted by the ethics committee of the Medical Faculty at Uppsala University and the Stockholm Regional Ethics Vetting Board. Informed consent was obtained from all participants.

      Results

       Individuals and Characteristics of Inflammatory Bowel Disease

      During the total follow-up period (maximum, 40 years; mean, 28 years) all participants (N = 20,162) contributed 560,288 person-years. IBD was diagnosed in 209 individuals, rendering an incidence rate of 37.3 per 100,000 person-years. Among them, 142 had UC (68%) and 67 had CD (32%), with incidence rates of 25.3 and 12.0 per 100,000 person-years, respectively. People diagnosed with IBD were younger at the baseline examination with a shorter follow-up period compared with non-IBD individuals. Patients with IBD also smoked more than the normal population. Baseline characteristics of individuals are summarized in Table 1.
      Table 1Baseline Characteristics of the Cohort
      IBDNon-IBD caseP values
      TotalUCCD
      Total2091426719,953
      Sex.91
       Male10472329847
       Female105703510,106
      Age at entry (y)
       Mean38.343.7<.0001
       14–244025152941
       25–345335184470
       35–444230123286
       45–543827113089
       55–64241682878
       65–7411832095
       75 +1101194
      Follow-up time (y)
       Mean21.927.8<.0001
       0–5241592055
       6–103018121356
       11–203423112509
       21–305239132627
       31+69472211,406
      Area of residence.18
       Town3828103073
       Rural6038226892
       Small community11176359988
      Tobacco user status.0004
       Never daily users6847219304
       Pure daily smokers12585409099
       Pure daily smokeless moist snuff users945864
       Combined users761686
      Alcohol consumption.09
       No or low3725124517
       Moderate or high1721175515,436

       Tooth Loss and Risk of Inflammatory Bowel Disease

      We estimated age-standard incidence rates and HRs for IBD, UC, and CD by different levels of tooth loss (Table 2). Among people with severe lack of oral hygiene as indicated by 5–6 teeth missing, the HR decreased to 0.56 (95% CI, 0.32–0.98; P = .04) for IBD and 0.55 (95% CI, 0.29–1.05; P = .07) for UC. Moreover, as shown by the P value for trend across all levels of tooth loss, the protective effect was strengthened with deterioration of oral hygiene for IBD (Ptrend = .05) and UC (Ptrend = .07). HRs were similar in men and women (data not shown). Sensitivity analyses, by excluding the first 2 or 5 years of follow-up or restricting IBD cases to ≥2 visit records, provided similar results.
      Table 2IR, HR, and 95% CI of IBD by Number of Tooth Loss
      Tooth loss
      Baseline number of teeth was checked on 6 selected teeth: #16, #21, #24, #36, #41, and #44.
      IBDUCCD
      No. CasesIR
      IR per 100,000 person-years, standardized to age distribution of person-years experienced by all participants using 5-year age categories.
      HR
      HRs for IBD were derived from Cox proportional hazards regression models, using attained age as underlying time-scale and further adjusted for attained calendar period in 10-year intervals (1973–2012). All models were also adjusted for covariates, including sex, tobacco use, alcohol consumption, and residential areas.
      (95% CI)
      No. CasesIRHR (95% CI)No. CasesIRHR (95% CI)
      None12348.9Ref.8335.1Ref.4013.8Ref.
      1–46446.70.86 (0.61–1.23)4321.60.79 (0.52–1.21)2125.11.05 (0.56–1.95)
      5–62216.70.56 (0.32–0.98)1612.80.55 (0.29–1.05)63.90.59 (0.21–1.68)
      P for trend
      P for trend was derived from Wald test treating number of tooth loss as a continuous variable.
      .05.07.53
      IR, incidence rate.
      a Baseline number of teeth was checked on 6 selected teeth: #16, #21, #24, #36, #41, and #44.
      b IR per 100,000 person-years, standardized to age distribution of person-years experienced by all participants using 5-year age categories.
      c HRs for IBD were derived from Cox proportional hazards regression models, using attained age as underlying time-scale and further adjusted for attained calendar period in 10-year intervals (1973–2012). All models were also adjusted for covariates, including sex, tobacco use, alcohol consumption, and residential areas.
      d P for trend was derived from Wald test treating number of tooth loss as a continuous variable.

       Dental Plaque Status and Future Inflammatory Bowel Disease

      Dental plaque status and risk of IBD was examined in 15,509 individuals with ≥2 remaining teeth out of the 6 examined. We regarded ≤1 tooth as the strongest marker of poor oral hygiene in the model (n = 4653). Age-standardized incidence rates of IBD, UC, and CD according to dental plaque status are shown in Table 3. The presence of dental plaques was associated with a lower risk of CD (HR, 0.32; 95% CI, 0.10–0.97), increasingly so with severe plaque accumulation (Ptrend = .03). No association was observed between dental plaque and UC.
      Table 3IR, HR, and 95% CI of IBD by Dental Plaque Status
      Dental plaque
      Dental plaque was checked on 6 selected teeth (#16, #21, #24, #36, #41, and #44) and categorized into none, acceptable (exposed surface ≤33%), and unacceptable (exposed surface >33%) dental plaque. The accuracy could be guaranteed when at least 2 teeth out of the 6 were examined (n = 15,509). The rest (n = 4653) missing 5–6 teeth examined were categorized as the subgroup of the poorest oral hygiene.
      IBDUCCD
      No. CasesIR
      IR per 100,000 person-years, standardized to age distribution of person-years experienced by all participants using 5-year age categories.
      HR
      HRs for IBD were derived from Cox proportional hazards regression models, using attained age as underlying time-scale and further adjusted for attained calendar period in 10-year intervals (1973–2012). All models were adjusted for covariates, including sex, tobacco use, alcohol consumption, and residential areas.
      (95% CI)
      No. CasesIRHR (95% CI)No. CasesIRHR (95% CI)
      None4243.6Ref.2526.0Ref.1717.5Ref.
      Acceptable12243.20.96 (0.67–1.37)8229.41.09 (0.69–1.72)4013.80.77 (0.43–1.38)
      Unacceptable2332.50.73 (0.43–1.23)1927.01.00 (0.54–1.86)45.50.32 (0.10–0.97)
      0–1 tooth remained2216.70.58 (0.33–1.01)1612.80.68 (0.35–1.35)63.90.42 (0.15–1.17)
      P for trend
      P for trend was derived from Wald test treating dental plaque status as a continuous variable.
      .03.28.03
      IR, incidence rate.
      a Dental plaque was checked on 6 selected teeth (#16, #21, #24, #36, #41, and #44) and categorized into none, acceptable (exposed surface ≤33%), and unacceptable (exposed surface >33%) dental plaque. The accuracy could be guaranteed when at least 2 teeth out of the 6 were examined (n = 15,509). The rest (n = 4653) missing 5–6 teeth examined were categorized as the subgroup of the poorest oral hygiene.
      b IR per 100,000 person-years, standardized to age distribution of person-years experienced by all participants using 5-year age categories.
      c HRs for IBD were derived from Cox proportional hazards regression models, using attained age as underlying time-scale and further adjusted for attained calendar period in 10-year intervals (1973–2012). All models were adjusted for covariates, including sex, tobacco use, alcohol consumption, and residential areas.
      d P for trend was derived from Wald test treating dental plaque status as a continuous variable.

       Oral Mucosal Lesions, Recurrent Aphthous Ulcer, and Future Inflammatory Bowel Disease

      Existence of OMLs seemed to be protective for IBD, UC, and CD, except for tongue lesions for UC (HR, 1.15; 95% CI, 0.72–1.84). Among all the OMLs, effect of fungal-associated OMLs was most obvious (IBD: HR, 0.71; 95% CI, 0.33–1.53; UC: HR, 0.77; 95% CI, 0.31–1.91; CD: HR, 0.61; 95% CI, 0.14–2.54). However, none of the observed associations reached statistical significance. Furthermore, we did not observe any relation between current and history of RAU and risks of IBD.

      Discussion

      Our study revealed a negative association between poor oral health and risk of overall IBD. The protective effect increased with the severity of poor dental hygiene. The association was different among the 2 subtypes. Among individuals losing 5–6 teeth out of the 6 examined, the risk of UC decreased to 0.55 (P = .07). By contrast, unacceptable dental plaque was significantly inversely related to the risk of CD, but not with UC. Although sharing some epidemiologic characteristics, marked differences between UC and CD were indicated in the immune responses against intestinal microflora.
      • Shanahan F.
      Pathogenesis of ulcerative colitis.
      Therefore, even faced with similar environmental factors, we should consider their heterogeneous manifestations.
      We are unaware of any earlier cohort studies on oral health and IBD. Although a number of case-control studies have been conducted before, these have shown inconsistent results. Three studies found no difference in tooth number between patients with IBD and healthy control subjects,
      • Singhal S.
      • Dian D.
      • Keshavarzian A.
      • et al.
      The role of oral hygiene in inflammatory bowel disease.
      • Vavricka S.R.
      • Manser C.N.
      • Hediger S.
      • et al.
      Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.
      • Grossner-Schreiber B.
      • Fetter T.
      • Hedderich J.
      • et al.
      Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study.
      whereas a fourth study reported fewer teeth in patients with UC.
      • Brito F.
      • de Barros F.C.
      • Zaltman C.
      • et al.
      Prevalence of periodontitis and DMFT index in patients with Crohn's disease and ulcerative colitis.
      Contrasting to our data, earlier case-control studies have found strikingly different associations between dental plaque and IBD (less dental plaque in patients with CD,
      • Brito F.
      • de Barros F.C.
      • Zaltman C.
      • et al.
      Prevalence of periodontitis and DMFT index in patients with Crohn's disease and ulcerative colitis.
      no difference between patients with IBD and healthy control subjects,
      • Koutsochristou V.
      • Zellos A.
      • Dimakou K.
      • et al.
      Dental caries and periodontal disease in children and adolescents with inflammatory bowel disease: A case-control study.
      whereas others have reported higher prevalence of plaques in patients with IBD).
      • Habashneh R.A.
      • Khader Y.S.
      • Alhumouz M.K.
      • et al.
      The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study.
      • Grossner-Schreiber B.
      • Fetter T.
      • Hedderich J.
      • et al.
      Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study.
      Accumulation of biofilms containing various bacterial species, on tooth surfaces and in subgingival areas, was referred to as dental plaques. Previous studies have indicated a correlation between changes in oral bacteria and intestinal microbiome among patients with IBD. In accordance with a less abundant microflora in the gut mucosa, significant reduction in overall diversity and in specific phyla (Fusobacteria and Firmicutes) was mirrored in tongue and buccal mucosal from samples of patients with CD.
      • Docktor M.J.
      • Paster B.J.
      • Abramowicz S.
      • et al.
      Alterations in diversity of the oral microbiome in pediatric inflammatory bowel disease.
      In 2 murine models of induced colitis, the percentage of changes in oral microbial diversity were similar with changes in stool samples.
      • Rautava J.
      • Pinnell L.J.
      • Vong L.
      • et al.
      Oral microbiome composition changes in mouse models of colitis.
      Unfortunately, we were unable to confirm our findings using 16S RNA sequencing to infer any causality.
      The hygiene hypothesis suggests that excessive reduction of exposure to multiple microbes weakens the immune tolerance and induces autoimmune disorders. Better living conditions, such as fewer number of siblings, higher birth order, and urban environment, seem to increase the risk of IBD.
      • Lakatos P.L.
      Environmental factors affecting inflammatory bowel disease: have we made progress?.
      • Klement E.
      • Lysy J.
      • Hoshen M.
      • et al.
      Childhood hygiene is associated with the risk for inflammatory bowel disease: a population-based study.
      Antibiotics use and surgery during childhood have also been incriminated in the development of IBD.
      • Card T.
      • Logan R.F.
      • Rodrigues L.C.
      • et al.
      Antibiotic use and the development of Crohn's disease.
      • Gearry R.B.
      • Richardson A.K.
      • Frampton C.M.
      • et al.
      Population-based cases control study of inflammatory bowel disease risk factors.
      Our data on a negative relationship between poor oral health and later IBD supports the hygiene hypothesis. We believe that excessive oral hygiene might generate dysbiosis in bacterial colonization, dysregulate the innate immune responses, and promote the inflammatory process. Conversely, poor oral health might contribute to the induction of immune tolerance and suppression of overreactive inflammation, thereby reducing the risk of immune-mediated diseases, such as IBD. However, plaque-induced oral mucosal inflammation, such as gingivitis and periodontits, has also been linked to IBD.
      • Singhal S.
      • Dian D.
      • Keshavarzian A.
      • et al.
      The role of oral hygiene in inflammatory bowel disease.
      • Vavricka S.R.
      • Manser C.N.
      • Hediger S.
      • et al.
      Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.
      Nevertheless, high prevalence of oral health problems among patients with IBD does not contradict our oral hygiene hypothesis, either as a consequence of dysbiosis in oral cavity or as oral complications of IBD, both of which can probably be caused by excessive oral hygiene in the origin.
      OMLs were grouped into 3 categories that are strongly related to poor oral hygiene. Although nonsignificant associations were found in the current study, HRs for IBD tended to be less than 1. We speculate that mucosal injuries have attenuated the immune barrier. Daily oral hygiene behaviors, such as tooth brushing and dental floss use, might have facilitated the entry of oral bacteria and their components into the circulation thereby inducing immune tolerance in the intestinal tract.
      • Hirschfeld J.
      • Kawai T.
      Oral inflammation and bacteremia: implications for chronic and acute systemic diseases involving major organs.
      The correlation between IBD and oral lesions has been positive in several case-control studies, whereas others disagreed.
      • Vavricka S.R.
      • Manser C.N.
      • Hediger S.
      • et al.
      Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.
      • Grossner-Schreiber B.
      • Fetter T.
      • Hedderich J.
      • et al.
      Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study.
      • Laranjeira N.
      • Fonseca J.
      • Meira T.
      • et al.
      Oral mucosa lesions and oral symptoms in inflammatory bowel disease patients.
      • Lisciandrano D.
      • Ranzi T.
      • Carrassi A.
      • et al.
      Prevalence of oral lesions in inflammatory bowel disease.
      Strengths of our study include the general population-based cohort design and the professional clinical examinations. Furthermore, through the unique PIN, we were able to link data from the national Total Population Register, the Cause of Death Register, and the Patient Register, with virtually complete follow-up.
      This study also had some shortcomings. Poor oral health may only exert an influence on IBD development after many years of exposure. To achieve increasing immune tolerance to mucosal tissue, the process should be chronic and continuous, which starts much earlier than the onset of the disease. However, dental care habits and oral hygiene conditions might change. Admittedly, absence of exposure changes (ie, oral health indicators) over time was our main limitation. Improvement of oral health care among participants might have weakened the association between exposure indicators and our final outcomes.
      Amelioration of public health and a Westernized lifestyle have influenced the epidemiology of oral hygiene directly or indirectly. In 1973, 1983, 1993, and 2003, Hugoson et al
      • Hugoson A.
      • Koch G.
      • Gothberg C.
      • et al.
      Oral health of individuals aged 3–80 years in Jonkoping, Sweden during 30 years (1973–2003). I. Review of findings on dental care habits and knowledge of oral health.
      examined dental and oral health data of 4 Swedish cross-sectional studies. Public oral health knowledge remained constant over time, whereas tooth-brushing frequency increased from 1973 to 2003. In age groups of 20–80 years, oral hygiene and periodontal health improved significantly over the 30 years.
      • Hugoson A.
      • Sjodin B.
      • Norderyd O.
      Trends over 30 years, 1973–2003, in the prevalence and severity of periodontal disease.
      Faster investigations, more advanced diagnostic techniques (scopes), and complicated environmental factors might contribute to the globally increasing incidence of IBD.
      • Bernstein C.N.
      • Fried M.
      • Krabshuis J.
      • et al.
      World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010.
      When taking attained age into consideration, we found that IBD was more common in 1993–2012 compared with in 1973–1992. In fact, the incidence increased by a factor of 2.2 (95% CI, 1.43–3.37) between the first and the last decade, explaining the higher incidence in our paper. Therefore, to avoid confounding from calendar period, 2 time scales were used in the model.
      Because etiologic mechanisms still remain unclear in IBD, a lack of data on potential confounding factors could bias the true relationship between exposures under study and the disease outcome. Although we attempted to limit socioeconomic confounding by adjusting for area of residence, confounding by social status, diet, corticosteroid use, and toothpaste consumption cannot be ruled out. Sullivan
      • Sullivan S.N.
      Hypothesis revisited: toothpaste and the cause of Crohn's disease.
      has previously suggested that the use of toothpaste increases the risk of IBD. Because poor oral hygiene is associated with lack of toothpaste, this may have influenced our results. Furthermore, poor oral hygiene might only be an aspect of the general hygiene status but also supports the hygiene hypothesis.
      Because of low incidence rate of IBD, small sample effect could not be avoided. Especially in CD, exposed cases were <10 individuals in some strata. This resulted in wide CIs and failure to reach statistical significance in some subanalyses. In addition, we just measured limited indicators to mirror a few aspects of oral hygiene. Unfortunately, we did not have data on periodontitis or gingivitis. Therefore, comprehensive and systemic evaluation with diverse indices is needed to provide a general picture of oral health and its effect on IBD.
      In conclusion, our data suggest a negative association between poor oral health and risks of IBD. The worse the oral health was, the stronger the protection against IBD. Our finding does not suggest discouraging better oral hygiene, but promotes the understanding of IBD etiology. At least, overprotective hygiene for daily life should be paid attention.

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      Linked Article

      • Dental Morbidities, Smoking, Oral Hygiene, and Inflammatory Bowel Diseases
        Clinical Gastroenterology and HepatologyVol. 14Issue 12
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          Yin et al1 suggested that poor oral hygiene protects against the onset of inflammatory bowel diseases (IBDs) (P < .05). We propose that this is an erroneous conclusion that resulted from collapsing 2 diseases with distinct etiologies: ulcerative colitis (UC) and Crohn’s disease (CD).2 Specifically, we suggest that Yin et al1 provided evidence in support of the hygiene hypothesis for CD, but not for UC.
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