Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol. 1994; 65:260-267
Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol. 1991; 62:123-131
Dietrich T, Jimenez M, Krall Kaye EA, Vokonas PS, Garcia RI. Age-dependent associations between chronic periodontitis/edentulism and risk of coronary heart disease. Circulation. 2008; 117:1668-1674
de Pablo P, Chapple ILC, Buckley CD, Dietrich T. Periodontitis in systemic rheumatic diseases. Nat Rev Rheumatol. 2009; 5:218-224
Tonetti MS, Chapple ILC. Biological approaches to the development of novel periodontal therapies – consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol. 2011; 38:114-118
Chapple ILC, Matthews JB. The role of reactive oxygen and antioxidant species in periodontal tissue destruction. Periodontology 2000. 2007; 43:160-232
Sies H, Jones D. Oxidative stress. In: Fink G (ed). London: Elsevier; 2007
Chapple I. Oxidative stress, nutrition and neutrogenomics in periodontal health and disease. Int J Dent Hyg. 2006; 4:15-21
Chapple ILC. Potential mechanisms underpinning the nutritional modulation of periodontal inflammation. J Am Dent Assoc. 2009; 140:178-184
Van der Velden U, Kuzmanova D, Chapple ILC. Micronutritional approaches to periodontal therapy. J Clin Periodontol. 2011; 38:142-158
Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8:349-361
Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J Dent Res. 2003; 82:82-90
Griffiths H, Lunec J. Ascorbic acid in the 21st century – more than a simple antioxidant. Environ Toxicol Pharmacol. 2001; 10:173-182
Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem. 2001; 57:43-56
Niki E. Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci. 1987; 498:186-199
Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Aspects Med. 2003; 24:345-351
Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001; 20:591-598
Esfahani A, Wong JM, Truan J, Villa CR, Mirrahimi A, Srichaikul K Health effects of mixed fruit and vegetable concentrates: a systematic review of the clinical interventions. J Am Coll Nutr. 2011; 30:285-294
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. In: Bjelakovic G (ed). Chichester, UK: John Wiley & Sons Ltd; 2012
Hickey S, Noriega L, Roberts H. Poor methodology in meta-analysis of vitamins. J Orthomol Med. 2007; 22:8-10
De Spirt S, Sies H, Tronnier H, Heinrich U. An encapsulated fruit and vegetable juice concentrate increases skin microcirculation in healthy women. Ski Pharmacol Physiol. 2012; 25:2-8
Roll S, Nocon M, Willich SN. Reduction of common cold symptoms by encapsulated juice powder concentrate of fruits and vegetables: a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2011; 105:118-122
Sutton G. Putrid gums and “dead men”s cloaths': James Lind aboard the Salisbury. J R Soc Med. 2003; 96:605-608
Baumgartner S, Imfeld T, Schicht O, Rath C, Persson RE, Persson GR. The impact of the stone age diet on gingival conditions in the absence of oral hygiene. J Periodontol. 2009; 80:759-768
Chapple ILC, Milward MR, Dietrich T. The prevalence of inflammatory periodontitis is negatively associated with serum antioxidant concentrations. J Nutr. 2007; 137:657-664
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Periodontitis is a ubiquitous, chronic inflammatory condition of the tooth-supporting apparatus. Various risk factors/indicators are associated with periodontal diseases, including nutritional status. With oxidative stress driving periodontal inflammation there is credibility in considering additional benefits from phytonutritional supplements when used in conjunction with conventional therapy for periodontal disease. Contemporary research utilizing robust methodology, such as double-blind, randomized, placebo-controlled trials, in conjunction with serum micronutrient levels to assess bioavailability of phytonutrients following nutritional supplementation, may begin to provide an evidence base for delivering nutritional advice as part of periodontal prevention/therapy.
CPD/Clinical Relevance: Some mechanisms underpinning nutritional modulation of inflammatory periodontal disease, as well as the evidence behind the use of Juice Powder Concentrates (JPCs), are of relevance in periodontal therapy.
Article
Periodontitis is a ubiquitous, chronic inflammatory condition of the tooth-supporting apparatus. The current disease paradigm points overwhelmingly towards an aetiology consisting of a ‘dysbiotic’ biofilm leading to an exaggerated host response in susceptible individuals being responsible for the majority of the subsequent periodontal tissue destruction; the literature suggesting that the aberrant host response contributes 80% of the risk of periodontal tissue destruction.1 Whilst resolution of the inflammatory process is achievable for some patients with a combination of non-surgical and surgical debridement, others fail to achieve the desired level of biofilm control, and long-term stability is only achieved with patient education on the various risk factors/indicators associated with periodontal disease, eg poor oral hygiene, smoking, stress, diabetes, micronutritional deficiency. Considering the close associations between nutrition and a variety of inflammatory systemic diseases, such as type 2 diabetes, rheumatoid arthritis and atherogenic cardiovascular disease (all of which also share associations with periodontitis2, 3, 4), it is not surprising that there has been a surge in research on the effects of nutrition and its potential impact on the biological and structural processes underlying periodontitis. The importance of nutritional advice as part of primary prevention in both periodontal disease and general health was highlighted in the Consensus of the Seventh European Workshop on Periodontology. This recommended that the dental team should advise on increased dietary intake of fibre, fish oils, fruit, vegetables and berries, as well as reducing intake of refined carbohydrates.5
Supplements containing recommended daily amounts of micronutrients are available over the counter and target the health-conscious consumer. However, in light of the evidence implicating oxidative stress as a driver of periodontal inflammation, there is credibility in considering additional benefits from phytonutritional supplements when used in conjunction with conventional therapy for periodontal diseases.
This review aims to:
Briefly explore the potential mechanisms underpinning the inflammatory processes of periodontal diseases involving micronutrients;
Discuss JPCs/nutritional supplements and their potential adjunctive role in periodontal disease management;
Explore some of the key literature underpinning supplementation as part of holistic periodontal management.
Nutrition and periodontal disease
Oxidative stress
Before discussing in further detail the potential mechanisms underlying nutritional regulation of periodontal disease, it is important to understand the basic concepts of oxidative stress. For a more detailed review of the complex nature and effects of oxidative stress in periodontitis, the reader is referred to more authoritative texts, as this is outside the scope of this review.6 At a molecular level, oxidative stress provides biologically plausible mechanisms, substantiated by growing evidence, in which nutrition can impact upon inflammatory status. Oxidative stress has been defined as an imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling, and control and/or molecular damage.7
Reactive oxygen species (ROS) is an umbrella term describing molecules that are either free radicals or are capable of producing free radicals (the oxidants). If the balance between ROS and antioxidant defence systems shifts in favour of ROS, oxidative stress results. The consequences of oxidative stress can be classified as either direct or indirect tissue effects.8
Direct tissue effects
Different mechanisms by which ROS may directly damage tissues include:
Lipid peroxidation – Where free radicals can damage cell membrane integrity;
Protein oxidation – Where free radicals react with constituent elements to form a covalent bond altering the physical structure of the protein and affecting its function;
DNA damage – Free radicals may cause breaks in the DNA strands, base pair hydroxylations, deletions and insertions.6
Indirect tissue effects
This occurs via the activation of redox-sensitive gene transcription factors, of which the most well known are Nuclear Factor kappa B (NFkB) and Activating Protein 1 (AP-1). Once activated by an environment of oxidative stress, they are involved in the production of pro-inflammatory cytokines, and matrix metalloproteinases.
Pro-inflammatory effects of nutrition
There are a variety of nutritional components that can potentially contribute to pro-inflammatory sequelae in the periodontium.
1. Refined carbohydrates
An increase in refined carbohydrates may stress and saturate the Krebs cycle and consequently produce excess electron leakage from mitochondria and subsequent superoxide radical formation following the single electron reduction of molecular oxygen. Furthermore, refined carbohydrates can lead to a chronic hyperglycaemic environment and, in turn, the irreversible production of advanced glycation end products (AGEs) through glucose binding to proteins in tissue. The binding of AGEs to their complementary receptor (RAGE) on inflammatory cell (eg neutrophil) surfaces activates pro-inflammatory cascades, including via the redox-sensitive gene transcription factors.9
2. Saturated fats
During periods of oxidative stress, lipid peroxidation leads to the formation of oxidized low density lipoproteins (oxLDL) and subsequent binding to pattern recognition receptors, in particular Toll-Like-Receptor 4. Binding of these receptors can activate redox-sensitive gene transcription factors (eg NFkB), triggering pro-inflammatory cytokine production, as well as activating the NADPH-oxidase (the respiratory burst) and generating further ROS.9, 10
Anti-inflammatory effects of nutrition
Aside from a reduction in refined carbohydrates and saturated fats, with an accompanying reduction in pro-inflammatory sequelae, micronutrients can actively antagonize oxidative stress.
1. Antioxidant micronutrients
Antioxidants provide a defence mechanism against free radicals. They can be classified in a variety of different ways including exogenous (phytonutrients – obtained only through the diet) or endogenous (synthesized by the body).6 The ways in which antioxidants act can range from scavenging harmful free radicals to preventing free radical accumulation via enzymatic actions.6Table 1 gives examples of beneficial antioxidants and the ways in which they act to combat oxidative stress.
Antioxidant Micronutrient
Dietary Sources
Mechanism of Action
Vitamin C(Absorbic Acid)
OrangesStrawberriesBroccoliKiwi
Following interaction with radicals, absorbic acid forms dehydro-absorbic acid (DHAA). This can be recycled back into absorbic acid and endogenously by GSH, demonstrating its interaction with other antioxidants.
There may also be a potential for absorbic acid to inhibit the activation of redox-sensitive genes.13
Absorbic acid is a co-factor for enzymes involved in collagen synthesis.
Absorbic acid may also improve chemotaxis of neutrophils and their phagocytic capacity.10
Vitamin E(α-tocopherol)
AlmondsSpinachAvocado
A vital antioxidant in maintaining the cell membrane and protecting against lipid peroxidation.
It is a chain-breaking antioxidant, reacting with peroxyl free radicals of poly-unsaturated fatty acids that would otherwise undergo a ‘free radical chain reaction’ disrupting the molecular structure of the cell membrane.
The product of the above redox reaction includes the α-tocopherol radical which could be considered pro-oxidant. Regeneration of α-tocopherol requires either absorbic acid and GSH (within cytosol) or ubinquinol (within cell membrane).14, 15
Carotenoids(β-carotene)
Green vegetablesTomatoes
Carotenoids main antioxidant function involves ROS scavenging of singlet molecular oxygen.
In particular, β-carotene is effective at scavenging singlet oxygen.
Glutathione
GSH cannot be obtained from diet and is synthesized by cells
In its reduced form (GSH) it is a potent scavenger of oxygen radicals.
GSH is cycled to its oxidized form (GSSG) and back by the enzymes glutathione peroxidase and glutathione reductase, respectively. This drives the redox status or ‘balance’ of neutrophils with the reductase reaction favoured towards GSH production.6
Co-Enzyme Q10
BeefBroccoli
An important molecule in the production of energy (ATP).
Exists in either an oxidized (ubiquinone) or reduced (ubiquinol) form and has high antioxidant function. It is found in abundance in the cell membrane along with various enzymes that are responsible for keeping it reduced (eg NADPH co-enzyme Q reductase), allowing it to remain active as an antioxidant.
Has the ability to reduce tocopheryl-radicals back to tocopheryl providing a further indirect mechanism of antioxidant action.17
2. Poly-unsaturated fatty acids (PUFAs)
The omega-3 poly-unsaturated fatty acids (Ω-3PUFAs) are the more important subgroup of PUFAs in relation to inflammation. They lower postprandial triglyceride concentrations and also inhibit lipid mediators of inflammation (such as prostaglandin E2, arachidonic acid, 5-lipoxygenase and cyclo-oxygenase) and increase antioxidant capacity.9
More recent discoveries have unravelled the active processes behind inflammatory resolution, via molecules known as pro-resolving lipid mediators (eg lipoxins, resolvins and protectins).11, 12 Resolvins are derived from Ω-3PUFAs and, unlike lipoxins, cannot be synthesized de novo, meaning dietary sources are essential (eg fish oils). Their discovery has been of significant importance in the field of periodontology as it adds evidence to the concept that the pathogenesis of periodontitis is, in part, due to the susceptible host being unable to ‘press the brakes’ on inflammation.
Nutritional supplements
Background
It is clear from the mechanisms described in the previous sections that consumption of fruit and vegetables has clear health benefits. However, improving diet is a public health issue that has seen limited success. The production of fruit and vegetable concentrates, also known as juice powder concentrates (JPCs) may provide health benefits for both nutritionally deficient and replete individuals.
A systematic review has focused on the various general health benefits of mixed fruit and vegetable concentrates.18 It found that the concentrates demonstrated high bioavailability and improved serum concentrations of various dietary antioxidants, including Vitamins E and C and carotenoids. It also went on to conclude a general reduction in oxidative stress following use, measured by various markers of oxidation of proteins, lipids and DNA across 11 trials. The review did, however, highlight research that provided no improvements in both outcomes (serum antioxidant concentrations and oxidative stress) and could be attributed to the variations in methodology employed across the limited literature available.
It is important to note that the literature does not bias towards the use of antioxidant supplements, and one Cochrane Collaboration systematic review concluded that there was no evidence to support the use of antioxidant supplements in primary or secondary prevention of mortality. On the contrary, their conclusions stated that there is a potential increase in mortality with the use of such supplements.19 Such controversial conclusions must be interpreted with care, and indeed the authors of the article have come under criticism for the methodologies employed in their review.20
One such fruit and vegetable concentrate is JuicePLUS+®; an encapsulated, powdered concentrate available in three different ‘blends’; fruit, vegetable or berry (Figure 1). They are also available in chewable forms.21 There is some evidence that suggests different health benefits with the use of JuicePLUS+®, including:
Reduction in moderate to severe common cold symptom days.23
Figure 1. JuicePLUS+® capsules available in a variety of ‘blends’.21
Despite the potential for micro-nutritional modulation of inflammation and that nutrition may be a modifiable risk factor for periodontal disease, there is a paucity of high quality research from which clinical recommendations can be made in relation to JPCs/nutritional supplements.
Associations between antioxidant micronutrients and periodontal disease
The role of nutrition in periodontal disease dates back to 1747 with James Lind's ‘seminal’ experiment demonstrating the cure of scurvy with citrus fruit.24 A more recent study placing individuals on a ‘stone-age’ diet, high in antioxidant micronutrients, demonstrated that, despite no access to modern oral hygiene equipment or toothpastes and despite increased plaque accumulation, gingival bleeding and probing pocket depths were reduced.25 Positive association studies between nutritional components and periodontal disease emerged in the 1970s and were predominantly cross-sectional in design, with a focus on Vitamin C. Earlier studies did investigate this relationship but interestingly negative findings were observed.10 However, it is important to recognize that the early methodologies employed dietary questionnaires as opposed to serum biomarkers, an approach that is being rectified with the advent of objective biomarkers of nutritional status.
A recent cross-sectional study reported a reduced serum antioxidant concentration in periodontitis subjects, but was unable to conclude whether this was a cause or effect of periodontal inflammation.26 Gingival crevicular fluid (GCF) antioxidant concentrations have also been found to be significantly reduced in patients with periodontitis compared with healthy controls.27 Subsequent evidence found that successful non-surgical periodontal therapy significantly increased GCF Total Antioxidant Capacity (TAOC). It was concluded that, as resolution of inflammation raised antioxidant defences locally, a reduced antioxidant concentration is an effect of periodontitis. However, the evidence does not refute the potential protection afforded to the periodontal tissues by antioxidant micronutrients.28
Focusing on individual antioxidants, a cross-sectional study by Linden et al, utilizing serum antioxidant levels, found that low β-carotene levels were associated with increased prevalence of periodontitis.29 Furthermore, the GSH:GSSG ratio (representing the ratio of reduced glutathione to oxidized glutathione), which dictates the redox status of cells such as neutrophils and is physiologically favoured towards GSH, has been found compromised in periodontitis patients. Ex vivo treatment of peripheral blood neutrophils with sulforaphane, a natural product found in cruciferous vegetables, was found to restore the GSH:GSSG ratio in both healthy and periodontitis subjects.30
Role of nutritional supplements in interventional studies
One of the first interventional studies utilizing a randomized, placebo-controlled methodology was completed in 2001, investigating the use of nutritional supplements as an adjunct to homecare in patients with mild periodontal disease. The supplements were taken twice daily and, after 60 days, there was a statistically significant reduction in gingival index, bleeding index and pocket depth in the experimental group.31
A further randomized, double-blind, placebo-controlled study examined the efficacy of Vitamin-B complex supplementation following access flap surgery. Following surgery, patients either took one capsule of Vitamin B-complex or placebo for 30 days. Whilst pocket depth reductions were comparable in both experimental and placebo groups, clinical attachment level gains were superior with the use of Vitamin B-complex supplements.32
A mixed fruit, vegetable and berry juice powder concentrate has also been investigated as an adjunct to non-surgical periodontal therapy in a double-blinded, placebo-controlled study.33 Patients were randomized into three different groups: i. FV Group – Given capsules containing fruit and vegetable concentrates; ii. FVB Group – Given capsules containing fruit, vegetable and berry concentrates; iii. Placebo.
Serum biochemistry was also utilized to assess the bioavailability of β-carotene across the different groups. Baseline measures of Vitamin C and α-tocopherol were taken to exclude vitamin deficiency but these were not assessed during the nutritional intervention. The results demonstrated statistically significant additional reductions in probing pocket depth at 2 months for the FV group versus placebo, but these improvements were not sustained at 8 months. Furthermore, the additional berry concentrates in the FVB group provided no further benefit in periodontal outcome measures. It was hypothesized that this may be due to the lack of bioavailability of β-carotene, inviting questions as to whether compounds within the FVB groups antagonized each other ultimately to reduce serum concentrations of the antioxidants, or whether nutrigenetic differences existed between test and placebo groups.
Nutrigenetics is a novel field in nutritional research, encompassing individuals' ability to convert nutritional components to their bioactive form based on their genetic profile.
Polymorphisms of specific genes have been identified and could account for differences in bioavailability of different compounds, despite providing the same doses as supplements.
Conclusions
Over the last decade, there has been an exponential increase in evidence relating nutritional status and supplementation to periodontal disease prevalence and management. However, there is a necessity for further randomized, double-blinded, placebo-controlled studies exploring the effects of nutritional supplementation as an adjunct to periodontal therapy. Only then can robust clinical guidelines begin to be implemented and potential recommendations for supplementation in specific patient groups advised. A detailed review of mechanisms underpinning specific micronutritional approaches to adjunctive periodontal therapy was available in 2018 and readers are referred to that article34 for more detailed explanations, which are beyond the remit of this paper. As further evidence emerges, new aspects of nutrition clearly need to be explored, in particular nutrigenetics. This variation in individual response to supplementation is likely to mean that no single ‘golden bullet’ will provide the optimal outcomes for all patients.
The various interactions and synergies between individual antioxidant micronutrients should not be overlooked. This may be the reason why supplementation with individual phytonutrients may not provide the benefits that are theoretically possible. It may also provide an argument for promotion of antioxidant micronutrient intake from whole foods rather than nutraceuticals. Consideration must also be given to potential negative effects of exceeding upper limits of micronutrient intake. Pro-oxidant effects of certain antioxidant molecules are described in specific conditions, in particular oxidized α-tocopherol.
Much of the current evidence is based on studies that have focused on the nutritionally replete patient and further evidence is required to elucidate the impact of supplementation for periodontal patients who are vitamin deficient.
It is hoped that this review has raised more questions than it has answered, particularly in an area of periodontal research that could still be considered in its infancy. Whilst the evidence is demonstrating that a robust nutritional status provides benefits to patients who may be susceptible to periodontal disease, further studies are required before we can recommend specific nutritional supplementation protocols to our patients.
Over the coming decade, the scientific community hopes to unravel further mechanisms behind nutritional modulation of periodontal inflammation and, more importantly, translate these findings into superior patient care.
