Medical Hypotheses xxx (2013) xxx–xxx
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Hygiene hypothesis and periodontitis – A possible association Bhumanapalli Venkata Ramesh Reddy ⇑, Vijay Kumar Chava, Sreenivas Nagarakanti, Sumanth Gunupati, Pramod Samudrala Department of Periodontology, Narayana Dental College and Hospital, Nellore, Andhra Pradesh 524002, India
a r t i c l e
i n f o
Article history: Received 7 August 2013 Accepted 6 November 2013 Available online xxxx
a b s t r a c t Hygiene hypothesis has been proposed more than two decades back to explain an increasing prevalence of allergic diseases and atopy. It states that, a lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases and atopy later in life. The evidence in relation to hygiene hypothesis is controversial and inconclusive. Moreover, its underlying mechanisms are elusive and remain to be elucidated. Periodontitis is an inflammatory disease initiated by microorganisms present in the plaque biofilm. Association between periodontitis and various systemic diseases has already been established and is currently an area of interest particularly in periodontal research. Consistent with hygiene hypothesis, some researchers believed that pathogens associated with periodontal diseases might have a protective role in the development of asthma and other allergic diseases. Very few studies attempted to explore the concept of association between periodontitis, asthma and other respiratory allergic diseases which could neither support such a protective role for periodontal diseases nor reject such an association. This suggests a need for additional research to examine the relevance of hygiene hypothesis in periodontics. The purpose of the present article is to review the plausible scientific explanations available for hygiene hypothesis, to review some studies relating periodontitis, asthma and other respiratory allergic diseases and to stress the need for further research. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction A recent upward trend in the prevalence of asthma and other respiratory allergic diseases in developed and developing nations is an observation of considerable concern [1]. Many theories have been proposed to explain such an upward trend. The most attractive and leading of all explanations is ‘hygiene hypothesis’. It contends that, early childhood infections inhibit the tendency to develop allergic disease [2]. This hypothesis was first proposed by D.P. Strachan in 1989. In his epidemiologic study, he observed that younger children in large families had less asthma and allergy. His presumption was that, increased exposure to infections that passed around in such large families could be the reason behind his observation and concluded with a comment that, ‘‘. . ..declining family sizes, improvements in household amenities and higher standards of personal cleanliness have reduced the opportunity for cross infection in young families. This may have resulted in more widespread clinical expression of atopic disease’’ [3]. However, this suggestion of infection as a protective factor against allergic diseases remains to be a speculative hypothesis lacking a clear scientific explanation and
attempts to investigate it further, generated controversial evidence [4–6]. Periodontitis is a chronic inflammatory disease initiated by microorganisms present in the plaque biofilm. The colonization of oral cavity with periodontal microflora begins early in life [7], which suggests that periodontal microflora might have an influence on the development of the immune system in a child. An association between periodontitis and various systemic diseases, including respiratory diseases is now, a well established fact and is the focus of much research in the past decade [8]. With the above facts, and in relation to hygiene hypothesis, there might probably be a role for periodontal microflora in the aetiology of asthma and other respiratory allergic diseases. Some researchers investigated this idea and some even went to the extent of questioning the age-old practise of oral hygiene and plaque control [9]. The purpose of the article is to review the plausible scientific explanations for hygiene hypothesis, studies relating periodontitis, asthma and other respiratory allergic diseases and to stress the need for research in this field.
Experimental evidence for hygiene hypothesis ⇑ Corresponding author. Tel.: +91 9849798990; fax: +91 8612305092. E-mail address: [email protected] (B.V. Ramesh Reddy).
Very recently in 2012, Olszak et al. conducted an experimental study, which by far is the best biological explanation to hygiene
0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.006
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
2
B.V. Ramesh Reddy et al. / Medical Hypotheses xxx (2013) xxx–xxx
hypothesis [10]. They grew mice under germ-free conditions and examined their susceptibility to oxazolone-induced colitis and ovalbumin-driven allergic asthma. The germ-free mice (GF mice) showed an increased sensitivity to these conditions. They further showed that such an increased sensitivity was characterized by an expansion of invariant natural killer T (iNKT) cells in the colon and lungs of GF mice. They next examined whether re-establishing microbiota in these mice would normalize iNKT cells and reduce their sensitivity to allergic conditions. Only very young GF mice, but not adult GF mice exposed to microbiota showed improvement. However surprisingly, pregnant female GF mice exposed to microbiota delivered mice that showed reduced susceptibility to the allergic conditions and with normalized iNKT cells. With these observations, they concluded that ‘‘early-life microbial exposure elicits long-lasting effects on iNKT cells, and in their absence, later-life exposure to factors that stimulate these cells may induce an auto inflammatory response’’. Immunologic explanations for hygiene hypothesis Th1/Th2 paradigm Earlier, infections were believed to be a potential trigger for allergic sensitization; this thinking lead to a delay in adopting hygiene hypothesis which suggested infections as protective influence against allergic diseases [11]. However with the discovery of two different subsets of T cells, namely, T helper 1 cells (Th1) and T helper 2 (Th2) cells in animal models [12] as well as in human subjects [13], this hypothesis began to gain popularity. Th1 cells secrete cytokines like interleukin (IL)-2, interferon (IFN)-c, tumor necrosis factor (TNF)-a, which contribute to phagocyte cell mediated immunity; whereas Th2 cells secrete cytokines like IL-4, 5, 6 and 13 which usually contribute to Ig E and eosinophil/mast cell mediated immunity [14]. Th1-cell mediated immunity is associated with bacterial and viral infections and autoimmune disorders; Th2-cell mediated immunity is associated with helminth parasitic infections and allergic diseases [15]. The cytokines produced by T helper cells amplify the same Thsubset cells and down-regulates the other Th-subset cells. This reciprocal down-regulation explains the hygiene hypothesis; an early stimulation of Th1-cell mediated immunity by infectious microorganisms might probably account for a down-regulation of Th2-cell mediated allergic diseases later in life. However, certain contrary observations were made, which the Th1/Th2 paradigm could not explain. Two such important observations were; one, a positive association between asthma (Th2-cell mediated) and autoimmune diseases like type I diabetes mellitus and others [16,17] (Th1-cell mediated); two, though helminth parasitic infections are mediated by Th2 cell immunity, some helminth parasitic infections also provide protection against allergic diseases [18,19]. T regulatory cells T regulatory (Treg) cells/CD4+ CD25+ cells are a population of T lymphocyte cells with suppressor function, and they down-regulate immune responses [20]. Treg cells express anti-inflammatory molecules like IL-10, transforming growth factor (TGF) b and inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA4), through which these cells control the inflammatory T cells (both Th1 and Th2 cells) and their down-stream effectors [21]. Treg cells either originate during thymic development or can be induced from naïve T cells. Dendritic cells play a key role in converting naïve T cells to Treg cells and also in promoting the function of existing Treg cells [21]. Exposure to pathogens and their products
activate the immature dendritic cells and promote their tolerogenicity which induce Treg cells that further control the immune responses [21]. However, the molecular basis for such a promotion of immune regulatory network is still not clear. Thus a possible explanation for hygiene hypothesis is that, early life microbial exposure not only induces a Th1 cell mediated response, but also promotes an anti inflammatory regulatory T cell network that later suppresses T cell mediated immune responses including Th2 cell mediated respiratory allergic diseases. Toll-like receptors Toll-like receptors mediate innate immunity through recognition of pathogen associated microbial patterns. They stimulate production of various cytokines and generate immune responses which might influence adaptive immunity and thus may have a role in allergic and autoimmune responses. Microbial components are recognised by toll like receptors and initiate inflammatory responses. Studies investigating the role of toll like receptors in asthma confirmed that activation of toll like receptors during allergen sensitization blocked the development of asthma [22]. Though the underlying molecular mechanisms are not yet clearly understood, it is believed that, production of immuno-regulatory cytokines and induction of Treg cells could be involved [14]. Antigenic-competition Another probable explanation for hygiene hypothesis is antigenic competition. It is believed that, antigens from infectious agents elicit strong immune responses which inhibit weak immune responses elicited by allergens and auto antigens [14]. Periodontitis and respiratory allergic diseases Most of the research related to hygiene hypothesis has been focussed on exploring the role of gastrointestinal microflora in relation to asthma and other respiratory allergies. Just like the gastrointestinal tract, oral cavity also harbours hundreds of species of microorganisms and their colonization also begins early in life. However, very few studies examined the role of oral infections in the aetiology of respiratory allergic diseases. Grossi et al. in 1994 [23] conducted a cross sectional study to identify risk indicators for periodontal disease, in which, for the first time, they reported a negative association between periodontal attachment loss and allergies. However, no mention about hygiene hypothesis was made; instead, they presumed that chronic use of anti-histamine medications by individuals suffering from allergies had a non-specific modulating effect on inflammation and host response to periodontal pathogens which resulted in the observed negative association. In addition, they believed that systemic antibiotics which are the second most commonly used medication by allergic groups might have had an effect by suppressing periodontal microorganisms. A decade later, in 2006, Friedrich et al. [24] analysed the association between periodontitis and three respiratory allergies which included hay fever, house dust mite allergy and asthma in a cross-sectional, epidemiological survey involving a large general adult population based sample. They reported a strong inverse association between periodontitis and hay fever; periodontitis and house dust mite allergy; but a weak inverse relation between periodontitis and asthma. They concluded that their findings support the hygiene hypothesis. In 2008, Friedrich et al. [25] conducted another cross sectional study to investigate the association between periodontitis and
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
B.V. Ramesh Reddy et al. / Medical Hypotheses xxx (2013) xxx–xxx
respiratory allergies in a population of patients with type I diabetes mellitus. They observed that the risk of respiratory allergies decreased with increased attachment loss in this group of population. Moreover, they compared these observations with their previous findings and concluded that the observed inverse relation was stronger in patients with type I diabetes mellitus than in subjects randomly selected from the general population. Arbes et al. in 2006 [26] using the national health and nutrition examination survey (NHANES) III data, investigated the association between asthma, wheeze and hay fever and serum concentrations of IgG antibodies to two oral bacteria; Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, which are commonly associated with periodontal disease. Their findings were consistent with hygiene hypothesis which showed a significant association of higher concentrations of IgG antibodies to P gingivalis with lower prevalence of asthma, wheeze and hay fever; similarly, higher concentrations of IgG antibodies to Aggregatibacter actinomycetemcomitans were significantly associated with a lower prevalence of wheeze. Hujoel et al. in 2008 [9] investigated association of periodontitis severity with patterns of medication use during seven years of follow up. They observed that there was a pronounced decrease in the use of allergy medications among subjects with moderate to advanced periodontitis and these patterns were consistent with hygiene hypothesis. Besides this explanation, they suggested another most likely non-causal explanation that a genetic predisposition to destructive periodontal disease protects against allergies and infections, which has to be reviewed further. Card et al. in 2010 [27] conducted an experimental study to investigate whether infection with P gingivalis modified allergic outcomes in a murine model of asthma. A subcutaneous chamber model was employed to infect the mice with P gingivalis and the mice were infected either before or after sensitization to allergen ovalbumin (OVA). The subcutaneous chamber model provided a low level systemic challenge which simulated a naturally occurring oral infection. P gingivalis infection established before allergen sensitization reduced the airway inflammation. The infection established after allergen sensitization, however, surprisingly reduced airway hyper-responsiveness, despite the presence of allergic airway inflammation. Contrary to these studies which established a negative association between periodontitis or periodontal microflora and respiratory allergic diseases, some studies also reported either a positive association [28–31] or a null association [32–34] between periodontitis and asthma. However, the fact that both asthma and periodontitis are multi-factorial diseases explains the observed variation in different studies. For example, mouth breathing habit and chronic use of inhalational drugs by asthmatics might affect the periodontal disease status. In addition, Salvi et al. [35] believed that Th1/Th2 paradigm is an oversimplification and argued against Th2 hypothesis for asthma. However, further evidence is needed to support this argument. Moreover, it is worth mentioning about an opposite cause-andeffect relationship of hygiene in established allergic disease that has been suggested [36]. According to this suggestion, after the establishment of asthma and allergic diseases in an individual, microbial exposure would worsen the disease rather than providing a protective influence. Hence, investigating adult individuals to establish a relationship between periodontitis and respiratory allergies would be a limitation of particular significance in most studies; especially, when hygiene hypothesis suggests that, childhood exposure to infections provide the best protection against allergic diseases. Very few studies involved children and adolescents as study subjects and they reported either a positive association or a null association between periodontitis and asthma [29,31,34].
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Need for research More than two decades ago, hygiene hypothesis had been suggested and since then, many research projects had been undertaken in various fields of medicine to verify it and to generate therapeutic strategies. Despite the fact that, colonization of oral cavity with hundreds of species of microorganisms occurs early in life and despite the evidence suggesting their influence on systemic health, very few studies have examined the role of oral microbiota in relation to hygiene hypothesis. One limitation of most studies was employing a cross sectional study design (very few studies employed case-control study design). Cross sectional study design provides weak evidence and is used to generate hypothesis rather than verify it. Moreover, no study examined the association between oral bacteria and allergic diseases directly (except Card et al. [27]; which is an experimental animal study). Instead, they examined relation of gingivitis/periodontitis; serum antibody concentrations of bacteria or prescription fill rates which may not directly suggest the role of oral microbiota. Moreover, Linneberg et al. [5] suggested that different bacteria may have different effects on the risk of developing atopy. Hence, the chances of only some oral pathogens providing protection against allergic diseases cannot be ruled out. Most of the studies were conducted either in American or European populations (only one study investigated Indian population [30]). Because variations in genetic makeup and susceptibility patterns to various pathogens exist among different populations, conducting multi-center studies might be of help in finding the variations and to assess the validity of hygiene hypothesis in specific populations. In the wake of weak evidence, there is a need for more research to verify this hypothesis in relation to oral microflora. Well planned case-control studies and progressive cohort studies involving young children to examine the association of bacteria directly sampled from the oral cavity in patients with allergic diseases might help in establishing a relation. Conclusion At a time when, meticulous plaque control and thorough oral hygiene maintenance are extensively being propagated for controlling periodontal infections and maintaining periodontal health, it would be foolish to suggest that periodontal infections be given, especially to children to protect them from asthma and other respiratory allergic diseases. However, conducting research and establishing evidence might help in developing therapeutic strategies for more serious diseases like asthma. In addition, the chances of identifying a role for any commensal oral bacteria in protection of allergic diseases might be of significant use in asthma and allergic diseases treatment. This research might also help us in further understanding the pathogenesis of periodontitis and allergic diseases and might also help in unravelling the unclear underlying molecular mechanisms. This hypothesis also signifies the need to avoid unnecessary antibiotic prescriptions for avoiding unrelated consequences that might arise from their use. Conflict of interest None. Source of funding The study was self-funded by the authors and there was no external funding from any organization, for this study.
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
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B.V. Ramesh Reddy et al. / Medical Hypotheses xxx (2013) xxx–xxx
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Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Hygiene hypothesis and periodontitis – A possible association Bhumanapalli Venkata Ramesh Reddy ⇑, Vijay Kumar Chava, Sreenivas Nagarakanti, Sumanth Gunupati, Pramod Samudrala Department of Periodontology, Narayana Dental College and Hospital, Nellore, Andhra Pradesh 524002, India
a r t i c l e
i n f o
Article history: Received 7 August 2013 Accepted 6 November 2013 Available online xxxx
a b s t r a c t Hygiene hypothesis has been proposed more than two decades back to explain an increasing prevalence of allergic diseases and atopy. It states that, a lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases and atopy later in life. The evidence in relation to hygiene hypothesis is controversial and inconclusive. Moreover, its underlying mechanisms are elusive and remain to be elucidated. Periodontitis is an inflammatory disease initiated by microorganisms present in the plaque biofilm. Association between periodontitis and various systemic diseases has already been established and is currently an area of interest particularly in periodontal research. Consistent with hygiene hypothesis, some researchers believed that pathogens associated with periodontal diseases might have a protective role in the development of asthma and other allergic diseases. Very few studies attempted to explore the concept of association between periodontitis, asthma and other respiratory allergic diseases which could neither support such a protective role for periodontal diseases nor reject such an association. This suggests a need for additional research to examine the relevance of hygiene hypothesis in periodontics. The purpose of the present article is to review the plausible scientific explanations available for hygiene hypothesis, to review some studies relating periodontitis, asthma and other respiratory allergic diseases and to stress the need for further research. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction A recent upward trend in the prevalence of asthma and other respiratory allergic diseases in developed and developing nations is an observation of considerable concern [1]. Many theories have been proposed to explain such an upward trend. The most attractive and leading of all explanations is ‘hygiene hypothesis’. It contends that, early childhood infections inhibit the tendency to develop allergic disease [2]. This hypothesis was first proposed by D.P. Strachan in 1989. In his epidemiologic study, he observed that younger children in large families had less asthma and allergy. His presumption was that, increased exposure to infections that passed around in such large families could be the reason behind his observation and concluded with a comment that, ‘‘. . ..declining family sizes, improvements in household amenities and higher standards of personal cleanliness have reduced the opportunity for cross infection in young families. This may have resulted in more widespread clinical expression of atopic disease’’ [3]. However, this suggestion of infection as a protective factor against allergic diseases remains to be a speculative hypothesis lacking a clear scientific explanation and
attempts to investigate it further, generated controversial evidence [4–6]. Periodontitis is a chronic inflammatory disease initiated by microorganisms present in the plaque biofilm. The colonization of oral cavity with periodontal microflora begins early in life [7], which suggests that periodontal microflora might have an influence on the development of the immune system in a child. An association between periodontitis and various systemic diseases, including respiratory diseases is now, a well established fact and is the focus of much research in the past decade [8]. With the above facts, and in relation to hygiene hypothesis, there might probably be a role for periodontal microflora in the aetiology of asthma and other respiratory allergic diseases. Some researchers investigated this idea and some even went to the extent of questioning the age-old practise of oral hygiene and plaque control [9]. The purpose of the article is to review the plausible scientific explanations for hygiene hypothesis, studies relating periodontitis, asthma and other respiratory allergic diseases and to stress the need for research in this field.
Experimental evidence for hygiene hypothesis ⇑ Corresponding author. Tel.: +91 9849798990; fax: +91 8612305092. E-mail address: [email protected] (B.V. Ramesh Reddy).
Very recently in 2012, Olszak et al. conducted an experimental study, which by far is the best biological explanation to hygiene
0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.006
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
2
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hypothesis [10]. They grew mice under germ-free conditions and examined their susceptibility to oxazolone-induced colitis and ovalbumin-driven allergic asthma. The germ-free mice (GF mice) showed an increased sensitivity to these conditions. They further showed that such an increased sensitivity was characterized by an expansion of invariant natural killer T (iNKT) cells in the colon and lungs of GF mice. They next examined whether re-establishing microbiota in these mice would normalize iNKT cells and reduce their sensitivity to allergic conditions. Only very young GF mice, but not adult GF mice exposed to microbiota showed improvement. However surprisingly, pregnant female GF mice exposed to microbiota delivered mice that showed reduced susceptibility to the allergic conditions and with normalized iNKT cells. With these observations, they concluded that ‘‘early-life microbial exposure elicits long-lasting effects on iNKT cells, and in their absence, later-life exposure to factors that stimulate these cells may induce an auto inflammatory response’’. Immunologic explanations for hygiene hypothesis Th1/Th2 paradigm Earlier, infections were believed to be a potential trigger for allergic sensitization; this thinking lead to a delay in adopting hygiene hypothesis which suggested infections as protective influence against allergic diseases [11]. However with the discovery of two different subsets of T cells, namely, T helper 1 cells (Th1) and T helper 2 (Th2) cells in animal models [12] as well as in human subjects [13], this hypothesis began to gain popularity. Th1 cells secrete cytokines like interleukin (IL)-2, interferon (IFN)-c, tumor necrosis factor (TNF)-a, which contribute to phagocyte cell mediated immunity; whereas Th2 cells secrete cytokines like IL-4, 5, 6 and 13 which usually contribute to Ig E and eosinophil/mast cell mediated immunity [14]. Th1-cell mediated immunity is associated with bacterial and viral infections and autoimmune disorders; Th2-cell mediated immunity is associated with helminth parasitic infections and allergic diseases [15]. The cytokines produced by T helper cells amplify the same Thsubset cells and down-regulates the other Th-subset cells. This reciprocal down-regulation explains the hygiene hypothesis; an early stimulation of Th1-cell mediated immunity by infectious microorganisms might probably account for a down-regulation of Th2-cell mediated allergic diseases later in life. However, certain contrary observations were made, which the Th1/Th2 paradigm could not explain. Two such important observations were; one, a positive association between asthma (Th2-cell mediated) and autoimmune diseases like type I diabetes mellitus and others [16,17] (Th1-cell mediated); two, though helminth parasitic infections are mediated by Th2 cell immunity, some helminth parasitic infections also provide protection against allergic diseases [18,19]. T regulatory cells T regulatory (Treg) cells/CD4+ CD25+ cells are a population of T lymphocyte cells with suppressor function, and they down-regulate immune responses [20]. Treg cells express anti-inflammatory molecules like IL-10, transforming growth factor (TGF) b and inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA4), through which these cells control the inflammatory T cells (both Th1 and Th2 cells) and their down-stream effectors [21]. Treg cells either originate during thymic development or can be induced from naïve T cells. Dendritic cells play a key role in converting naïve T cells to Treg cells and also in promoting the function of existing Treg cells [21]. Exposure to pathogens and their products
activate the immature dendritic cells and promote their tolerogenicity which induce Treg cells that further control the immune responses [21]. However, the molecular basis for such a promotion of immune regulatory network is still not clear. Thus a possible explanation for hygiene hypothesis is that, early life microbial exposure not only induces a Th1 cell mediated response, but also promotes an anti inflammatory regulatory T cell network that later suppresses T cell mediated immune responses including Th2 cell mediated respiratory allergic diseases. Toll-like receptors Toll-like receptors mediate innate immunity through recognition of pathogen associated microbial patterns. They stimulate production of various cytokines and generate immune responses which might influence adaptive immunity and thus may have a role in allergic and autoimmune responses. Microbial components are recognised by toll like receptors and initiate inflammatory responses. Studies investigating the role of toll like receptors in asthma confirmed that activation of toll like receptors during allergen sensitization blocked the development of asthma [22]. Though the underlying molecular mechanisms are not yet clearly understood, it is believed that, production of immuno-regulatory cytokines and induction of Treg cells could be involved [14]. Antigenic-competition Another probable explanation for hygiene hypothesis is antigenic competition. It is believed that, antigens from infectious agents elicit strong immune responses which inhibit weak immune responses elicited by allergens and auto antigens [14]. Periodontitis and respiratory allergic diseases Most of the research related to hygiene hypothesis has been focussed on exploring the role of gastrointestinal microflora in relation to asthma and other respiratory allergies. Just like the gastrointestinal tract, oral cavity also harbours hundreds of species of microorganisms and their colonization also begins early in life. However, very few studies examined the role of oral infections in the aetiology of respiratory allergic diseases. Grossi et al. in 1994 [23] conducted a cross sectional study to identify risk indicators for periodontal disease, in which, for the first time, they reported a negative association between periodontal attachment loss and allergies. However, no mention about hygiene hypothesis was made; instead, they presumed that chronic use of anti-histamine medications by individuals suffering from allergies had a non-specific modulating effect on inflammation and host response to periodontal pathogens which resulted in the observed negative association. In addition, they believed that systemic antibiotics which are the second most commonly used medication by allergic groups might have had an effect by suppressing periodontal microorganisms. A decade later, in 2006, Friedrich et al. [24] analysed the association between periodontitis and three respiratory allergies which included hay fever, house dust mite allergy and asthma in a cross-sectional, epidemiological survey involving a large general adult population based sample. They reported a strong inverse association between periodontitis and hay fever; periodontitis and house dust mite allergy; but a weak inverse relation between periodontitis and asthma. They concluded that their findings support the hygiene hypothesis. In 2008, Friedrich et al. [25] conducted another cross sectional study to investigate the association between periodontitis and
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
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respiratory allergies in a population of patients with type I diabetes mellitus. They observed that the risk of respiratory allergies decreased with increased attachment loss in this group of population. Moreover, they compared these observations with their previous findings and concluded that the observed inverse relation was stronger in patients with type I diabetes mellitus than in subjects randomly selected from the general population. Arbes et al. in 2006 [26] using the national health and nutrition examination survey (NHANES) III data, investigated the association between asthma, wheeze and hay fever and serum concentrations of IgG antibodies to two oral bacteria; Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, which are commonly associated with periodontal disease. Their findings were consistent with hygiene hypothesis which showed a significant association of higher concentrations of IgG antibodies to P gingivalis with lower prevalence of asthma, wheeze and hay fever; similarly, higher concentrations of IgG antibodies to Aggregatibacter actinomycetemcomitans were significantly associated with a lower prevalence of wheeze. Hujoel et al. in 2008 [9] investigated association of periodontitis severity with patterns of medication use during seven years of follow up. They observed that there was a pronounced decrease in the use of allergy medications among subjects with moderate to advanced periodontitis and these patterns were consistent with hygiene hypothesis. Besides this explanation, they suggested another most likely non-causal explanation that a genetic predisposition to destructive periodontal disease protects against allergies and infections, which has to be reviewed further. Card et al. in 2010 [27] conducted an experimental study to investigate whether infection with P gingivalis modified allergic outcomes in a murine model of asthma. A subcutaneous chamber model was employed to infect the mice with P gingivalis and the mice were infected either before or after sensitization to allergen ovalbumin (OVA). The subcutaneous chamber model provided a low level systemic challenge which simulated a naturally occurring oral infection. P gingivalis infection established before allergen sensitization reduced the airway inflammation. The infection established after allergen sensitization, however, surprisingly reduced airway hyper-responsiveness, despite the presence of allergic airway inflammation. Contrary to these studies which established a negative association between periodontitis or periodontal microflora and respiratory allergic diseases, some studies also reported either a positive association [28–31] or a null association [32–34] between periodontitis and asthma. However, the fact that both asthma and periodontitis are multi-factorial diseases explains the observed variation in different studies. For example, mouth breathing habit and chronic use of inhalational drugs by asthmatics might affect the periodontal disease status. In addition, Salvi et al. [35] believed that Th1/Th2 paradigm is an oversimplification and argued against Th2 hypothesis for asthma. However, further evidence is needed to support this argument. Moreover, it is worth mentioning about an opposite cause-andeffect relationship of hygiene in established allergic disease that has been suggested [36]. According to this suggestion, after the establishment of asthma and allergic diseases in an individual, microbial exposure would worsen the disease rather than providing a protective influence. Hence, investigating adult individuals to establish a relationship between periodontitis and respiratory allergies would be a limitation of particular significance in most studies; especially, when hygiene hypothesis suggests that, childhood exposure to infections provide the best protection against allergic diseases. Very few studies involved children and adolescents as study subjects and they reported either a positive association or a null association between periodontitis and asthma [29,31,34].
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Need for research More than two decades ago, hygiene hypothesis had been suggested and since then, many research projects had been undertaken in various fields of medicine to verify it and to generate therapeutic strategies. Despite the fact that, colonization of oral cavity with hundreds of species of microorganisms occurs early in life and despite the evidence suggesting their influence on systemic health, very few studies have examined the role of oral microbiota in relation to hygiene hypothesis. One limitation of most studies was employing a cross sectional study design (very few studies employed case-control study design). Cross sectional study design provides weak evidence and is used to generate hypothesis rather than verify it. Moreover, no study examined the association between oral bacteria and allergic diseases directly (except Card et al. [27]; which is an experimental animal study). Instead, they examined relation of gingivitis/periodontitis; serum antibody concentrations of bacteria or prescription fill rates which may not directly suggest the role of oral microbiota. Moreover, Linneberg et al. [5] suggested that different bacteria may have different effects on the risk of developing atopy. Hence, the chances of only some oral pathogens providing protection against allergic diseases cannot be ruled out. Most of the studies were conducted either in American or European populations (only one study investigated Indian population [30]). Because variations in genetic makeup and susceptibility patterns to various pathogens exist among different populations, conducting multi-center studies might be of help in finding the variations and to assess the validity of hygiene hypothesis in specific populations. In the wake of weak evidence, there is a need for more research to verify this hypothesis in relation to oral microflora. Well planned case-control studies and progressive cohort studies involving young children to examine the association of bacteria directly sampled from the oral cavity in patients with allergic diseases might help in establishing a relation. Conclusion At a time when, meticulous plaque control and thorough oral hygiene maintenance are extensively being propagated for controlling periodontal infections and maintaining periodontal health, it would be foolish to suggest that periodontal infections be given, especially to children to protect them from asthma and other respiratory allergic diseases. However, conducting research and establishing evidence might help in developing therapeutic strategies for more serious diseases like asthma. In addition, the chances of identifying a role for any commensal oral bacteria in protection of allergic diseases might be of significant use in asthma and allergic diseases treatment. This research might also help us in further understanding the pathogenesis of periodontitis and allergic diseases and might also help in unravelling the unclear underlying molecular mechanisms. This hypothesis also signifies the need to avoid unnecessary antibiotic prescriptions for avoiding unrelated consequences that might arise from their use. Conflict of interest None. Source of funding The study was self-funded by the authors and there was no external funding from any organization, for this study.
Please cite this article in press as: Ramesh Reddy BV et al. Hygiene hypothesis and periodontitis – A possible association. Med Hypotheses (2013), http:// dx.doi.org/10.1016/j.mehy.2013.11.006
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