Anti-Inflammatory Benefits of Food Ingredients in Periodontal Diseases

Periodontitis is a multi-faceted inflammatory disease that impacts the gingiva and the structures that support our teeth, and may eventually increase tooth mobility and the risk of tooth loss. Inflammation is a viable therapeutic target of periodontitis for both biologic (dietary) and host modulatory agents/drugs. Conventional therapeutic approaches for periodontitis, including nonsurgical or surgical periodontal therapy as well as occasional adjunctive antimicrobial therapy, have been only marginally effective. Malnutrition, or at least poor dietary habits, can be highly prevalent among patients with periodontal diseases. As several food nutrients can aid in periodontal healing and regeneration, there is a critical need to evaluate natural dietary sources and supplement ingredients that can counterbalance the inflammatory processes and improve the periodontal status of our patients. Here, we reviewed the current state of knowledge (search period: 2010 to 2022; PubMed and Web of Science) on the anti-inflammatory actions of food ingredients and supplements in clinical studies of patients with periodontal diseases. A diet that includes fruits and vegetables, omega-3 polyunsaturated fatty acids, and supplements of vitamins and plant-derived compounds seems to counteract gingival inflammation and has a promising therapeutic impact in patients with periodontal diseases. Despite the positive indications that several nutrients can be used as an adjunct to periodontal therapy, additional studies with bigger sample sizes and longer follow-up periods are needed to elucidate their therapeutic benefits and the most effective doses and administration.


Introduction
Periodontitis is the sixth most common health condition in the world and the primary reason for tooth loss in adults [1]. At least 47% of adults aged 30 and older in the United States have periodontitis, among whom 7.8% are diagnosed with severe periodontitis [2]. Periodontitis is characterized by the inflammation of the gingiva and the surrounding structures of the teeth, which is triggered by dental bacterial plaque. If periodontitis is not treated, destruction of the periodontal attachment apparatus may occur, which can increase tooth mobility and the risk of tooth loss [3].
Periodontitis is a multifaceted chronic disease involving constant interactions between bacteria and the host immune/inflammatory response, which are modified by genetic and environmental factors. Although dental bacterial plaque has been mainly considered the crucial triggering factor for periodontal diseases, patients do not all have the same susceptibility and the same response to treatment; the host immune response is ultimately what largely guides the pathological process [4]. Periodontal health is characterized by stable periodontal microflora and a controlled host immune/inflammatory response which coexist in a state of dynamic equilibrium, known as symbiosis or homeostasis. Dysbiosis can disrupt the homeostasis in periodontal tissues by either dysregulating the inflammatory

Materials and Methods
An electronic database search on MEDLINE (PubMed) and Web of Science was conducted to identify empirical human clinical studies on the anti-inflammatory effects of different nutrients on periodontal diseases published between 1 January 2010 and 31 December 2022. The electronic search using the combination of keywords that represent periodontal diseases (Periodontal OR Periodontitis OR Gingivitis) and those that represent the nutrients (Supplements OR Diet OR Nutrition, OR Food OR Omega OR Probiotics OR Vitamins OR Polyphenols OR Natural products) allowed us to identify 553 possible eligible studies. After excluding duplicate articles, the number of studies decreased to 303. The 303 articles from the electronic search were further filtered by selecting only randomized clinical trials, case-control studies, and cohort studies published in English, as well as studies conducted only in human subjects (clinical studies). We further manually searched all available studies and excluded any formulations of different nutrients in oral health products (mouthwash, toothpaste, gels, strips) that could be used for the management of periodontal diseases, as we would like to focus our review only on the oral intake of nutrients. The total number of articles that were included in this review were 46 clinical studies, which are summarized into different nutrient categories and presented in tables throughout the manuscript.

Diet
A well-balanced daily diet plays a crucial role in our general health and in supporting our defense against infections, including those from periodontal pathogens and bacterial plaque.
Nutrients derived from our diet are necessary for our health as they provide a vital energy source (macronutrients) as well as essential cofactors required for enzyme function, structural elements, and transport (micronutrients) [11]. Studies on patients with a Westerntype diet (WD), which characterizes the diet in Western societies and includes high amounts of refined grains, sugar, and saturated, trans, and omega-6 fatty acids and low amounts of micronutrients and fibers, favored a pronounced gingival inflammatory response [12,13]. On the other side, a Mediterranean diet, which mainly characterizes the diet of southern Italians and Greeks around the 1950s and 1960s, is considered the "gold standard" diet for maintaining optimal health, with benefits in weight loss and in decreasing the risk of several chronic conditions, including diabetes mellitus and metabolic syndrome [13]. The modification of our diet can also reduce periodontal inflammation and the risk of periodontal diseases, according to studies described below and summarized in Table 1.
A recent randomized controlled trial (RCT) evaluated the impact of the Mediterranean diet on gingival inflammation [13]. The experimental group of subjects had to modify their diets for 6 weeks into one that included a high intake of vegetables, fruits, olive oil, herbs, and fatty sea fish, while a control group did not change their habitual diet. While dental bacterial plaque scores remained similar between the groups, gingival inflammation was reduced, with decreased gingival index (GI) and bleeding on probing (BOP) scores in subjects who adhered to the Mediterranean diet [13]. This RCT confirmed findings from previous pilot studies showing that switching to a diet low in carbohydrates, high in omega-3 fats, and rich in vitamins C and D, antioxidants, and fiber for 4 weeks results in a decrease in all periodontal inflammatory parameters, to approximately half of the baseline values [14,15]. Another pilot study in patients with gingivitis showed that treatment with an eight-week high-fiber, low-fat diet significantly improved markers of periodontal disease, as well as metabolic profiles (body weight, HbA1c, and high C-reactive protein levels) [16]. Fruit RCT 30 patients were included in the study; they were randomized to supplement their diet with extra fruits or nuts, each at +7 kcal/for 2 months. Periodontal parameters were analyzed before and after treatment, as well as serum vitamin C, β-carotene/cholesterol, and α-tocopherol/cholesterol.

weeks
Significant reduction in the number of subjects with PPD ≥4 mm in group with fruits compared to nuts, while PI and BoP remained unchanged in both groups.
Vitamin C levels increased in both groups and α-tocopherol/cholesterol increased in the fruit group and decreased in the nut group, as did β-carotene/cholesterol.
2018 [21] Kiwifruit RCT 50 patients were divided into 2 groups. Test group received 2 kiwis/day for 5 months and control group did not. The first SRP was performed after 2 months of treatment. Periodontal parameters and blood samples were evaluated after 2 and 5 months.

and 5 months
Test group showed reduced gingival bleeding in 2 months, which was also maintained after treatment.
Systemic biomarkers and vital signs showed no clinically relevant differences between groups.
Filippo Graziani et al., 2017 [22] A large population-based survey in Finland (n = 2187 subjects) using a validated food frequency questionnaire showed that the Nordic diet, which is rich in fruits, vegetables, cereals, and fish and low in unsaturated fats, was inversely associated with gingival bleeding and periodontal pocket depth (PPD) in patients with poor oral hygiene [17]. A recent population-based study in Malmö, Sweden, showed that fatty fish consumption was associated with reduced gingival inflammation and periodontal pockets [23]. A diet rich in nitrate by repeated lettuce juice consumption in gingivitis patients [18] and patients with a history of periodontitis (reduced periodontium) [19] resulted in a reduction in gingival inflammation and bleeding on probing (BOP), accompanied by significant compositional changes within the subgingival microbiome 14 days after periodontal recall care. Although the Atkins low-carb ketogenic diet has been shown to reduce the risk of inflammatory diseases, it did not improve clinical periodontal parameters in a 6-week period [20].
Fruit is often endorsed as a nutrient source rich in vitamins, antioxidants, and fiber, and its consumption is reported to counteract inflammation [24]. Diets rich in fruit and vegetables have been positively associated with periodontal health and with improved healing after periodontal therapy [25]. In a recent RCT, 30 healthy, non-obese participants were randomly distributed to either supplement their diet with extra fruits or nuts, each at +7 kcal/kg body weight/day, for two months. A large increase in fruit intake resulted in a significant reduction in the number of subjects with PPD ≥4 mm, compared to an increased intake of nuts [21]. The consumption of two kiwifruits/day for two months reduced gingival bleeding in patients with periodontitis without any other periodontal treatment [22]. Interesting findings were also obtained from another RCT on gingivitis patients, where the consumption of a cranberry functional beverage as an adjunct to nonsurgical periodontal therapy resulted in a significant reduction in gingival index (GI) and plaque index (PI), but not BOP, compared to patients who consumed only water [26].
In our next section, we describe how specific micronutrients and vitamins in the diet counteract with gingival inflammation and explain the contribution of a diet rich in fruit and vegetables on periodontal health.

Vitamins
Vitamins play a key role in the coordination of the immune system and in the prevention and delay of the progression of several diseases. Vitamins have already been approved to have anti-inflammatory and antibacterial effects, in addition to regulating osteoblastic function in periodontal diseases, which makes them great targets as adjunctive treatments in patients with periodontitis [27]. The impact of vitamin deficiencies on periodontal diseases has been reviewed thoroughly before [11,28], so here, we focus on human clinical studies on vitamin supplementation as adjuncts to periodontal treatment, which are described in the next section and summarized in Table 2.    Vitamin D stands out as the main target of research studies in periodontal therapy. 360 patients with moderate or severe periodontitis were randomly prescribed, after 3 months of nonsurgical periodontal therapy, 2000 international units (IU)/d of vitamin D3, 1000 IU/d of vitamin D3, or placebo for 3 months [29]. Vitamin D supplementation in both dose groups resulted in a slight, but significant, reduction in PPD and clinical attachment loss (CAL) for moderate and deep periodontal pockets. However, it was concluded that vitamin D supplementation had a modest effect as an adjunct to periodontal therapy, with limited clinical relevance. A possible limitation of that study [29] could be the short followup period (3 months). Another RCT with a significantly smaller sample of patients with periodontitis but for a longer period of evaluation, 6 months, evaluated the effectiveness of a higher dose of vitamin D supplementation (25,000 IU/week;~3570 IU/day)) with nonsurgical periodontal treatment. Both the experimental and control groups showed improvements in all evaluated clinical parameters (PPD, BOP, PI); however, the reduction in PPD was greater in the test group that received the supplementation of vitamin D [30]. In another RCT, a dose of 400 IU/day of vitamin D supplementation for 6 weeks as an adjunct to nonsurgical periodontal therapy resulted in similar improvements in periodontal indices compared to nonsurgical periodontal treatment [31]. In this study, the authors also evaluated bone mineral density by a qualitative ultrasound; however, no significant difference was observed between comparison groups. Very few clinical studies have investigated changes in subclinical markers such as reductions in gingival crevicular fluid (GCF) and serum IL-1β [32] and decreases in serum cytotoxic T cells (CD3 and CD8) and of salivary cytokines [33] associated with vitamin D supplementation. The crucial role of vitamin D in maintaining periodontal health has been recognized; however, more clinical trials with longer follow-up periods are needed to determine the most efficient dosage and duration of vitamin D supplementation.
Vitamin C deficiency has been strongly associated with severe gingivitis, periodontal disease, and generalized gingival bleeding. In a case-control study, periodontitis patients were shown to have lower plasma vitamin C levels than individuals without periodontal breakdown [42]. In another case-control study, periodontitis patients with tooth loss reported a higher intake of vitamin C compared to patients without periodontitis [35]. The benefits of combining vitamin C supplements with periodontal therapy have not been investigated enough with clinical studies. Only one RCT evaluated the supplementation of vitamin C with nonsurgical periodontal therapy for 4 weeks [34], without showing any additional improvement in periodontal parameters in the test group. However, in this RCT, only 20% of the periodontitis patients were vitamin-C-depleted (plasma concentration < 4 mg/L), highlighting the importance of monitoring serum vitamin levels before adding supplements to our patients, as we do not know if they are already sufficiently replete with this added micronutrient.
Vitamin E has important antioxidant and anti-inflammatory properties. Deficiencies in vitamin E have controversial associations with periodontitis [11]. The administration of 200 mg vitamin E every other day for 3 months in addition to SRP in periodontitis patients resulted in a significant improvement in periodontal parameters and salivary superoxide dismutase compared to SRP alone [36]. In a multicenter RCT in patients with mild to moderate periodontitis, a fixed dose of the combination of vitamin C, vitamin E, lysozyme, and carbazochrome (CELC), combined with SRP, was tested for 4 weeks and resulted in a significant reduction in GI compared to SRP and placebo, without any differences in other periodontal parameters between studied groups [37]. The adjunctive intake of 400 mcg folic acid tablets with SRP resulted in a significant additional clinical attachment level (CAL) gain in periodontitis patients compared to SRP and placebo tablets, without any significant change in biochemical parameters between the studied groups [38]. Further clinical and biochemical data in larger clinical trials are needed to support the present findings.
Combined micronutrient supplements have also been investigated in patients with periodontal diseases. Patients with severe periodontitis who adhered to the Mediterranean died and received SRP with multi-micronutrient food supplement administration, includ-ing the co-enzyme Q10 multicomposite, docosahexaenoic acid (DHA), B. serrata, vitamins, mineral salts, and fish oil, did not show any significant advancement in clinical periodontal parameters compared to SRP and olive oil [39]. However, this clinical study included a very small number of patients per group (n = 15), and this small sample size does not allow us to draw definite conclusions yet. Collagen peptides are very popular anti-inflammatory supplements, especially for the prevention of arthritis. Periodontal recall patients with a history of treated periodontitis who received collagen peptides after professional mechanical debridement showed significantly lower gingival bleeding and periodontal inflamed surface area (PISA) compared to patients who received professional mechanical debridement and placebo, decreasing the risk of re-activation of periodontitis [40]. The adjunctive intake of a nutraceutical agent containing baicalin (Neuridase ® , Enfarma SRL, Misterbianco, Italy) with SRP in patients with moderate periodontitis significantly decreased PPD and BoP but also pain after SRP, compared to SRP and placebo [41]. More studies on nutraceutical agents and other micronutrient supplements are needed to better evaluate their adjunctive effect on periodontal therapy.

Omega-3 Fatty Acids
Omega-3 (n-3) polyunsaturated fatty acid (PUFA) dietary supplementation has been promoted for chronic inflammatory disorders such as RA and cardiovascular disease [43], diabetes, cancer [44], and COVID-19. Linolenic acid (LNA) is a fatty acid that can be found in vegetables, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are derived from marine food sources. The most popular n-3 PUFA supplements include fish oil, krill oil, and algal oils. [45]. The dosing, time course, and formulations of n-3 PUFAs in clinical studies vary and remain ill-defined [10]. The anti-inflammatory effects, however, are clearly dose-dependent, and higher doses (2.0-6.0 g/day) show stronger efficacy [43,44]. n-3 PUFA supplementation decreases the systemic indicators of chronic inflammation in plasma, such as CRP, IL-6, TNF-, and adiponectin, according to recent meta-analyses of human clinical studies [45]. Markers of chronic inflammation in plasma include CRP, IL-6, TNF-α, and adiponectin [45]. Increased bleeding time, allergy to fish or ASA, diarrhea, and steatorrhea are a few possible n-3 PUFA adverse effects [10]. A longitudinal study in older Japanese patients showed that a high n-6 to n-3 PUFA diet was associated with a greater risk of periodontal disease events, highlighting the potential advantages of diets rich in omega-3 or omega-3 supplements [46]. The benefits of dietary supplementation with omega-3 (n-3) PUFAs have been described in several human clinical studies on periodontal diseases [47][48][49][50][51][52], which are described below and summarized in Table 3.

months
Additional PPD reduction of 0.17 mm and higher reduction in number of sites with PPD ≥5 mm for DHA and ASA.
Significant reduction in CRP and IL-1β in GCF but not IL- 6 for DHA and aspirin.

Naqvi et al., 2014 [54]
Omega-3 and Aspirin RCT Patients with moderate to severe chronic periodontitis with grade II furcation (N = 40). Both groups received open-flap debridement with bone graft (DFDBA). The test group received omega-3 (3 g fish oil) +75 mg aspirin for 6 months, while the control group received placebo capsules.

months
Additional PPD reduction of 0.7 mm and CAL gain of 0.4 mm for omega-3 and aspirin group.

Significant reduction in IL-1β
in GCF for omega-3 and aspirin group.
ElKhouli AM et al., 2011 [49]   A recent systematic review that assessed omega-3 PUFAs as an adjunct to nonsurgical periodontal treatment in patients with periodontitis showed that the use of omega-3 PUFAs resulted in a significant PPD reduction and CAL gain of 0.42 mm and 0.58 mm, respectively, when compared to nonsurgical periodontal treatment alone [53]. Several studies, though, evaluate the combined effect of omega-3 with aspirin in periodontal therapy, making it harder to attribute this positive therapeutic effect only to omega-3 supplementation. In an RCT in Egypt, patients with advanced chronic periodontitis were randomized to receive SRP with either fish oil supplements (3 g) and aspirin (81 mg) or placebo capsules. A significant reduction in PPD and CAL gain was shown in the test group compared to the control at 6 months [48]. The combined daily use of omega-3 and aspirin for 2 months as an adjunct to SRP (either two months before or two months after debridement) in patients with moderate/severe periodontitis and uncontrolled diabetes mellitus type II resulted in more patients achieving the clinical endpoint of treatment (less than or equal to four sites with PPD ≥5 mm) compared to the control group. However, no significant differences in clinical periodontal outcomes between test and control groups were observed, in addition to the fact that there was no difference in the improvement in periodontal status between different administration timings of omega-3 and aspirin [47]. Low doses of omega-3 PUFAs in the diet combined with SRP caused a significant decrease in TNF-α levels in the saliva of patients with periodontitis, without improving additional clinical periodontal parameters [55]. The impact of omega-3 nutrition as a monotherapy on periodontal clinical parameters has also been investigated. When compared to placebo plus 81 mg of aspirin, the monotherapy of 2000 mg of DHA per day dramatically reduced gingival inflammation and moderate periodontitis [54]. Despite the positive indications that omega-3 PUFA supplements can be used as an adjunct to periodontal therapy, more studies with larger sample sizes and longer follow-up periods are essential to elucidate their therapeutic benefits and the most effective doses and administration.

Plant-Derived Compounds
Plant-derived compounds have been potential therapeutic agents recognized for their vigorous antioxidant and anti-inflammatory properties. Polyphenols are beneficial ingredients in many plant foods and can be classified into flavonoids, proanthocyanidins, phenolic acid, polyphenolic amides, and other polyphenols, such as resveratrol and curcumin [56]. The types of food that have the highest polyphenol content per serving include berries, herbs and spices, cocoa powder, flaxseeds, vegetables, olives, red wine, coffee, and tea [57]. Due to the anti-inflammatory and antibacterial actions of polyphenols and other derived nutrients, several clinical studies have investigated their contribution to the improvement in therapeutic outcomes in patients with periodontal diseases. The studies are described below and summarized in Table 4. RCT N = 20 dental students followed a 21-day protocol of experimental gingivitis and randomly either received oligomeric proanthocyanidin nutritional supplements treatment consisting of 90 mg exocian cran 408 and 120 mg of vitamin C (test) or placebo capsules (control). Oral hygiene was not performed for 21 days.

days
Silness and Löe index and gingival bleeding index were significantly lower in the test group compared to the control. Plaque index was significantly higher in the test group.
R.M Diaz Sanchez et al., 2017 [58] Encapsulated fruit, vegetable, and berry juice RCT A total of 60 nonsmoking subjects with periodontitis were randomized into 3 groups: Daily supplementation with capsules with fruit/vegetable (FV) juice powder, fruit/vegetable/berry (FVB) juice powder, and placebo (control) for 2 months after SRP.
8 months PPD, CAL, and BOP at 2 months were improved in all groups, with additional improvement in the FV group compared to the placebo one (p < 0.03). FV groups showed better BOP % and plaque scores when compared to control at 5 months (p < 0.05). No differences between FV and FVB groups.
Adherence/β-carotene plasma levels were significantly higher in both FV and FVB groups compared to control (p < 0.001). GCF volume was significantly reduced in both supplement groups (FV, FVB), compared to control.
Chapple et al., 2012 [59] Cranberry functional beverage RCT 50 gingivitis patients were randomized into two groups: The test group received a daily 750 mL of cranberry functional beverage (CFB) for 8 weeks, while the control group was given the same amount of water, both combined with nonsurgical periodontal therapy.

Weeks
Significant reduction in GI and PI scores in the test group compared to control, but no differences in BOP scores between the two groups.
Saliva and serum levels of total anti-oxidant status, malonyldialdehyde, and IL-1β were not significantly different between comparison groups.
Number of Streptococcus mutans were reduced in the test group but not in the control.   Bilberries RCT (N = 24) subjects with gingivitis were divided into placebo and two test groups who either consumed 250 g or 500 g of bilberries daily.

week
The mean reduction in BOP before and after intervention was 31% in the placebo group, 41% for those who consumed 250 g, and 59% for 500 g of bilberries/day. Propolis RTC 104 patients with gingivitis and incipient periodontitis were randomized into 2 groups: Test group ingested a capsule containing propolis daily for 8 weeks, while the control group received a placebo capsule. SRP was provided to all patients at the end of the study (8 weeks).

weeks
Test group showed significant improvement in gingival index after 4 and 8 weeks of treatment compared to control group.
In the test group, IL-6 was reduced and MMP-9 increased after 8 weeks.
Jin-Young Park et al., 2021 [67] Propolis RTC 50 patients with periodontitis and type 2 diabetes mellitus received initial SRP and were divided into 2 groups. Test group received 400 mg of propolis orally 1x/day for 6 months, while the control group received placebo capsules.

and 6 months
Test group showed significantly higher PPD reduction and CAL gain after 3 and 6 months of treatment.
Test group showed significant reduction in HbA1C after treatment.
El-Sharkawy et al., 2016 [68]   A new nutritional supplement made of oligomeric proanthocyanidins (OPCs) was evaluated in an RCT using a 21-day established protocol of experimental gingivitis by quitting oral hygiene in dental students in Seville, Spain [58]. The Silness and Löe index was higher in the control group than in the test group, reaching a two-fold difference between the groups, while the gingival bleeding index was significantly lower in the test group, suggesting that this nutritional supplement made of OPCs can help in the management of gingival inflammation. A higher intake of fruits and vegetables has been associated with improved healing and therapeutic outcomes after periodontal therapy, and was discussed earlier in this review. A double-blind RCT of nonsmoking patients with periodontitis (n = 60) evaluated the impact of an adjunctive phytonutrient supplement after SRP [59]. The use of fruit/vegetable juice powder capsule supplementation resulted in higher plasma levels of adherence/β-carotene and an additional improvement in PPD and BOP reduction compared to placebo capsules, outcomes that can be attributed to the greater micronutrient bioavailability triggered by the supplements. In addition, the consumption of a cranberry functional beverage for 8 weeks after nonsurgical periodontal treatment in patients with gingivitis improved gingival and plaque indices without increasing any risk of caries development [26].
Resveratrol, a polyphenol present in various foods derived from fruits and vegetables, has been considered a promising natural drug for the prevention and therapy of various inflammatory diseases due to its ability to inhibit the oxidative damage and mitochondrial dysfunction in cells [70]. Resveratrol supplementation as a monotherapy was studied in patients with aggressive periodontitis, showing that resveratrol improved clinical periodontal outcomes (BOP, PPD, CAL, PI) by decreasing inflammatory markers and systemic endotoxin [60]. Daily supplementation with 500 mg resveratrol capsules was the recommended treatment for patients with periodontitis [60], confirming a previous study where daily supplementation with 480 mg resveratrol capsules improved PPD reduction after nonsurgical periodontal therapy in patients with periodontitis and diabetes mellitus type II [61]. More studies with larger sizes and longer follow-up periods are needed to verify these positive therapeutic benefits of resveratrol in periodontal treatment.
Herbs have been considered a source of powerful antioxidants and polyphenols, with potential anti-inflammatory actions in the periodontium. The daily consumption of green tea had a positive adjunctive therapeutic benefit with nonsurgical periodontal therapy in patients with chronic periodontitis [62,63], attributed to an increase in the antioxidant capacity of GCF [63]. Chicory leaf extract (an herbal plant with polyphenols) capsules or placebo ones containing wheat flour were randomly administered to periodontitis patients in combination with SRP; the intervention group showed a significantly higher reduction in PPD, most likely due to increased serum levels of antioxidants [64]. The daily consumption of bilberries (blueberries) rich in antioxidants and polyphenols for one week had a positive effect on reducing BOP in patients with gingivitis by decreasing GCF levels of inflammatory markers [65].
Caffeine has been found to modulate both innate and adaptive immune responses and reduce inflammation [66]. In a large longitudinal study in males (N = 1152), a small but significant decrease in the number of teeth with periodontal bone loss was linked to greater coffee consumption [66]. The oral administration of propolis, a viscous substance produced by bees, has been shown beneficial in the management of periodontal inflammation. A cohort of 104 patients with gingivitis and incipient periodontitis were randomized to receive either a capsule containing propolis or placebo, without any periodontal therapy. This RCT showed that the administration of propolis reduced the gingival index and IL-6 in GCF [67]. A 6-month daily regimen of 400 mg propolis in patients with periodontitis and type II diabetes mellitus combined with SRP resulted in a significantly higher PPD reduction and CAL gain, but also in a significant reduction in HbA1C compared to the control group, who received placebo capsules [68]. Turmeric, especially its most active compound curcumin, have been found to have anti-inflammatory properties and promote wound healing by downregulating the activities of lipoxygenases and cyclooxygenases in experimental periodontitis (in vivo) [71]. However, the daily oral administration of curcumin capsules (200 mg) in periodontitis patients in Saudi Arabia after periodontal surgery (open-flap debridement for PPD elimination) did not result in any significant differences in postoperative pain and discomfort compared to mefenamic acid [69].

Conclusions
Periodontitis is a major source of oral and systemic inflammation and a significant cause for tooth loss in adults. The role of a dysregulated hyperactivated host immune response in periodontitis is clear. Differences between individuals in the response to bacterial plaque may be a result of variation in host susceptibility and immune response, with some individuals being very sensitive and developing aggressive forms of periodontitis at a relatively young age, whilst others are resistant and never develop periodontitis [4,72]. Living in the era of personalized medicine, it is of paramount importance to customize the diagnosis with risk factors for periodontal diseases and periodontal treatment for each patient.
Modifying our diet to a Mediterranean diet one that involves a high intake of vegetables, fruits, olive oil, herbs, and fatty sea fish seems to decrease gingival inflammation and bleeding on probing. A high consumption of fruit seems to counteract inflammation and favors the return to periodontal health. Although the role of vitamin D in regulating bone homeostasis has been recognized, the vitamin D supplementation had a modest effect as an adjunct to periodontal therapy, with limited clinical relevance. Limited evidence on the adjunctive effect of supplementation with other vitamins and micronutrients, such as collagen peptides, on periodontal therapy is currently available, and more clinical trials are needed. Despite the positive therapeutic effect of omega-3 PUFAs, with or without aspirin, in patients with periodontitis, more studies are needed to elucidate the most effective doses of administration of omega-3 PUFAs. Plant-derived compounds including polyphenols, herbs, and phytonutrient supplements are promising therapeutic agents in the management of periodontal inflammation; however, more clinical investigations are required to draw a decisive conclusion. In summary, several clinical studies on food ingredients and types of diet have revealed their positive impact on periodontal therapy due to their antiinflammatory effects. The limitations of the current available clinical studies are the small sample sizes and the short follow-up periods. More human studies with larger sizes and longer follow-up periods are needed to verify these positive therapeutic benefits of food ingredients and supplements in periodontal treatment.
The nutritional assessment of our patients with questionnaires has not received adequate attention in clinical practice and needs to be more frequently integrated. It is very important that clinicians identify patients who might receive inadequate nutrients with anti-inflammatory properties in their diet and consider recommending them to modify their diet and enrich it with food compounds and supplements that may ultimately enhance the outcomes of periodontal treatment and reduce their risk of the progression of periodontal diseases. It is also critical to investigate further nutrients that would promote the maintenance of homeostasis in the periodontium, where inflammation is controlled and eubiosis (symbiosis) in the oral cavity is retained. Therefore, more clinical studies on several other food ingredients such as cocoa, honey, mastic gum, red wine, and coconut oil are needed, to investigate their effect on modifying the inflammatory response in the periodontium and improving the periodontal status and wound-healing process. Unique formulations of different nutrients in oral health products (mouthwash, toothpaste, gels, strips) need also to be explored and developed further as possible therapeutic agents for periodontal inflammation.
Author Contributions: E.P. contributed to the conception, design, collection, and interpretation of the data quoted in this review, and drafted and critically revised the manuscript; R.A. and M.A.d.G. contributed to design, collection, and interpretation of the data, and critically revised the manuscript. All authors have read and agreed to the published version of the manuscript.