|Year : 2016 | Volume
| Issue : 3 | Page : 88-93
Bromelain: A potential strategy for the adjuvant treatment of periodontitis
Felipe Rodolfo Pereira da Silva1, Any Carolina Cardoso Guimaraes Vasconcelos2, Even Herlany Pereira Alves3, Paulo Vinicius de Oliveira Junior3, Jefferson Soares de Oliveira1, Daniel Fernando Pereira Vasconcelos4
1 Department of Biomedicine, Post Graduate Program in Biomedical Sciences, Parnaiba-PI, Brazil
2 Department of Scientific Methodology, Medicine School, Education Institute of Parnaiba Valley; Department of Biomedicine, Laboratory of Histological Analysis and Preparation, Parnaiba-PI, Brazil
3 Department of Biomedicine, Laboratory of Histological Analysis and Preparation, Parnaiba-PI, Brazil
4 Department of Biomedicine, Post Graduate Program in Biomedical Sciences; Department of Biomedicine, Laboratory of Histological Analysis and Preparation; Department of Dentistry, Post Graduation Program in Dentistry, Federal University of Piaui, Parnaiba-PI, Brazil
|Date of Web Publication||14-Sep-2016|
Daniel Fernando Pereira Vasconcelos
Universidade Federal do Piauí - UFPI; Campus Ministro Reis Veloso; Colegiado de Biomedicina; Av. São Sebastião, 2819, Reis Veloso; Parnaíba
Source of Support: None, Conflict of Interest: None
Introduction: Bromelain, a mixture of proteases derived from different parts of pineapple, has been described to have therapeutic benefits in a diversity of inflammatory diseases. Such effects are associated to its proteolytic activity. As one of the most common and multifactorial diseases, periodontitis is a bacterial infection that results from the damage to the integrity of the tissues around the tooth, which includes gingiva, periodontal ligament, and alveolar bone. In periodontitis, the recruitment of defense cells occurs, which releases several pro-inflammatory cytokines. At elevated levels, they can potentiate the alveolar bone loss. Studies have been conducted trying to alleviate the damage to the periodontium, however, the regeneration of the periodontal tissues is still limited. The Hypotheses: Based on previous studies showing that bromelain can act by decreasing the periodontal microorganism growth by proteolytically cleaving important cell surface molecules in leucocytes, by reducing neutrophils migration to periodontal sites, by downregulating the inflammation mediator levels, and by decreasing alveolar bone loss in the periodontitis. Evaluation of the Hypothesis: In a first moment, to evaluate this hypothesis, could be used two animal models: the ligature or bacteria inoculation induced periodontitis. If studies using animal models show encouraging results, appropriate clinical trials should be designed to evaluate the effect of bromelain as a complementary treatment for periodontal disease in humans, during the active phase or after the healing phase of mechanical therapy could be tested; to conduct a placebo-controlled study where health and periodontitis patients could be used.
Keywords: Bone, inflammation, periodontal disease, protease
|How to cite this article:|
da Silva FR, Vasconcelos AC, Alves EH, Junior PV, de Oliveira JS, Vasconcelos DF. Bromelain: A potential strategy for the adjuvant treatment of periodontitis. Dent Hypotheses 2016;7:88-93
|How to cite this URL:|
da Silva FR, Vasconcelos AC, Alves EH, Junior PV, de Oliveira JS, Vasconcelos DF. Bromelain: A potential strategy for the adjuvant treatment of periodontitis. Dent Hypotheses [serial online] 2016 [cited 2019 Jun 20];7:88-93. Available from: http://www.dentalhypotheses.com/text.asp?2016/7/3/88/190483
| Introduction|| |
Periodontitis is a bacterial infection involving accumulative plaque beyond gingival sulcus and host-immune response with multifactorial processes.  It is well established that the inflammation resulting from periodontitis compromises the integrity of the tissues around the tooth, which includes gingiva, periodontal ligament, and alveolar bone. 
As a multifactorial disease, locally, lipopolysaccharides derived from bacteria such as Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, Tannerella forsythia and Aggregatibacter actinomycetemcomitans, induce inflammatory infiltrate with the recruitment of polymorphonuclear neutrophils (PMN), leukocytes, and macrophages. Neutrophils degranulate large quantities of tissue-destroying enzymes, e.g., matrix metalloproteinases and generate reactive oxygen species. ,,]
In addition, these cells release several pro-inflammatory cytokines such as factor-alpha tumor necrosis (TNF-α), IFN-γ,  granulocyte-macrophage-colony-stimulating factor (GMCSF),  which are involved with the inflammation response and bone resorption,  acting via RANK/RANKL/OPG (RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand, and OPG, osteoprotegerin) pathway. ,
Scaling and root planning, mechanical therapy, and oral hygiene instructions have been used as the most frequently therapy for periodontitis. Although scaling and root planning plus oral hygiene instruction promotes an enhancement in the clinical periodontal parameters in the majority of patients, it is usually insufficient to a profile compatible with periodontal health. This way, studies have been conducted trying to alleviate the damage to the periodontium, ,, and still in this trend several hypotheses have been presented. ,, However, the repair of the periodontal tissues still is limited.
In this direction, bromelain, an extract derived from Ananas comosus (popularly known as pineapple), contains proteinases that exhibits anti-inflammatory properties. , Studies have shown efficacy similar to standard anti-inflammatory drugs ,, for the bromelain treatment. Furthermore, bromelain presents a large variety of activities such as anti-inflammatory properties in endometriosis,  reduction of the neutrophil migration to sites of inflammation,  antibacterial effect against periodontopathogens,  and what may influence the periodontal disease. This article hypothesizes the possible mechanisms of bromelain to ameliorate the development and progression of periodontitis.
Bromelain: Its biological and anti-inflammatory activities
Bromelain is a term used to describe proteolytic enzymes found in tissues, such as the stem, fruit, and leaves of pineapple. It mainly comprises multiple glycosylated enzymes from the papain superfamily, with different proteolytic enzymatic activities, molar masses from 20 to 31 kDa, and isoelectric points between 4.6 and 10. , However, bromelain also contains peroxidase, acid phosphatase, and several protease inhibitors. Although a complex mixture constitutes bromelain, some of its pharmacological properties such as anti-inflammatory and antibacterial effects require that the bromelain be proteolytically active. ,,
The anti-inflammatory properties of bromelain treatment are evidenced by decreased secretion of several pro-inflammatory cytokines, such as interferon gamma (IFNγ), tumor necrosis factor (TNF-α) and GMCSF in patients with Crohn's disease.  These cytokines are involved in the development and progression of periodontitis. ,
There are two important inflammation mediators, ciclooxigenase (Cox) type 1 (Cox-1) and 2 (Cox-2). Cox-1 is constitutively expressed in several tissues and supports the prostaglandin biosynthesis necessary for maintaining tissue homeostasis. Cox-2 is induced during the stimulation with pro-inflammatory molecules as IFNγ, TNF-α, and GMCSF. It is upregulated during inflammation.  Cox-2 is involved in the synthesis of prostaglandin E2 (PGE-2), which has been demonstrated to appear in significantly higher levels in gingival crevicular fluid of patients exhibiting periodontal diseases than it does in periodontally healthy individuals. , Interestingly, bromelain treatment has been shown to downregulate Cox-2 expression in several experiments. ,,
Furthermore, a study  revealed that bromelain treatment also removed several cell surface molecules involved in leucocytes adhesion and activation by its proteolytic activity. Cells are present in higher amounts in inflamed periodontal sites. 
In addition, bromelain showed inhibition of the growth of Saccharomyces cerevisiae, Escherichia coli, and Staphylococcus aureus. A similar effect was demonstrated for Streptococcus mutans, Enterococcus fecalis, Aggregatibacter actinomycetemcomitans (Aa), and Porphyromonas gingivalis (Pg), microorganisms found in the periodontal disease.  Numerous clinical trials of bromelain have shown effectiveness for treating inflammation conditions. These include osteoarthritis of the hip,  osteoarthritis of the knee,  and rhinosinusitis. 
| The Hypothesis|| |
Periodontitis is a disease with a multifactorial etiology;  the regeneration of periodontal tissues is still limited. Periodontal disease starts with the accumulation of microorganisms that stimulate the immunologic system response. This response can occur with the migration of leucocytes, especially neutrophils, and the release of several cytokines from different cells. One of the results of this process is alveolar bone loss.  Our research team believes that bromelain treatment could be useful for the adjuvant periodontal treatment because of the properties discussed above.
Our hypotheses is based on the following points: (1) Bromelain can decrease the periodontal microorganism growth; (2) Bromelain may proteolytically remove important cell surface molecules (CD25) in leucocytes; (3) Bromelain may reduce neutrophils migration to periodontal sites; (4) Bromelain can downregulate the inflammation mediators such as IFNγ, TNF, GMCSF, and Cox-2; and (5) Bromelain can decrease the osteoclastogenesis process with a decrease in alveolar bone loss in periodontitis [Figure 1].
|Figure 1: The figures represent the possible mechanisms of action of bromelain ameliorating the progression and development of periodontitis, indicated by five points: (a) Bromelain can decrease the periodontal microorganism growth; (b) Bromelain proteolytically can remove important cell surface molecules in leucocytes; (c) Bromelain can reduce neutrophils migration to periodontal sites; (d) Bromelain downregulates the inflammation mediators; (e) Bromelain can decrease the osteoclastogenesis process with reduction of alveolar bone loss in periodontitis|
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First, bromelain was able to inhibit the growth of a wide array of microorganisms including A. actinomycetemcomitans (Aa), P. gingivalis (Pg), and S. mutans, which are mainly associated with periodontitis  [Figure 1]a. Bromelain has an anti-adhesion property that prevents the bacteria from adhering to specific glycoprotein receptors located on the surface, similar to the hypothesis of Praveen et al. 
Second, this hypothesis is supported by the in vivo capacity of bromelain to proteolytically remove cell surface molecules, reducing activated CD4+ T leukocytes, especially CD4+ CD25+ T cells, when administered in a murine model of allergic airway disease,  along with a reduction of CD25 molecules in a dose-dependent manner, keeping the biological function of the CD4+ T cells in vitro. Immunohistological analyses demonstrated an elevated infiltrate of CD4+ CD25+ T cells in periodontitis lesions.  Therefore, we hypothesized that bromelain treatment can ameliorate the condition of the periodontal tissues, reducing the effects caused by the CD4+ CD25+ T cells that suppress immune responses to self.  [Figure 1]b.
Third, it is well-known that the hyperactivity of neutrophils results in damage to the periodontium.  A study demonstrated that the severity of gingival inflammation is consistent with elevated neutrophil count in patients with periodontitis.  In addition, the neutrophils release several pro-inflammatory cytokines.  Bromelain was able to reduce the migration of neutrophils in 50-85% and affect the firm adhesion of leukocytes to blood vessels, removing CD128 from the surface of the neutrophils  [Figure 1]c.
Fourth, bromelain downregulates the inflammation mediators such as IFNγ, TNF, and GMCSF in patients with Crohn's disease,  as well as Cox-2 expression in mouse skin papillomas stimulated by 7,12-dimethylbenz(a) anthracene.  All mentioned inflammation mediators appeared in the periodontitis at elevated concentrations when compared to healthy periodontum. , We believe that bromelain treatment may also downregulate the same mediators in periodontitis [Figure 1]d, promoting the reduction of clinical inflammatory parameters. Inchiongolo et al.  tested the anti-inflammatory effect of bromelain treatment after third molar surgery and found a reduction of postoperative pain and edema in patients that was comparable to diclofenac sodium treatment. De la Barrera-Núñez et al.  demonstrated less inflammation and improved oral aperture, even though the bromelain treatment was done with 150 mg per day, whereas in the study by Inchiongolo et al.,  a dose of 250 mg per day was used.
Fifth, bromelain may reduce the rate of bone resorption in periodontal inflammation due to the capacity of inhibition of MAP kinase signaling pathway  because the pro-inflammatory cytokines contribute with bone resorption through osteoclast differentiation by MAP kinase-JAK-STAT signaling,  as well as by interfering in the mechanism of osteoclastogenesis. Bromelain inhibited the phosphorylation of Ser-32 residue of phosphor-inhibitor kappa B (IkB), an important molecule for the translocation and function of nuclear factor-kappa B (NF-kB),  consequently blocking NF-kB action. , NF-kB, its receptor activator (also known as RANK) and ligand (RANKL) are involved in bone resorption during periodontitis due to the enhancement of osteoclast differentiation and stimulation of osteoclastogenesis.  We have hypothesized that this process can be decreased by bromelain treatment [Figure 1]e.
| Evaluation of the Hypothesis|| |
First, studies using animals should be designed to evaluate this hypothesis. A potential approach to confirm this hypothesis is to evaluate the effect of bromelain (commercially available by Sigma-Aldrich;) on periodontitis models in mice or rats. Two models could be used to investigate the periodontitis, i.e., using the ligature , or bacteria inoculation, , both of which have been widely used in initial studies. We believe that both methods could be tested; we suggest a minimal regime of the 20 days for bromelain treatment in the periodontitis-induced animals. We suggest administrating bromelain at a dosage of 15 mg/kg body weight daily because our research team has already obtained encouraging results with this treatment design in other animal models (unpublished data). In addition, the ligature model to induce periodontitis can possible confirm the hypothesis regarding the effect of bromelain on bacterial growth inhibition. Using this study design, it is possible evaluate the benefits on periodontium as well the potential systemic effects.
To confirm the hypothesis, the data must show that animals treated with bromelain demonstrate significant reduction of osteoclastogenesis, neutrophils migration to periodontal site, inflammation mediators' levels such as IFNγ, TNF, GMCSF and Cox-2 than the ones treated with placebo. Therefore, this finding would characterize amelioration in the progression and development of periodontitis.
If studies using animal models show encouraging results, such as significant reduction in alveolar bone loss, inflammation histological and clinical score, myeloperoxidase, stress oxidative, lipid peroxidation, and pro-inflammatory cytokines, appropriate clinical trials should be designed to evaluate this hypothesis. A possible way to evaluate the effect of bromelain as a complementary treatment for periodontal disease in humans is to conduct a placebo-controlled, double blind, randomized study where patients with periodontitis are divided in groups such as "bromelain and periodontal therapy" and "periodontal therapy," or "bromelain gel (topic application) and periodontal therapy" and "periodontal therapy." This idea is based on the most frequent therapy for periodontitis, scaling and root planning, as well as oral hygiene instructions in non-surgical therapy. Bromelain as a complementary treatment for periodontal disease in humans can also be tested for complementing the surgical therapies.
The dosages of bromelain selected for previous studies could be based in previous clinical trials ,,,, that administrated 150-250 mg per day. Patients treated with bromelain should exhibit improvement in clinical parameters when compared to patients that did not receive bromelain treatment, providing support for the utility of bromelain as a complementary treatment of periodontitis. According to a recent meta-analysis that demonstrated the clinical efficacy of probiotics as an adjunctive therapy to nonsurgical periodontal treatment of chronic periodontitis,  bromelain as an adjuvant treatment of periodontitis presents a potential future.
| Conclusion|| |
This article indicates the possible mechanisms through which bromelain may ameliorate the progression and development of periodontitis. Bromelain can act by decreasing periodontal microorganism growth, by proteolytically cleaving important cell surface molecules in leucocytes, by reducing neutrophil migration to periodontal sites, by downregulating the inflammation mediator levels, and by decreasing alveolar bone loss in periodontitis.
Financial support and sponsorship
Study supported by the Federal University of Piaui (UFPI - BIAMA 03/2014 and Edital PIBIC 2014/2015), CNPq (455104/2014-0).
Conflicts of interest
There are no conflicts of interest.
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