Review Article
OMICS A Journal of Integrative Biology Volume 19, Number 8, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2015.0077
Two Cheers for Crohn’s Disease and Periodontitis: Beta-Defensin-2 as an Actionable Target to Intervene on Two Clinically Distinct Diseases Mutlu Keskin,1,2 Fares Zeida´n-Chulia´,1,3 Mervi Gursoy,1 Eija Ko¨no¨nen,1,4 Jaana Rautava,5* and Ulvi Kahraman Gursoy1*
Abstract
Recent advances in multi-omics approaches encompassing genomics, transcriptomics, proteomics, and metabolomics offer hitherto unprecedented insights on common complex human diseases. A unique angle pertinent for both diagnostic and therapeutic sciences involves rethinking clinically distinct diseases with a view to their shared molecular targets, interactomes, and pathophysiologies. Reflecting at a scale of disease-to-disease associations might help clinicians, public health practitioners, drug and biotechnology developers, and associated knowledge industries in the current era. This review article examines the hypothesis that ‘‘Intersecting Molecular Pathways Permit Interventions on Multiple Clinical Endpoints’’, thus uniquely bringing together Crohn’s disease and periodontitis. Furthermore, we propose a novel connector molecular target between these two ostensibly distinct diseases at a clinical level, human beta defensin (hBD)-2, and suggest pathways by which hBD-2 can conceivably connect Crohn’s disease and periodontitis by virtue of regulating the innate-immune response. We conclude by emphasizing different approaches where hBD-2 can be employed as a diagnostic and therapeutic tool to improve the quality of life of susceptible individuals and minimize the economic costs of these two major global public health problems. The strategy presented here also presents potentials for targeting of multiple diseases through a unique ‘‘nodal molecular target’’ that ‘‘speaks to’’ multiple clinical endpoints.
Introduction
Concept ‘‘Intersecting Molecular Pathways Permit Interventions on Multiple Clinical Endpoints’’
I
ntegrative biology and interactome analyses are transforming old concepts of disease and pathophysiology (Dimitrakopoulou et al., 2014; Podder and Latha, 2014), not to forget drug repurposing research (Sun et al., 2015). A unique angle pertinent for both diagnostic and therapeutic sciences (i.e., the emerging field of theranostics), involves rethinking clinically distinct diseases with a view to their shared molecular targets, interactomes, and pathophysiologies. Reflecting at a scale of disease-to-disease associations might help clinicians, public health practitioners, drug and biotechnology developers, and associated knowledge industries in the current era. This review article examines the integrative biology concept presented below, thus uniquely bringing together Crohn’s disease and periodontitis.
The current moves to conceptualize common complex diseases as syndromes with a shared clinical typology, comprised of multiple molecular pathways, have important corollaries. This means that at certain molecular intersection points it might be possible to intervene on more than one disease or several subtypes of an apparently homogenous disease-syndrome. Defining common risk groups for widespread diseases, exploring their underlying shared risk factors, and constructing cost-effective preventive measures for those public health problems will minimize the psychological and economic impacts of these diseases on individuals, and eventually, on public.
Departments of 1Periodontology, and 5Oral Pathology, Institute of Dentistry, University of Turku, Turku, Finland. 2_ Istanbul Kemerburgaz University, Vocational School of Health Services, Istanbul, Turkey. 3 Departamento de Bioquı´mica, Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 4 Oral Health Care, Welfare Division, City of Turku, Turku, Finland. *These authors contributed equally.
1
2
This mini-review applies the above hypothesis to the case of Crohn’s disease and periodontitis through human beta defensin (hBD)-2. Ulcerative colitis (UC), which is another form of inflammatory bowel disease, will not be included into this review because genetic expression profiles, including that of hBD-2, are different in Crohn’s disease and UC (Fellermann et al., 2006). Connecting the Dots with Beta Defensin-2
Crohn’s disease and UC are two forms of inflammatory bowel disease (IBD). Both diseases are characterized by a chronic dysregulation of mucosal immune response of the gastrointestinal tract and share similarities in their pathophysiology. While Crohn’s disease can affect any part of the gastrointestinal tract, UC is restricted to colon and rectum (Ananthakrishnan, 2015). In Europe, the incidence of Crohn’s disease is between 0.3–12.7 per 100,000 persons (Ananthakrishnan, 2015), and it creates an economic burden of 2.1–16.7 billion euros (Floyd et al., 2015). Traditionally, the incidence of IBD has been highest in developed continents, such as in North America and Europe. Nevertheless, with the constant westernization of the life styles of emerging populations, for example, in Asian nations, the incidence of IBD is increasing throughout the world. Periodontitis, on the other hand, is an infection-induced inflammatory disease of the tooth-supporting tissues. It usually demonstrates a chronic, asymptomatic, and episodic character. It differs from gingivitis, the inflammation of gingiva, in that periodontitis is accompanied with degradation of hard tissues, the alveolar bone. At individual level, it causes tooth loss and, consequently, defects in speech and nutrition, and thereby reduces the quality of life. At the public level, it is an escalating burden to the healthcare economy (Chapple, 2014). Among the global adult population, the prevalence of advanced periodontitis ranges from 5%–15% (Dye, 2012). Several lines of evidence and rationales connect Crohn’s disease and periodontitis. If we can connect these two distinct diseases through a common genetic background, this may mean that individuals who develop Crohn’s disease can be in risk of developing periodontitis as well. With that knowledge, it can be possible to develop health policies to invest in preventive treatment of risk groups, rather than treating disease in larger populations. Therefore, below, we will define the prevalence of periodontal diseases in individuals with periodontal disease, describe the similarities in the pathogenesis of Crohn’s disease and periodontitis, connect these two distinct diseases with hBD-2, and finally suggest applicable approaches to support healthcare economy. Periodontal Diseases in Individuals with Crohn’s Disease
While the prevalence of oral findings in subjects with Crohn’s disease is relatively high, reports on a putative association specifically between periodontal diseases and Crohn’s disease are limited (Katsanos et al., 2015). One plausible reason for the lack of reports in this literature domain is that the association studies were performed hitherto on subjects with both Crohn’s disease and UC, under a common diagnosis of IBDs. The first report on the oral findings of a subject with Crohn’s disease dates back to 1969 (Dudeney, 1969). Most common oral symptoms of Crohn’s
KESKIN ET AL.
disease include apthous-ulcerative lesions, nonspecific swellings, and cobblestone architecture of the oral mucosa (Scheper and Brand, 2002; Harty et al., 2005). Moreover, the caries prevalence was found to be higher in subjects with Crohn’s disease than in healthy controls (Brito et al., 2008). The clinical findings of Crohn’s disease were not limited to mucosal changes and caries, but it was also observed that Crohn’s disease can accompany with symptoms of periodontal diseases (Brito et al., 2008; Flemmig et al., 1991; Gro¨ssner et al., 2006; Stein et al., 2010; Vavricka et al., 2013). A case of a young male with Crohn’s disease suffering from rapidly progressive periodontitis was the first to mention a relation between these two different disease entities (Lamster et al., 1978). Later, a greater gingival inflammation, but less periodontal tissue destruction, was demonstrated on 10 subjects with IBD (6 subjects with Crohn’s disease and 4 with UC), in comparison to a group of age- and sex-matched systemically healthy periodontitis patients (Van Dyke et al., 1986). Interestingly, in the same study, the authors presented a defect in neutrophil chemotaxis and an increased prevalence of motile gram-negative species of the genus Wolinella (currently Camphylobacter) in periodontal pockets (Van Dyke et al., 1986). In a larger study population with 107 IBD patients (46 Crohn’s disease and 61 UC patients), it was demonstrated that periodontal disease in IBD subjects was more generalized but less severe when compared to a general population in the USA (Flemmig et al., 1991). In a successive case-control study in 121 subjects, including 62 IBD patients, a slightly higher prevalence of clinical attachment loss was observed in the IBD group, in comparison to systemically healthy controls (Gro¨ssner et al., 2006). While the probing pocket depth scores in Crohn’s disease patients showed similarities as reported before (Flemmig et al., 1991), clinical signs of inflammation in the IBD group were not significantly different from the controls (Gro¨ssner et al., 2006). A study by Brito et al. (2008) compared the periodontal health status of 179 IBD patients (99 Crohn’s disease and 80 UC patients) to 74 systemically healthy subjects. After adjustment for race, gender, smoking habit, age, and dental plaque, Crohn’s disease patients were found to have significantly deeper probing pocket depths than controls. Furthermore, among nonsmokers, Crohn’s disease patients showed significantly fewer sites with plaque but deeper pocket depths compared to controls. The prevalence of periodontitis was significantly higher in the patient groups than in their controls (Brito et al., 2008). It is noteworthy that in certain studies (Flemmig et al., 1991; Gro¨ssner et al., 2006) probing pocket depth and clinical attachment level scores were measured either in two sites (Flemmig et al., 1991) or four sites (Gro¨ssner et al., 2006) of only two quadrants. It is well proven that partial-mouth designs underestimate the severity of periodontitis (Thomson and Williams, 2002). When measuring the periodontal parameters from six sites of all teeth, Stein et al. (2010) demonstrated greater probing pocket depths and a higher prevalence of periodontitis in Crohn’s disease patients, than in previous studies mentioned above. The severity of periodontitis, however, was shown to be similar in all studies (Brito et al., 2008; Flemmig et al., 1991; Gro¨ssner et al., 2006; Stein et al., 2010). Habashneh et al. (2012) investigated the association between the prevalence, severity, and extent of periodontitis among patients with UC (n = 101) or Crohn’s disease (n = 59)
CROHN’S DISEASE AND PERIODONTITIS
and their systemically healthy controls (n = 100). All periodontal parameters (plaque index, gingival index, probing pocket depth, clinical attachment level, and gingival recession) were elevated in subjects with Crohn’s disease. Moreover, the prevalence of periodontitis was higher in the age group of 18–45 year controls. The high prevalence of periodontitis in young adults is surprising, since initiation and progression of periodontitis is highly related with age and the prevalence of periodontitis is relatively low in young adults (
OMICS A Journal of Integrative Biology Volume 19, Number 8, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2015.0077
Two Cheers for Crohn’s Disease and Periodontitis: Beta-Defensin-2 as an Actionable Target to Intervene on Two Clinically Distinct Diseases Mutlu Keskin,1,2 Fares Zeida´n-Chulia´,1,3 Mervi Gursoy,1 Eija Ko¨no¨nen,1,4 Jaana Rautava,5* and Ulvi Kahraman Gursoy1*
Abstract
Recent advances in multi-omics approaches encompassing genomics, transcriptomics, proteomics, and metabolomics offer hitherto unprecedented insights on common complex human diseases. A unique angle pertinent for both diagnostic and therapeutic sciences involves rethinking clinically distinct diseases with a view to their shared molecular targets, interactomes, and pathophysiologies. Reflecting at a scale of disease-to-disease associations might help clinicians, public health practitioners, drug and biotechnology developers, and associated knowledge industries in the current era. This review article examines the hypothesis that ‘‘Intersecting Molecular Pathways Permit Interventions on Multiple Clinical Endpoints’’, thus uniquely bringing together Crohn’s disease and periodontitis. Furthermore, we propose a novel connector molecular target between these two ostensibly distinct diseases at a clinical level, human beta defensin (hBD)-2, and suggest pathways by which hBD-2 can conceivably connect Crohn’s disease and periodontitis by virtue of regulating the innate-immune response. We conclude by emphasizing different approaches where hBD-2 can be employed as a diagnostic and therapeutic tool to improve the quality of life of susceptible individuals and minimize the economic costs of these two major global public health problems. The strategy presented here also presents potentials for targeting of multiple diseases through a unique ‘‘nodal molecular target’’ that ‘‘speaks to’’ multiple clinical endpoints.
Introduction
Concept ‘‘Intersecting Molecular Pathways Permit Interventions on Multiple Clinical Endpoints’’
I
ntegrative biology and interactome analyses are transforming old concepts of disease and pathophysiology (Dimitrakopoulou et al., 2014; Podder and Latha, 2014), not to forget drug repurposing research (Sun et al., 2015). A unique angle pertinent for both diagnostic and therapeutic sciences (i.e., the emerging field of theranostics), involves rethinking clinically distinct diseases with a view to their shared molecular targets, interactomes, and pathophysiologies. Reflecting at a scale of disease-to-disease associations might help clinicians, public health practitioners, drug and biotechnology developers, and associated knowledge industries in the current era. This review article examines the integrative biology concept presented below, thus uniquely bringing together Crohn’s disease and periodontitis.
The current moves to conceptualize common complex diseases as syndromes with a shared clinical typology, comprised of multiple molecular pathways, have important corollaries. This means that at certain molecular intersection points it might be possible to intervene on more than one disease or several subtypes of an apparently homogenous disease-syndrome. Defining common risk groups for widespread diseases, exploring their underlying shared risk factors, and constructing cost-effective preventive measures for those public health problems will minimize the psychological and economic impacts of these diseases on individuals, and eventually, on public.
Departments of 1Periodontology, and 5Oral Pathology, Institute of Dentistry, University of Turku, Turku, Finland. 2_ Istanbul Kemerburgaz University, Vocational School of Health Services, Istanbul, Turkey. 3 Departamento de Bioquı´mica, Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 4 Oral Health Care, Welfare Division, City of Turku, Turku, Finland. *These authors contributed equally.
1
2
This mini-review applies the above hypothesis to the case of Crohn’s disease and periodontitis through human beta defensin (hBD)-2. Ulcerative colitis (UC), which is another form of inflammatory bowel disease, will not be included into this review because genetic expression profiles, including that of hBD-2, are different in Crohn’s disease and UC (Fellermann et al., 2006). Connecting the Dots with Beta Defensin-2
Crohn’s disease and UC are two forms of inflammatory bowel disease (IBD). Both diseases are characterized by a chronic dysregulation of mucosal immune response of the gastrointestinal tract and share similarities in their pathophysiology. While Crohn’s disease can affect any part of the gastrointestinal tract, UC is restricted to colon and rectum (Ananthakrishnan, 2015). In Europe, the incidence of Crohn’s disease is between 0.3–12.7 per 100,000 persons (Ananthakrishnan, 2015), and it creates an economic burden of 2.1–16.7 billion euros (Floyd et al., 2015). Traditionally, the incidence of IBD has been highest in developed continents, such as in North America and Europe. Nevertheless, with the constant westernization of the life styles of emerging populations, for example, in Asian nations, the incidence of IBD is increasing throughout the world. Periodontitis, on the other hand, is an infection-induced inflammatory disease of the tooth-supporting tissues. It usually demonstrates a chronic, asymptomatic, and episodic character. It differs from gingivitis, the inflammation of gingiva, in that periodontitis is accompanied with degradation of hard tissues, the alveolar bone. At individual level, it causes tooth loss and, consequently, defects in speech and nutrition, and thereby reduces the quality of life. At the public level, it is an escalating burden to the healthcare economy (Chapple, 2014). Among the global adult population, the prevalence of advanced periodontitis ranges from 5%–15% (Dye, 2012). Several lines of evidence and rationales connect Crohn’s disease and periodontitis. If we can connect these two distinct diseases through a common genetic background, this may mean that individuals who develop Crohn’s disease can be in risk of developing periodontitis as well. With that knowledge, it can be possible to develop health policies to invest in preventive treatment of risk groups, rather than treating disease in larger populations. Therefore, below, we will define the prevalence of periodontal diseases in individuals with periodontal disease, describe the similarities in the pathogenesis of Crohn’s disease and periodontitis, connect these two distinct diseases with hBD-2, and finally suggest applicable approaches to support healthcare economy. Periodontal Diseases in Individuals with Crohn’s Disease
While the prevalence of oral findings in subjects with Crohn’s disease is relatively high, reports on a putative association specifically between periodontal diseases and Crohn’s disease are limited (Katsanos et al., 2015). One plausible reason for the lack of reports in this literature domain is that the association studies were performed hitherto on subjects with both Crohn’s disease and UC, under a common diagnosis of IBDs. The first report on the oral findings of a subject with Crohn’s disease dates back to 1969 (Dudeney, 1969). Most common oral symptoms of Crohn’s
KESKIN ET AL.
disease include apthous-ulcerative lesions, nonspecific swellings, and cobblestone architecture of the oral mucosa (Scheper and Brand, 2002; Harty et al., 2005). Moreover, the caries prevalence was found to be higher in subjects with Crohn’s disease than in healthy controls (Brito et al., 2008). The clinical findings of Crohn’s disease were not limited to mucosal changes and caries, but it was also observed that Crohn’s disease can accompany with symptoms of periodontal diseases (Brito et al., 2008; Flemmig et al., 1991; Gro¨ssner et al., 2006; Stein et al., 2010; Vavricka et al., 2013). A case of a young male with Crohn’s disease suffering from rapidly progressive periodontitis was the first to mention a relation between these two different disease entities (Lamster et al., 1978). Later, a greater gingival inflammation, but less periodontal tissue destruction, was demonstrated on 10 subjects with IBD (6 subjects with Crohn’s disease and 4 with UC), in comparison to a group of age- and sex-matched systemically healthy periodontitis patients (Van Dyke et al., 1986). Interestingly, in the same study, the authors presented a defect in neutrophil chemotaxis and an increased prevalence of motile gram-negative species of the genus Wolinella (currently Camphylobacter) in periodontal pockets (Van Dyke et al., 1986). In a larger study population with 107 IBD patients (46 Crohn’s disease and 61 UC patients), it was demonstrated that periodontal disease in IBD subjects was more generalized but less severe when compared to a general population in the USA (Flemmig et al., 1991). In a successive case-control study in 121 subjects, including 62 IBD patients, a slightly higher prevalence of clinical attachment loss was observed in the IBD group, in comparison to systemically healthy controls (Gro¨ssner et al., 2006). While the probing pocket depth scores in Crohn’s disease patients showed similarities as reported before (Flemmig et al., 1991), clinical signs of inflammation in the IBD group were not significantly different from the controls (Gro¨ssner et al., 2006). A study by Brito et al. (2008) compared the periodontal health status of 179 IBD patients (99 Crohn’s disease and 80 UC patients) to 74 systemically healthy subjects. After adjustment for race, gender, smoking habit, age, and dental plaque, Crohn’s disease patients were found to have significantly deeper probing pocket depths than controls. Furthermore, among nonsmokers, Crohn’s disease patients showed significantly fewer sites with plaque but deeper pocket depths compared to controls. The prevalence of periodontitis was significantly higher in the patient groups than in their controls (Brito et al., 2008). It is noteworthy that in certain studies (Flemmig et al., 1991; Gro¨ssner et al., 2006) probing pocket depth and clinical attachment level scores were measured either in two sites (Flemmig et al., 1991) or four sites (Gro¨ssner et al., 2006) of only two quadrants. It is well proven that partial-mouth designs underestimate the severity of periodontitis (Thomson and Williams, 2002). When measuring the periodontal parameters from six sites of all teeth, Stein et al. (2010) demonstrated greater probing pocket depths and a higher prevalence of periodontitis in Crohn’s disease patients, than in previous studies mentioned above. The severity of periodontitis, however, was shown to be similar in all studies (Brito et al., 2008; Flemmig et al., 1991; Gro¨ssner et al., 2006; Stein et al., 2010). Habashneh et al. (2012) investigated the association between the prevalence, severity, and extent of periodontitis among patients with UC (n = 101) or Crohn’s disease (n = 59)
CROHN’S DISEASE AND PERIODONTITIS
and their systemically healthy controls (n = 100). All periodontal parameters (plaque index, gingival index, probing pocket depth, clinical attachment level, and gingival recession) were elevated in subjects with Crohn’s disease. Moreover, the prevalence of periodontitis was higher in the age group of 18–45 year controls. The high prevalence of periodontitis in young adults is surprising, since initiation and progression of periodontitis is highly related with age and the prevalence of periodontitis is relatively low in young adults (
