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Does Poor Oral Health Protect Against Inflammatory Bowel Disease?
Accepted Manuscript Does Poor Oral Health Protect Against Inflammatory Bowel Disease? Judith R. Kelsen, MD, Lindsey Albenberg, DO
PII: DOI: Reference:
S1542-3565(16)31245-9 10.1016/j.cgh.2016.12.020 YJCGH 55045
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 21 December 2016 Please cite this article as: Kelsen JR, Albenberg L, Does Poor Oral Health Protect Against Inflammatory Bowel Disease?, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2016.12.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Does Poor Oral Health Protect Against Inflammatory Bowel Disease?
RI PT
Judith R. Kelsen, MD1, Lindsey Albenberg, DO 1
M AN U
Correspondence: Judith R. Kelsen, MD 7NW, Division of Pediatric Gastroenterology 3400 Civic Center Blvd The Children’s Hospital of Philadelphia Philadelphia, PA 19104 Tel: 267-426-6822 Fax: 215-590-5326 [email protected]
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Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA
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Disclosures: None of the authors have disclosures related to this manuscript.
ACCEPTED MANUSCRIPT
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Oral manifestations of IBD are relatively common and can precede the onset of intestinal symptoms. The authors of “Poor oral health may protect against inflammatory bowel disease: a prospective cohort study [1],” explored the relationship between poor oral health and the development of IBD. The authors attempted to add to the body of literature which implicates the “hygiene hypothesis” as a significant contributor to the increasing incidence of IBD around the world. Modernity has brought about changes in the human microbiome through, in part, marked changes in environmental exposures. As improvements in hygiene such as clean water supply, less crowded housing, refrigeration, and availability of antibiotics have occurred, the incidence of allergic and autoimmune disorders has increased. The rapid rise in the incidence of inflammatory bowel disease may be secondary to the “hygiene hypothesis” and the subsequent changes in the education of the mucosal immune system that occur. Indeed, interactions between the host genome and environmental factors, notably the gut microbiota, are thought to play a critical role in the pathogenesis of IBD.
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While the associations between the composition of the intestinal microbiota and IBD have been well studied, the microbiota of the oral mucosa in IBD is less well characterized. Oral manifestations are commonly observed in IBD, with an incidence of 5-80% [2-4]. Pediatric patients with oral CD frequently develop oral manifestations prior to the onset of gastrointestinal symptoms, allowing earlier diagnosis [3]. All areas of the oral cavity can be involved in CD, with the most commonly affected being the buccal, gingival and labial mucosa. Manifestations include prototypical gingival lesions, aphthous lesions, edema of the mucosa, gingivitis, and periodontitis. Gingival CD, a common oral finding, is described as cobblestone-like gingival mucosa and significant thickening of the tissue. These are similar to the intestinal findings of active CD, often associated with isolated edema of the mucosa, a cobblestoned appearance of the tissue, and aphthous lesions. The oral microbiota has been associated with the development of periodontitis, gingivitis and dental caries. [5] [6] [7] [8] [9]. The epithelial layer in the subgingival crevice is the initial interface between peridontopathic organisms and the host [10] [11]. The presence of bacteria in the subgingival environment leads to the development of a biofilm that interacts with the host, resulting in an innate immune response associated with the production of cytokines and antimicrobial peptides. This interaction in the subgingival compartment is reminiscent of the host-microbial interaction at the mucosal interface in the gut. Thus, it was reasonable for Dr. Yin and colleagues to explore the relationship between poor
ACCEPTED MANUSCRIPT
oral health and the presumed changes in the oral microbiome that occur and the development of IBD.
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RI PT
The role of oral hygiene has been evaluated by several studies with inconsistent results.[12-14] Some of these studies have indicated that patients with IBD have improved oral hygiene, while others have shown an increase in gingivitis, periodontitis and oral ulcers in patients with IBD. The present prospective study looked at 20, 162 residents of 2 municipalities of Uppsala County in Sweden between 1973 and2012. Oral examinations were performed at study entry. Other exposures were captured through questionnaires. 209 patients with IBD were identified. The authors found an inverse relationship between poor oral health and the development of IBD, particularly apparent with more severely poor oral health. Indeed, loss of 5-6 teeth was protective against the development of UC and increased plaque was associated with protection against the development of CD, although not UC. Existence of oral mucosal lesions (OMLs) was protective for IBD, UC and CD. Fungal associated OMLs (angular cheilitis, pseudomembranous candidiasis, chronic candidiasis, atrophic and nodular leukoplakia, median type of atrophy of tongue papillae and unspecified glossitis) was the strongest association with IBD, although not statistically significant. The authors hypothesized that excessive oral hygiene may result in dysbiosis and contribute to the pathogenesis of IBD. Further, they speculated that poor oral health may decrease the risk of IBD through induction of immune tolerance. Is this Consistent with prior studies in the literature?
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These data demonstrate that dental disease and overall poor oral health may be protective against the development of IBD. This is in contrast to the data that demonstrates increased rates of caries, periodonits and gingivitis in patients with IBD [15] [12] [16, 17]. Multiple studies have demonstrated an association between oral disease and IBD, including pathogenesis of the disease as well a contributing factor of disease complications, such as malignancies. Arecent publication demonstrated that oral cancer is increased in patients with IBD [18] , but this needs to be further studied and the mechanisms will need to be further elucidated. Regarding association disease pathogenesis and disease activity, several publications have shown oral hygiene to be an important factor. Recently, Laranjeira et al studied the association of oral mucosal lesions and symptoms with relation to oral hygiene, smoking and disease activity in 113 IBD patients as compared to 58 healthy control subjects [13]. The authors divided the patients into 5 groups based on therapy: untreated, treatment with salicylate therapy, corticosteroids, azathioprine and cyclosporine, and anti-TNF therapy.
ACCEPTED MANUSCRIPT
RI PT
Smoking status was assessed as well. The results showed that patients with IBD had a higher prevalence of oral mucosal lesions compared to the control group and more so during active disease. There were no differences in oral hygiene between the two groups, however. Koutsochristou et al, in a study evaluating 55 pediatric patients with IBD and 55 healthy controls, showed that there was an increase in periodontal disease and gingivitis in pediatric patients with IBD [19]. In addition, these patients had poor oral health in terms of decayed, missing, and filled teeth as compared to healthy controls. This was despite similar oral hygiene status in the two groups.
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Thus, the above studies demonstrated that patients with IBD had worse oral health than healthy controls, but did not identify an association of poor oral hygiene and risk of onset of disease, or demonstrate a causal role in the disease development. Several studies have evaluated the oral microbiota and CD, showing decreased diversity in patients with CD compared to healthy controls [20] [21] and increased subgingivial bacteria related to opportunistic infections in patients with IBD and chronic periodonititis [20] [14]. This current study included a larger cohort of healthy controls with extensive dental exams and clinical metadata. While the strengths of this study include a large cohort with a long study window, the conclusion that poor oral health is protective because of increased exposures to oral microorganisms (i.e. the opposite of the hygiene hypothesis) is speculative. This study demonstrates an association only. Alteration of the bacterial community structure or dysbiosis would provide more robust strength to this hypothesis. A further study incorporating microbiome analysis would be of benefit and of great interest. However, in general, the IBD literature is lacking prospective studies demonstrating that the dysbiotic microbiota is causal.
AC C
What is necessary to further link oral hygiene and IBD? A large prospective longitudinal cohort study may provide more information regarding oral hygiene and the hygiene hypothesis in the pathogenesis of IBD. An ideal study would follow a cohort prior the diagnosis of IBD, and a pediatric population may be the best to provide rich longitudinal information. Additionally, a prospective study will allow for assessment of oral hygiene and oral exams to be conducted with subsequent exams to detect development of disease. These studies should have the power to stratify patients with IBD based on presence or absence of oral lesions, disease phenotype and severity, and medication use. Additionally, a dietary evaluation to adjust for effects of diet on the oral microbiome would strengthen this study. Additionally, patients with IBD are often
ACCEPTED MANUSCRIPT
exposed to antibiotic therapy, and this is also an important factor to consider when studying oral disease and IBD.
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EP
TE D
M AN U
SC
RI PT
Conclusions The association of oral health and IBD remains unclear. This study takes advantage of a large cohort and its findings of an inverse relationship between poor oral health and the development of IBD contrasts prior literature. Overall, there is an agreement amongst investigators that periodontal disease is seen more frequently in patients who already have IBD as compared to healthy controls. The literature also suggests that there is likely an important role for the oral microbiome in IBD. However, further studies are needed to evaluate the role of the hygiene hypothesis, particularly as it relates to oral health, and the pathogenesis of IBD. Although poor oral health seemed to be protective against the development of IBD in this study, there are obviously many other consequences of poor dental health. Ultimately, it could be very useful to better understand the relationship between oral health, the oral microbiome, and IBD as there is potential for modulation of the oral microbiome to treat oral manifestations of the disease. Modulation of the oral microbiome could also have even broader effects in the IBD population. Large prospective studies may be able to address these questions.
ACCEPTED MANUSCRIPT
1. 2.
Yin, W., et al., Inverse Association Between Poor Oral Health and Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol, 2016. Plauth, M., H. Jenss, and J. Meyle, Oral manifestations of Crohn's disease. An analysis of 79 cases. J Clin Gastroenterol, 1991. 13(1): p. 29-37. Pittock, S., et al., The oral cavity in Crohn's disease. J Pediatr, 2001. 138(5): p. 767-71. Harty, S., et al., A prospective study of the oral manifestations of Crohn's disease. Clin Gastroenterol Hepatol, 2005. 3(9): p. 886-91. Hovav, A.H., Dendritic cells of the oral mucosa. Mucosal Immunol, 2014. 7(1): p. 27-37. Di Benedetto, A., et al., Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol, 2013. 2013: p. 503754. Teles, R., et al., Lessons learned and unlearned in periodontal microbiology. Periodontol 2000, 2013. 62(1): p. 95-162. Colombo, A.P., et al., Impact of periodontal therapy on the subgingival microbiota of severe periodontitis: comparison between good responders and individuals with refractory periodontitis using the human oral microbe identification microarray. J Periodontol, 2012. 83(10): p. 1279-87. Mdala, I., et al., Multilevel analysis of bacterial counts from chronic periodontitis after root planing/scaling, surgery, and systemic and local antibiotics: 2-year results. J Oral Microbiol, 2013. 5. Handfield, M., et al., Distinct transcriptional profiles characterize oral epithelium-microbiota interactions. Cell Microbiol, 2005. 7(6): p. 811-23. Chung, W.O., et al., Interplay of protease-activated receptors and NOD pattern recognition receptors in epithelial innate immune responses to bacteria. Immunol Lett, 2010. 131(2): p. 113-9. Brito, F., et al., Prevalence of periodontitis and DMFT index in patients with Crohn's disease and ulcerative colitis. J Clin Periodontol, 2008. 35(6): p. 55560. Laranjeira, N., et al., Oral mucosa lesions and oral symptoms in inflammatory bowel disease patients. Arq Gastroenterol, 2015. 52(2): p. 105-10. Brito, F., et al., Subgingival microflora in inflammatory bowel disease patients with untreated periodontitis. Eur J Gastroenterol Hepatol, 2013. 25(2): p. 239-45. Asquith, P., R.A. Thompson, and W.T. Cooke, Oral manifestations of Crohn's disease. Gut, 1975. 16(4): p. 249-54.
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References:
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Katz, J., et al., Oral signs and symptoms in relation to disease activity and site of involvement in patients with inflammatory bowel disease. Oral Dis, 2003. 9(1): p. 34-40. Grossner-Schreiber, B., et al., Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study. J Clin Periodontol, 2006. 33(7): p. 478-84. Katsanos, K.H., et al., Increased Risk of Oral Cancer in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol, 2016. 14(3): p. 413-20. Koutsochristou, V., et al., Dental Caries and Periodontal Disease in Children and Adolescents with Inflammatory Bowel Disease: A Case-Control Study. Inflamm Bowel Dis, 2015. 21(8): p. 1839-46. Docktor, M.J., et al., Alterations in diversity of the oral microbiome in pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2012. 18(5): p. 935-42. Kelsen, J., et al., Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts. Inflamm Bowel Dis, 2015. 21(12): p. 2797-805.
SC
16.
PII: DOI: Reference:
S1542-3565(16)31245-9 10.1016/j.cgh.2016.12.020 YJCGH 55045
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 21 December 2016 Please cite this article as: Kelsen JR, Albenberg L, Does Poor Oral Health Protect Against Inflammatory Bowel Disease?, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2016.12.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Does Poor Oral Health Protect Against Inflammatory Bowel Disease?
RI PT
Judith R. Kelsen, MD1, Lindsey Albenberg, DO 1
M AN U
Correspondence: Judith R. Kelsen, MD 7NW, Division of Pediatric Gastroenterology 3400 Civic Center Blvd The Children’s Hospital of Philadelphia Philadelphia, PA 19104 Tel: 267-426-6822 Fax: 215-590-5326 [email protected]
SC
Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA
AC C
EP
TE D
Disclosures: None of the authors have disclosures related to this manuscript.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Oral manifestations of IBD are relatively common and can precede the onset of intestinal symptoms. The authors of “Poor oral health may protect against inflammatory bowel disease: a prospective cohort study [1],” explored the relationship between poor oral health and the development of IBD. The authors attempted to add to the body of literature which implicates the “hygiene hypothesis” as a significant contributor to the increasing incidence of IBD around the world. Modernity has brought about changes in the human microbiome through, in part, marked changes in environmental exposures. As improvements in hygiene such as clean water supply, less crowded housing, refrigeration, and availability of antibiotics have occurred, the incidence of allergic and autoimmune disorders has increased. The rapid rise in the incidence of inflammatory bowel disease may be secondary to the “hygiene hypothesis” and the subsequent changes in the education of the mucosal immune system that occur. Indeed, interactions between the host genome and environmental factors, notably the gut microbiota, are thought to play a critical role in the pathogenesis of IBD.
AC C
EP
TE D
While the associations between the composition of the intestinal microbiota and IBD have been well studied, the microbiota of the oral mucosa in IBD is less well characterized. Oral manifestations are commonly observed in IBD, with an incidence of 5-80% [2-4]. Pediatric patients with oral CD frequently develop oral manifestations prior to the onset of gastrointestinal symptoms, allowing earlier diagnosis [3]. All areas of the oral cavity can be involved in CD, with the most commonly affected being the buccal, gingival and labial mucosa. Manifestations include prototypical gingival lesions, aphthous lesions, edema of the mucosa, gingivitis, and periodontitis. Gingival CD, a common oral finding, is described as cobblestone-like gingival mucosa and significant thickening of the tissue. These are similar to the intestinal findings of active CD, often associated with isolated edema of the mucosa, a cobblestoned appearance of the tissue, and aphthous lesions. The oral microbiota has been associated with the development of periodontitis, gingivitis and dental caries. [5] [6] [7] [8] [9]. The epithelial layer in the subgingival crevice is the initial interface between peridontopathic organisms and the host [10] [11]. The presence of bacteria in the subgingival environment leads to the development of a biofilm that interacts with the host, resulting in an innate immune response associated with the production of cytokines and antimicrobial peptides. This interaction in the subgingival compartment is reminiscent of the host-microbial interaction at the mucosal interface in the gut. Thus, it was reasonable for Dr. Yin and colleagues to explore the relationship between poor
ACCEPTED MANUSCRIPT
oral health and the presumed changes in the oral microbiome that occur and the development of IBD.
TE D
M AN U
SC
RI PT
The role of oral hygiene has been evaluated by several studies with inconsistent results.[12-14] Some of these studies have indicated that patients with IBD have improved oral hygiene, while others have shown an increase in gingivitis, periodontitis and oral ulcers in patients with IBD. The present prospective study looked at 20, 162 residents of 2 municipalities of Uppsala County in Sweden between 1973 and2012. Oral examinations were performed at study entry. Other exposures were captured through questionnaires. 209 patients with IBD were identified. The authors found an inverse relationship between poor oral health and the development of IBD, particularly apparent with more severely poor oral health. Indeed, loss of 5-6 teeth was protective against the development of UC and increased plaque was associated with protection against the development of CD, although not UC. Existence of oral mucosal lesions (OMLs) was protective for IBD, UC and CD. Fungal associated OMLs (angular cheilitis, pseudomembranous candidiasis, chronic candidiasis, atrophic and nodular leukoplakia, median type of atrophy of tongue papillae and unspecified glossitis) was the strongest association with IBD, although not statistically significant. The authors hypothesized that excessive oral hygiene may result in dysbiosis and contribute to the pathogenesis of IBD. Further, they speculated that poor oral health may decrease the risk of IBD through induction of immune tolerance. Is this Consistent with prior studies in the literature?
AC C
EP
These data demonstrate that dental disease and overall poor oral health may be protective against the development of IBD. This is in contrast to the data that demonstrates increased rates of caries, periodonits and gingivitis in patients with IBD [15] [12] [16, 17]. Multiple studies have demonstrated an association between oral disease and IBD, including pathogenesis of the disease as well a contributing factor of disease complications, such as malignancies. Arecent publication demonstrated that oral cancer is increased in patients with IBD [18] , but this needs to be further studied and the mechanisms will need to be further elucidated. Regarding association disease pathogenesis and disease activity, several publications have shown oral hygiene to be an important factor. Recently, Laranjeira et al studied the association of oral mucosal lesions and symptoms with relation to oral hygiene, smoking and disease activity in 113 IBD patients as compared to 58 healthy control subjects [13]. The authors divided the patients into 5 groups based on therapy: untreated, treatment with salicylate therapy, corticosteroids, azathioprine and cyclosporine, and anti-TNF therapy.
ACCEPTED MANUSCRIPT
RI PT
Smoking status was assessed as well. The results showed that patients with IBD had a higher prevalence of oral mucosal lesions compared to the control group and more so during active disease. There were no differences in oral hygiene between the two groups, however. Koutsochristou et al, in a study evaluating 55 pediatric patients with IBD and 55 healthy controls, showed that there was an increase in periodontal disease and gingivitis in pediatric patients with IBD [19]. In addition, these patients had poor oral health in terms of decayed, missing, and filled teeth as compared to healthy controls. This was despite similar oral hygiene status in the two groups.
EP
TE D
M AN U
SC
Thus, the above studies demonstrated that patients with IBD had worse oral health than healthy controls, but did not identify an association of poor oral hygiene and risk of onset of disease, or demonstrate a causal role in the disease development. Several studies have evaluated the oral microbiota and CD, showing decreased diversity in patients with CD compared to healthy controls [20] [21] and increased subgingivial bacteria related to opportunistic infections in patients with IBD and chronic periodonititis [20] [14]. This current study included a larger cohort of healthy controls with extensive dental exams and clinical metadata. While the strengths of this study include a large cohort with a long study window, the conclusion that poor oral health is protective because of increased exposures to oral microorganisms (i.e. the opposite of the hygiene hypothesis) is speculative. This study demonstrates an association only. Alteration of the bacterial community structure or dysbiosis would provide more robust strength to this hypothesis. A further study incorporating microbiome analysis would be of benefit and of great interest. However, in general, the IBD literature is lacking prospective studies demonstrating that the dysbiotic microbiota is causal.
AC C
What is necessary to further link oral hygiene and IBD? A large prospective longitudinal cohort study may provide more information regarding oral hygiene and the hygiene hypothesis in the pathogenesis of IBD. An ideal study would follow a cohort prior the diagnosis of IBD, and a pediatric population may be the best to provide rich longitudinal information. Additionally, a prospective study will allow for assessment of oral hygiene and oral exams to be conducted with subsequent exams to detect development of disease. These studies should have the power to stratify patients with IBD based on presence or absence of oral lesions, disease phenotype and severity, and medication use. Additionally, a dietary evaluation to adjust for effects of diet on the oral microbiome would strengthen this study. Additionally, patients with IBD are often
ACCEPTED MANUSCRIPT
exposed to antibiotic therapy, and this is also an important factor to consider when studying oral disease and IBD.
AC C
EP
TE D
M AN U
SC
RI PT
Conclusions The association of oral health and IBD remains unclear. This study takes advantage of a large cohort and its findings of an inverse relationship between poor oral health and the development of IBD contrasts prior literature. Overall, there is an agreement amongst investigators that periodontal disease is seen more frequently in patients who already have IBD as compared to healthy controls. The literature also suggests that there is likely an important role for the oral microbiome in IBD. However, further studies are needed to evaluate the role of the hygiene hypothesis, particularly as it relates to oral health, and the pathogenesis of IBD. Although poor oral health seemed to be protective against the development of IBD in this study, there are obviously many other consequences of poor dental health. Ultimately, it could be very useful to better understand the relationship between oral health, the oral microbiome, and IBD as there is potential for modulation of the oral microbiome to treat oral manifestations of the disease. Modulation of the oral microbiome could also have even broader effects in the IBD population. Large prospective studies may be able to address these questions.
ACCEPTED MANUSCRIPT
1. 2.
Yin, W., et al., Inverse Association Between Poor Oral Health and Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol, 2016. Plauth, M., H. Jenss, and J. Meyle, Oral manifestations of Crohn's disease. An analysis of 79 cases. J Clin Gastroenterol, 1991. 13(1): p. 29-37. Pittock, S., et al., The oral cavity in Crohn's disease. J Pediatr, 2001. 138(5): p. 767-71. Harty, S., et al., A prospective study of the oral manifestations of Crohn's disease. Clin Gastroenterol Hepatol, 2005. 3(9): p. 886-91. Hovav, A.H., Dendritic cells of the oral mucosa. Mucosal Immunol, 2014. 7(1): p. 27-37. Di Benedetto, A., et al., Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol, 2013. 2013: p. 503754. Teles, R., et al., Lessons learned and unlearned in periodontal microbiology. Periodontol 2000, 2013. 62(1): p. 95-162. Colombo, A.P., et al., Impact of periodontal therapy on the subgingival microbiota of severe periodontitis: comparison between good responders and individuals with refractory periodontitis using the human oral microbe identification microarray. J Periodontol, 2012. 83(10): p. 1279-87. Mdala, I., et al., Multilevel analysis of bacterial counts from chronic periodontitis after root planing/scaling, surgery, and systemic and local antibiotics: 2-year results. J Oral Microbiol, 2013. 5. Handfield, M., et al., Distinct transcriptional profiles characterize oral epithelium-microbiota interactions. Cell Microbiol, 2005. 7(6): p. 811-23. Chung, W.O., et al., Interplay of protease-activated receptors and NOD pattern recognition receptors in epithelial innate immune responses to bacteria. Immunol Lett, 2010. 131(2): p. 113-9. Brito, F., et al., Prevalence of periodontitis and DMFT index in patients with Crohn's disease and ulcerative colitis. J Clin Periodontol, 2008. 35(6): p. 55560. Laranjeira, N., et al., Oral mucosa lesions and oral symptoms in inflammatory bowel disease patients. Arq Gastroenterol, 2015. 52(2): p. 105-10. Brito, F., et al., Subgingival microflora in inflammatory bowel disease patients with untreated periodontitis. Eur J Gastroenterol Hepatol, 2013. 25(2): p. 239-45. Asquith, P., R.A. Thompson, and W.T. Cooke, Oral manifestations of Crohn's disease. Gut, 1975. 16(4): p. 249-54.
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References:
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Katz, J., et al., Oral signs and symptoms in relation to disease activity and site of involvement in patients with inflammatory bowel disease. Oral Dis, 2003. 9(1): p. 34-40. Grossner-Schreiber, B., et al., Prevalence of dental caries and periodontal disease in patients with inflammatory bowel disease: a case-control study. J Clin Periodontol, 2006. 33(7): p. 478-84. Katsanos, K.H., et al., Increased Risk of Oral Cancer in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol, 2016. 14(3): p. 413-20. Koutsochristou, V., et al., Dental Caries and Periodontal Disease in Children and Adolescents with Inflammatory Bowel Disease: A Case-Control Study. Inflamm Bowel Dis, 2015. 21(8): p. 1839-46. Docktor, M.J., et al., Alterations in diversity of the oral microbiome in pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2012. 18(5): p. 935-42. Kelsen, J., et al., Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts. Inflamm Bowel Dis, 2015. 21(12): p. 2797-805.
SC
16.