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Original Hypothesis

Bromelain: A potential strategy for the adjuvant

treatment of periodontitis
Felipe Rodolfo Pereira da Silva1, Any Carolina Cardoso Guimarães Vasconcelos2,3,
Even Herlany Pereira Alves3, Paulo Vinicius de Oliveira Júnior3, Jefferson Soares de Oliveira1,
Daniel Fernando Pereira Vasconcelos1,3,4
1
Department of Biomedicine, Post Graduate Program in Biomedical Sciences, 3Department of Biomedicine, Laboratory of Histological Analysis
and Preparation, 4Department of Dentistry, Post Graduation Program in Dentistry, Federal University of Piaui, 2Department of Scientific
Methodology, Medicine School, Education Institute of Parnaiba Valley, Parnaiba-PI, Brazil

A B S T R A C T

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.

Key words: Bone, inflammation, periodontal disease, protease

Introduction As a multifactorial disease, locally, lipopolysaccharides

Periodontitis is a bacterial infection involving
accumulative plaque beyond gingival sulcus and
host‑immune response with multifactorial processes.[1]
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.[2]
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derived from bacteria such as Porphyromonas gingivalis,
Prevotella intermedia, Treponema denticola, Tannerella
forsythia and Aggregatibacter actinomycetemcomitans[3,4]
induce inflammatory infiltrate with the recruitment of
polymorphonuclear neutrophils (PMN), leukocytes,
and macrophages. Neutrophils degranulate large
This is an open access article distributed under the terms of the
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DOI: Cite this article as: da Silva FR, Vasconcelos AC, Alves EH, Junior PV,
10.4103/2155-8213.190483 de Oliveira JS, Vasconcelos DF. Bromelain: A potential strategy for the adjuvant
treatment of periodontitis. Dent Hypotheses 2016;7:88-93.

Corresponding Author: Dr. Daniel F. P. Vasconcelos, Universidade Federal do Piauí – UFPI; Campus Ministro Reis Veloso;
Colegiado de Biomedicina; Av. São Sebastião, 2819, Reis Veloso; Parnaíba, Brazil. E‑mail: vasconcelos@ufpi.edu.br

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da silva, et al.: Bromelain and the treatment of periodontitis
quantities of tissue‑destroying enzymes, e.g., matrix
metalloproteinases and generate reactive oxygen
species.[5‑7]
In addition, these cells release several pro‑inflammatory
cytokines such as factor‑alpha tumor necrosis (TNF‑α),
IFN‑γ,[8] granulocyte‑macrophage‑colony‑stimulating
factor (GMCSF), [9] which are involved with the
inflammation response and bone resorption,[10] acting
via RANK/RANKL/OPG (RANK, receptor activator of
NF‑κB; RANKL, receptor activator of NF‑κB ligand, and
OPG, osteoprotegerin) pathway.[11,12]
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, [13‑15]
and still in this trend several hypotheses have been
presented.[16‑18] 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.[19,20] Studies have shown efficacy similar to
standard anti‑inflammatory drugs[21‑23] for the bromelain
treatment. Furthermore, bromelain presents a large
variety of activities such as anti‑inflammatory properties
in endometriosis, [19] reduction of the neutrophil
migration to sites of inflammation,[24] antibacterial effect
against periodontopathogens,[25] 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.[26,27]
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
Jul-Sep 2016 / Vol 7 | Issue 3
and antibacterial effects require that the bromelain be
proteolytically active.[19,20,25]
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.[20] These cytokines
are involved in the development and progression of
periodontitis.[28,29]
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.[30] 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.[31,32] Interestingly, bromelain treatment
has been shown to downregulate Cox‑2 expression in
several experiments.[33‑35]
Furthermore, a study [36] 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.[5]
In addition, bromelain showed inhibition of the
growth of Saccharomyces cerevisiae, Escherichia coli,
and Staphylococcus aureus.[37] A similar effect was
demonstrated for Streptococcus mutans, Enterococcus
fecalis, Aggregatibacter actinomycetemcomitans (Aa),
and Porphyromonas gingivalis (Pg), microorganisms
found in the periodontal disease. [25] Numerous
clinical trials of bromelain have shown effectiveness
for treating inflammation conditions. These include
osteoarthritis of the hip,[38] osteoarthritis of the knee,[39]
and rhinosinusitis.[40]
The Hypothesis
Periodontitis is a disease with a multifactorial etiology;[1]
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
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da silva, et al.: Bromelain and the treatment of periodontitis

of leucocytes, especially neutrophils, and the release of
several cytokines from different cells. One of the results
of this process is alveolar bone loss.[2] 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].
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 [25]  [Figure 1a]. 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.[25]
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,[41] along with a reduction of CD25 molecules in a
dose‑dependent manner, keeping the biological function
of the CD4+ T cells in vitro.[42] Immunohistological
analyses demonstrated an elevated infiltrate of
CD4+ CD25+ T cells in periodontitis lesions.[43]
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.[44] [Figure 1b].
Third, it is well‑known that the hyperactivity of neutrophils
results in damage to the periodontium. [6] A study
demonstrated that the severity of gingival inflammation
is consistent with elevated neutrophil count in patients
with periodontitis.[7] In addition, the neutrophils release
several pro‑inflammatory cytokines. [10] 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[24] [Figure 1c].
Fourth, bromelain downregulates the inflammation
mediators such as IFNγ, TNF, and GMCSF in patients with
Crohn’s disease,[20] as well as Cox‑2 expression in mouse
skin papillomas stimulated by 7,12‑dimethylbenz(a)
anthracene.[33] All mentioned inflammation mediators

a b c

d e
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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da silva, et al.: Bromelain and the treatment of periodontitis
appeared in the periodontitis at elevated concentrations
when compared to healthy periodontum.[31,32] We believe
that bromelain treatment may also downregulate the
same mediators in periodontitis [Figure 1d], promoting
the reduction of clinical inflammatory parameters.
Inchiongolo et al.[45] 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.[22] 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.,[45]
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[46] because
the pro‑inflammatory cytokines contribute with bone
resorption through osteoclast differentiation by MAP
kinase‑JAK‑STAT signaling,[47] 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),[48] consequently blocking NF‑kB action.[33,48]
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.[12]
We have hypothesized that this process can be decreased
by bromelain treatment [Figure 1e].
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[49,50] or bacteria inoculation,[3,9] 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
Jul-Sep 2016 / Vol 7 | Issue 3
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[22,38,39,40,45] 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,[51] 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
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da silva, et al.: Bromelain and the treatment of periodontitis
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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Jul-Sep 2016 / Vol 7 | Issue 3 Dental Hypotheses 93