Role of nutritional supplements on oral health in adults – A systematic review

Purpose: The word ‘diet’ usually encompasses the consumption of food that includes all the necessary nutrients required for the optimal functioning of the body. Nutritional supplements hold a supreme position due to the demanding lifestyles or medical conditions in this current era. Although medical literature has sufficient evidence exploring the effect of nutrients on general health, this systematic review aimed at specifically evaluating the role of nutritional supplements on oral health in adults. Methods: PRISMA guidelines were followed in conducting this systematic review where four electronic databases including Scopus, PubMed, EMBASE, and Web of Science were reviewed. Based on the inclusion criteria, four studies exploring the effect of oral nutritional supplements on oral health among the adult population were included in this systematic review. Results: This review generated evidence suggesting a positive effect of nutritional supplements on oral health. These findings were depicted in the form of a reduction in plaque scores, probing depths, gingival inflammation, and greater improvement in periodontal healing among individuals with higher intakes of nutritional supplements within recommended doses. Conclusions: The systematic review outlines the positive impact of consuming nutritional supplements in the recommended dosage on oral health. Additionally, this review stresses the necessity for interventional studies to further investigate the effects of nutritional supplements on oral health, particularly in regard to periodontal healing. PROSPERO registration: CRD42021287797 (27/11/2021).


Introduction
The term "diet" generally refers to the entirety of the food that a person consumes, with the implication that it includes all the necessary nutrients essential for the body (Leech et al., 2015). Nutrition plays a vital role in meeting the fundamental requirements for maintaining good health, impacting both overall wellness and oral health significantly. Essential nutrients are chemical substances in food which cannot be synthesized in our body at all or in sufficient amounts but are vital for life, growth and tissue repair (Leaf & Weber, 1987;Mann & Truswell, 2017). It has been noted that taking essential nutrients before undergoing surgery and maintaining them at optimal levels can significantly enhance the effectiveness of the treatment. (Miresmaeili et al., 2015). This makes diet and nutrition an indispensable component in patient care (Sobotka & Forbes, 2019).
Various dietary nutrients play a significant role in the maintenance of oral health. Vitamin A plays a role in preserving the mucosal membranes, salivary glands, teeth, and protecting against cleft palate (Purvis et al., 1973). Despite the prevalence of vitamin A deficiency in developing countries (Haslam, 2019), it's important to recognize its positive effects on oral health. Vitamin E, with its anti-inflammatory action, helps to decrease the effect of oxygen-free radicals in the cells during the process of bone formation, thus having a positive impact on tooth formation (Esenlik et al., 2012;Sufarnap et al., 2020). Vitamin D plays a crucial part in absorption of calcium, magnesium and phosphorus from gut and insufficiency of vitamin D might lead to enamel and dentin hypoplasia and delayed eruption (Adegboye et al., 2010;Lowenstam & Weiner, 1985). Vitamin K has an association with fetal facial deformity (Howe & Webster, 1994). The role of ascorbic acid has been studied extensively in relation to collagen synthesis and therefore, vitamin C deficiency eventually leads to scurvy, which causes inflammation of the gingiva, commonly seen in populations who have limited intake of food like the elderly, and others include smokers and alcoholics (Onigbinde OO et al., 2021;Van Rooij et al., 2003). The marginal deficiency of ascorbic acid can also cause periodontitis (Alvares et al., 1981;Krasse, 1960). It has been observed that a daily intake of a 1 gram supplement of vitamin C was significantly associated with a decrease in sulcular epithelial permeability and an increase in collagen formation in humans (Leggott et al., 1986).
Deficiency of folic acid is usually said to have its association with neural tube defects and a reduction in cleft lip/cleft palate has been observed when pregnant women take folic acid supplement (Burgess et al., 2018;Van rooij et al., 2004;). Folic acid deficiency also impairs the sulcular barrier function (Burt, 1982;Dhamo et al., 2021), and few studies have suggested that supplementation with folate might help in reducing the gingival fluid flow as well as the bleeding index. Vitamin B12 is known to contribute towards mucosal wound healing and facilitating bone health, both of which are necessary for recovery in cases of periodontitis. This fact is backed by studies which have demonstrated an inverse association between vitamin B12 and tooth count (Hugar et al., 2017;Zong et al., 2016). Calcium and vitamin D have a significant association with bone mineralization and osteoporosis where mineralization defects are seen in severe deficiency of vitamin D, while calcium causes negative calcium balance and bone loss. This loss of bone is apparent not only throughout the body but also in the alveolar bone (Adegboye et al., 2010;Jimenez M et al., 2014;Lowenstam & Weiner, 1985). Zinc is known to decrease the sulcular epithelial permeability by inhibiting the leukocyte activity, thereby decreasing gingival fluids and hence the gingival inflammation (Garcia et al., 2011;Rapisarda & Long, 1981;Vratsanos & Mandel, 1985). Diet is also known to have a considerable contribution towards prevention of particular oral tumors (Morse, 2005). There is evidence which suggests that individuals who consume adequate amounts of vegetables, whole grain foods and fruits, have a 40-80% lowered risk of developing oral or pharyngeal cancers in comparison to people who have a lower consumption of these food types (Franceschi et al., 1999;Mclaughlin et al., 1988).
There is a lack of literature on the consumption of nutrients and balanced diet on oral health. There are relatively fewer studies which explore the possible effects of oral nutritional supplements on oral health. Therefore, this systematic review aimed to evaluate the role of nutritional supplements on oral health in the adult population.

Methods
This systematic review was conducted as per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (Shenoy, 2023) statement and the literature search was started in April 2021 and concluded in October 2021. The protocol of the present systematic review was registered with PROSPERO (CRD42021287797) (date of registration-27/11/2021).

Study selection
A complete literature search was performed across four electronic databases i.e. Scopus, PubMed, EMBASE and Web of Science. Peer-reviewed literature, either published in English language or with availability of translated text in English, were included for the present systematic review. The papers published in or after 2010 and which met the pre-determined inclusion and exclusion criteria were included in this systematic review.
Inclusion Criteria: Randomized controlled trials and cross-sectional studies with outcomes based on the effect of nutritional supplements on plaque score, gingival health and periodontal health among adult population were included in the present systematic review. Papers with full text access and either published in English language or with availability of translated text in English were included in this review.
Exclusion criteria: Studies on children and animal studies were excluded along with studies which utilized an intravenous mode of administration for nutritional supplements. Studies which explored the effect of nutritional supplements on general health as well as unpublished papers or study protocols were excluded from this review.

Search strategy
The search strategy followed across the four databases is presented in Table 1. Initially, the PubMed database yielded 235 search results, five articles were later excluded when a BOOLEAN term "NOT COVID" was added.

Selection process
The databases were searched by two authors (AR, RS) using the search strategy, which was followed by removal of duplicates, if any. Following which title and abstract screening was performed by two authors (AR, RS) independently, where the authors responded with a 'Yes', 'No' or 'Maybe' for each entry based on the inclusion and exclusion criteria. Any disagreements were resolved with discussion by mutual consensus. The articles included following title and abstract screening, then underwent full-text review by two authors (AR, RS) independently. Disagreements were resolved through discussion with a third author (PD). The articles which qualified at this stage were finalized for quality appraisal and data extraction for this systematic review.

Quality assessment
Following full-text review, the studies included in this systematic review underwent quality assessment by two authors (AR, RS) independently. Among the four studies included for the present systematic review, three were cross-sectional studies while one was a randomized controlled trial. Therefore, the appropriate version of the Newcastle-Ottawa Quality Assessment Scale (Wells GA et al., 2021) was utilized for quality assessment of these studies respectively. This risk of bias tool covers three domains i.e., selection criteria, comparability criteria and outcome/exposure criteria, where every study is scored for each domain by giving stars. The selection criteria allotted with maximum of four stars, the comparability criteria with maximum of two stars and the outcome criteria with maximum of four stars.

Data extraction
The data from the full-text articles was extracted independently by two authors (AR, RS) using a pre-decided format which collected information pertaining to the authors, year of publication, study design, sample size, population studied, intervention or exposure provided, type of nutritional supplement intake, outcome measures, main findings, comparison groups if any, and limitations of the study. The data extracted by the two authors was jointly reviewed and was combined as one to fill out any missing information.

Results
The PRISMA flow diagram representing the results of the review process is depicted in Figure 1.
Among the four studies chosen for this systematic review, one was a randomized controlled trial (RCT) while the other three studies were cross-sectional studies. The studies which were selected following full text review underwent quality assessment utilizing the appropriate Newcastle Ottawa Scale and the number of stars allotted to the selected study are depicted in Table 2. The summary of data extraction from these four studies is provided in Table 3.     (Adegboye et al., 2013;Dodington et al., 2015;Luo et al., 2018). Only the RCT included in this systematic review included an additional nutritional supplement provided as an intervention, while the cross-sectional studies were based on dietary recall methods such as interviews and questionnaires which also considered additional nutritional supplements if taken by participants along with the dietary nutrients being studied.
The mean age of the participants in the three cross sectional studies was above 50 years, with older adults (65 years and above) being the prime focus in the study by Adegboye et al. (2013), while the mean age of study participants was 27.1 AE 3.0 years in the RCT (Willershausen et al., 2011) selected for this systematic review. Among the studies included in this systematic review, the effects of nutritional supplements on oral health were studied via outcome measures such as dental assessment including number of teeth, salivary flow and analysis, plaque score, probing depth, bleeding on probing, microbiological analysis, reduction in periodontal disease and severity.

Discussion
This systematic review intended to explore the effects of nutritional supplements on oral health in the adult population.
The major findings of this systematic review revolved around the positive impact of nutritional supplements on oral structures, plaque scores and general inflammatory processes. A better understanding of the relationship between an individual's diet and oral health can be gained by recognizing the contribution of micronutrients in generating an adequate immune response (Moynihan, 2005).
Several animal and human studies have very well demonstrated the modulatory role of specific micronutrients on the host's inflammatory response by decreasing inflammatory biomarkers and ultimately bone loss (Chapple, 2009). A similar trend was observed in one of the studies included in this systematic review by Willershausen et al. (2011) where the authors noted that the C-reactive protein (CRP) values, a marker of inflammatory processes, showed a lesser increase among study participants taking the nutritional supplements and a slightly positive effect on gingival inflammation as compared to the control group, where both groups consisted of dental students under high examination stress. In another study included in this systematic review, it was seen that the severity of periodontal disease increased with lesser intake of vitamins A, B1, C, E, iron, folate and phosphorus (Luo et al., 2018). Although the mechanism of action between nutrition and periodontal disease is not completely understood, Chapple et al. observed an inverse relationship between total antioxidant properties and periodontal disease, thereby shedding some light on the complex relationship between nutrition and inflammation leading to periodontal disease (Chapple et al., 2007). These findings are supported by evidence which recognizes the antioxidant properties of vitamins A, B1, C and E (Higashi-Okai et al., 2006;Muniz et al., 2015;Palace et al., 1999).
The study by Dodington et al. focused on observing the effect of dietary nutrients on periodontal healing among smokers and non-smokers with chronic generalized periodontitis following scaling and root planning. The authors observed a significant reduction in probing depth with higher intake of fruits and vegetables, α-tocopherol, vitamin C, β-carotene, EPA and DHA intakes among non-smokers while no such association was seen in smokers. This association can again be partly due to greater antioxidant intake in the form of fruits and vegetables in the diet. The findings of this study also suggested that whole-food sources, rich in anti-oxidants, are far more beneficial in comparison to supplements with purified compounds in promoting optimal periodontal healing. Beneficial outcomes of EPA and DHA supplements were also observed in participants in this study, which could be explained by the effects of a downstream metabolite of DHA, Resolvin D1, that has exhibited downregulation of inflammatory mediators in an in vitro study on periodontal ligament (Mustafa et al., 2013).
Another included study by Adegboye et al. observed protective effects of increased intakes of dietary calcium and dairy products (within recommendations) on the plaque scores among older adults aged 65 years and above with higher vitamin D intakes (more than 6.8 μg/d). This association was presented after adjusting for other confounding factors and participants with lower vitamin D intakes (less than 6.8μg/d) did not demonstrate this association between dietary calcium and plaque scores. This is in line with earlier evidence which is suggestive of an inverse association between higher intakes of calcium, dairy-products and vitamin D with dental caries and periodontitis (Dixon et al., 2009;Merritt et al., 2006). Since the effect of calcium intake was stratified according to vitamin D in the study by Adegboye et al., it seems that higher intake of vitamin D can improve the positive effects of increased calcium intake, likely by improving the absorption of calcium. This could be explained by the findings of Laky et al. who reported that deficiency in vitamin D levels was observed in larger proportions among individuals with severe periodontal disease in comparison with healthy adults (Laky et al., 2017). In another study included in this systematic review, the second highest level of vitamin D intake (3.2-6.0 μg), was found to be associated with reduced severity of periodontal disease in comparison to the highest level intake (≧ 6.0 μg), which indicates towards an optimal range of 3.2-6.0 μg when considering vitamin D intake (Luo et al., 2018). This explains the need for further investigation into the optimum levels of vitamin D for oral health promotion and periodontal disease prevention.
The results of the systematic review suggest that developing appropriate dietary interventions focused on oral health, especially periodontal health, might be beneficial alongside routine therapy in prevention of periodontal conditions. These results should be considered with caution due to the limitations of individual studies such as small sample size, high drop-out rates, lack of details regarding supplemental calcium intakes and self-reported dietary assessment method.

Future direction
The present systematic review retrieved articles from the four databases. The majority of studies included had a crosssectional design, highlighting the need for more interventional studies in this area. It is necessary to conduct further research to assess the effects of nutritional intervention on individuals with periodontitis, with the goal of developing effective nutritional therapies to manage periodontal inflammation.

Conclusion
Based on the included literature, this systematic review highlights the beneficial effects of nutritional supplements on oral health when consumed in a recommended dose. These benefits of nutritional supplements were observed in the form of a reduction in plaque scores, gingival inflammation and probing depth and a greater degree of periodontal healing. This systematic review also wishes to highlight the need for interventional studies in this area to explore the effects of nutritional supplements on oral health, especially relating to periodontal healing. The review also stresses the necessity for interventional studies to further investigate the effects of nutritional supplements on oral health, particularly in regards to periodontal healing.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.