How dietary interventions impact oral conditions: a systematic review

Abstract

Background

Oral diseases, including periodontal disease, salivary gland dysfunction and oral squamous cell carcinoma, are characterized by chronic inflammation and metabolic dysregulation. Dietary interventions have demonstrated systemic anti-inflammatory and metabolic benefits; however, their effects on the oral cavity remain insufficiently explored.

Methods

A systematic review was conducted in PubMed and Web of Science to identify relevant studies published up to September 2025 assessing the effects of fasting, caloric restriction, and ketogenic diet on oral conditions. The search strategy combined MeSH terms and keywords related to these dietary interventions and oral health conditions. Data on study characteristics, interventions, outcomes, and limitations were extracted and synthesized.

Results

Fourteen studies were included, comprising preclinical in vitro and in vivo studies as well as a limited number of clinical trials. Caloric restriction and intermittent fasting were generally associated with improvements in periodontal inflammation and metabolic parameters, without significant effects on oral microbiota composition. Alternate-day fasting demonstrated beneficial effects on salivary gland function and inflammatory responses in preclinical models. In oral squamous cell carcinoma, fasting-related interventions enhanced treatment sensitivity and reduced tumor growth in experimental studies; however, clinical evidence remains scarce, and feasibility, particularly for ketogenic diet, is limited and mainly derived from small pilot studies with methodological constraints.

Conclusion

Caloric restriction and intermittent fasting may exert potential beneficial effects in oral health by modulating inflammation, tissue regeneration, and metabolic pathways. However, current evidence remains largely preclinical and heterogeneous. Well-designed clinical trials and mechanistic studies in humans are required to establish their clinical relevance and to support their integration into evidence-based oral health practice.

Review registration

This review was registered in PROSPERO (Registration ID: 1085293) and conducted in accordance with PRISMA 2020 guidelines [1].

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12903-026-09090-z.

Background

Oral diseases such as periodontal disease (PD), salivary gland (SG) dysfunction and oral squamous cell carcinoma (OSCC) represent a major global health burden [2–12]. Their pathogenesis is associated with chronic inflammation, metabolic dysregulation, oxidative stress, and impaired tissue homeostasis [2, 6, 13–16]. In recent years, there has been growing interest in the role of nutrition and metabolic interventions in modulating these biological processes [2, 10].

Among these strategies, dietary interventions (DI) -including intermittent fasting (IF), alternate-day fasting (ADF), short-term fasting (STF), caloric restriction (CR), fasting-mimicking diet (FMD) and ketogenic diet (KD)- have been practiced for millennia for therapeutic purposes [17]. Modern research has demonstrated that these approaches can influence key metabolic, inflammatory, and molecular pathways, thereby affecting longevity and the risk of chronic diseases. Notably, studies by Valter D. Longo have elucidated the molecular and cardiovascular mechanisms through which fasting modulates metabolism, inflammation, and aging [17–19]. These systemic effects -including reduced inflammation, decreased oxidative stress, and modulation of nutrient-sensing pathways- suggest a potential role for DI in maintaining oral tissue health and preventing conditions such as PD, SG dysfunction, and OSCC.

CR, IF, and KD have attracted particular attention due to their ability to reduce insulin and insulin-like growth factor-1 (IGF-1) signaling, enhance autophagy, and decrease the production of pro-inflammatory cytokines [2, 4, 10, 11, 13–15, 17, 18, 20–27]. These mechanisms are directly implicated in pathways underlying periodontal breakdown, SG degeneration, and tumor progression [2, 4, 10, 11, 13, 21–23].

Despite rising scientific interest [2, 28], these interventions remain relatively unfamiliar in contemporary societies [2, 18, 29], where continuous food availability and culturally reinforced eating patterns tend to promote overconsumption [2, 29]. Consequently, dietary strategies are often perceived as unconventional, and their potential therapeutic relevance in chronic inflammatory and neoplastic conditions is not yet widely acknowledged [2].

Notwithstanding this emerging interest, their specific implications for oral tissues and oral diseases remain insufficiently defined [2, 10, 28–31]. Current evidence is fragmented and largely limited to small-scale clinical studies and isolated experimental models [2, 10, 28].

To address this gap, this systematic review aimed to evaluate the impact of DI on PD, SG and OSCC by synthesizing currently available preclinical and clinical evidence.

Methods

Research strategy

A systematic literature search was conducted in PubMed and Web of Science databases to identify relevant studies published up to September 2025.

Database search strategy and relevant keywords were chosen after detailing the scientific question using the PICOS methodology [1]:

• Population (P): Participants who received DI such as CR, IF, ADF, STF, FMD and KD.

• Intervention (I): Use of DI, including CR, IF, ADF, STF, FMD or KD.

• Comparison (C): Participants who did not receive DI.

• Outcome (O): The effects of nutrition on various tissues of the oral cavity such as inflammation, variations of indicators like bleeding on probing (BOP) and periodontal probing depth (PPD), saliva flow or impact on OSCC.

• Study types (S): original preclinical and clinical studies.

The literature search was conducted in accordance with the PRISMA 2020 guidelines (Additional file 1) [1]. A systematic search was performed using Medical Subject Headings (MeSH) and free-text terms. The search strategy combined terms related to fasting and DI, including fasting, IF, STF, FMD, CR, and KD, with terms related to oral and periodontal conditions, including oral cancer, OSCC, head and neck squamous cell carcinoma (HNSCC), mouth neoplasms, oral cavity, PD, oral health, SG and teeth. When relevant, terms related to chemotherapy were also included. Boolean operators (AND/OR) were applied to combine search terms. So, the search strategy combined: (fasting[Mesh] OR “short term fasting” OR “intermittent fasting“[Mesh] OR “fasting mimicking diet” OR “caloric restriction” OR “ketogenic diet” OR “food-restricted” ) AND ( “oral squamous cell carcinoma” OR “oral cancer” OR “mouth cancer” OR HNSCC OR “head and neck squamous cell carcinoma” OR “oral cavity cancer” OR periodontitis OR “oral health” OR “Sjögren’s syndrome”) ) OR ( “Valter Longo” AND fasting[Mesh]).

This review was registered in PROSPERO (Registration ID: 1085293) and conducted in accordance with PRISMA 2020 guidelines [1].

Selection of articles

Report selection began with the removal of duplicates using Zotero. The selection process, comprising an initial assessment of titles and abstracts, followed by a full reading of the texts, was conducted by MP and verified by SB.

Studies investigating DI, including CR, IF, ADF, STF, FMD or KD, in relation to oral tissues or oral diseases were considered eligible. For the purpose of this review, the term “oral cavity” referred to structures and conditions directly involving periodontal tissues, SG, oral mucosa, teeth, and OSCC. Conditions not directly involving oral tissues, such as dysphagia, esophageal disorders, or systemic metabolic outcomes without oral endpoints, were excluded.

Because evidence regarding dietary interventions in oral health remains limited, both preclinical (in vitro and in vivo) and clinical studies were included to provide a broader overview of the available evidence. The studies were subsequently categorized according to their design and analyzed separately.

Original preclinical and clinical studies were eligible for inclusion. Narrative reviews, systematic reviews, editorials, conference abstracts, and case reports were excluded from the formal data extraction and synthesis process.

Studies unrelated to the oral cavity, or published in a language other than English or French, were excluded. The country of origin of the study and year of publication did not influence study selection.

Data extraction

For each study included in the review, the articles were thoroughly examined, focusing on the characteristics of the DI, its duration, the follow-up, the observed outcomes, population characteristics and assessed parameters.

Data from the included studies were extracted and systematically organized into a summary table comprising the following items: authors, year of publication, country, study design, population, diets investigated, outcomes, and main findings (Table 1). This process was conducted by MP and independently verified by SB.

Table 1.

Overview of the included studies

Authors	Year	Country	Study design	Population/Sample size	Dietary intervention	Oral health outcomes	Findings
Soares et al. [3]	2021	Brazil	In vivo study	48 rats	CR	PD	CR reduces alveolar bone loss and improves periodontal parameters.
Soares et al. [34]	2021	Brazil	In vivo study	48 rats	CR	PD	CR reduces alveolar bone loss and improves metabolic and inflammatory status, without negative effects on bone biomarkers.
Branch-Mays et al. [21]	2008	USA	In vivo study	55 macaques	CR	PD	CR reduces gingival inflammation and slows the progression of periodontal destruction.
Woelber [9]	2021	Germany	Clinical Trial	20 patients	KD	PD	No significant changes in periodontal parameters.
Pappe et al. [31]	2025	Germany	Clinical Trial	66 patients	IF	PD	IF reduces experimental gingival inflammation and decreases BOP.
Lira-Junior et al. [28]	2024	Sweden	Clinical Trial	18 patients	IF	PD	IF improves in metabolic and periodontal parameters, but no change in microbiota composition.
Li et al. [14]	2022	USA	In vivo study	24 mice	ADF	SG dysfunction	ADF improves salivary flow rate and glandular function and reduces inflammation.
Li et al. [35]	2024	USA/ Japan	In vivo study	18 mice	ADF	SG dysfunction	ADF increases the proportion of salivary stem cells, reduces senescence and inflammation, and remodels cellular metabolism.
Aboulfotoh et al. [8]	2024	Egypt	In vivo study	18 rats	KD	SG dysfunction	KD has deleterious effects on the submandibular SG of rats.
Barzotti et al. [30]	2025	Brazil	In vivo study	20 rats	IF	SG dysfunction	IF preserves the function and histological structure of the SG, but induces moderate oxidative stress
Ma et al. [7]	2021	USA	Clinical Trial + in vivo study	12 patients + mice	KD	OSCC	KD may increase tumor sensitivity to radiotherapy through increased oxidative stress within the tumor, but clinical tolerability is low.
Thurman et al. [33]	1997	USA	In vivo study	192 rats	CR	OSCC	Significant reduction in the incidence of OSCC.
Wang et al. [32]	2025	China	In vitro + in vivo study	Human oral cancer cell lines + mice	FMD	OSCC	FMD sensitizes tumor cells to gefitinib and significantly reduces tumor growth, proliferation, and macrophage infiltration.
Sheykhbahaei et al. [4]	2024	Iran	In vitro study	HN5 cell line + healthy human oral keratinocytes	STF	OSCC	STF enhances the pro-apoptotic effects of cisplatin on cancer cells.

Risk of bias assessment

Risk of bias assessment was conducted in accordance with PRISMA 2020 reporting guidelines (additional file 2) [1].

Preclinical animal studies were evaluated using the SYRCLE Risk of Bias tool for animal intervention studies.

Non-randomized intervention studies were assessed using the ROBINS-I tool.

As no validated risk of bias tool exists for in vitro studies, methodological quality was assessed using a predefined checklist based on previously published criteria, including adequacy of controls, randomization procedures, blinding, reproducibility, completeness of outcome reporting, and selective reporting.

Risk of bias assessment was performed independently by MP and verified by SB.

Results

Study selection

During the research process, a total of 2 234 reports were identified, including 624 from PubMed and 1 610 from Web of Science. After removing duplicates, screening titles and abstracts, and analyzing the remaining reports, 14 studies were included (Fig. 1).

Fig. 1.

PRISMA flowchart [1]

The number of articles was drastically reduced, firstly due to the removal of duplicates, and secondly because many studies were not relevant to the topic. For instance, some articles included the term “fasting” in the context of blood sampling after fasting rather than as part of a fasting-based intervention. Additionally, nine narrative and systematic reviews were excluded from the analysis.

Of the 14 studies included, 2 were preclinical in vitro experiments [4, 32], 10 were preclinical in vivo experiments [3, 7, 8, 14, 21, 30, 32–34] and 4 were clinical trials [7, 9, 28, 31]. Some articles combined two study designs [7, 32].

Risk of bias assessment

Risk of bias assessment revealed substantial methodological heterogeneity across the included studies. Most preclinical animal studies were judged to present a moderate to high risk of bias, mainly due to insufficient reporting of random sequence generation, lack of allocation concealment, absence of blinding procedures, and limited sample size calculations.

Among SG studies, the main concerns were related to the absence of blinded histological assessment and incomplete reporting of randomization procedures. In OSCC experimental studies, several animal models also demonstrated high risk of bias due to small sample sizes, absence of blinding, and potential selection bias. Notably, the study by Thurman et al. [33] showed a high risk of selection bias because entire litters were allocated to experimental groups, introducing possible familial clustering effects.

The non-human primate periodontal study demonstrated a moderate risk of bias, whereas the human pilot intervention study by Lira-Junior et al. [28]. presented a high risk of bias because of its non-randomized design, participant attrition, and potential confounding factors. The three-arm clinical trial by Pappe et al. [31]. demonstrated an overall moderate risk of bias due to incomplete randomization across all intervention groups despite blinded outcome assessment and predefined primary outcomes.

Overall, the predominance of preclinical studies and the methodological limitations identified reduce the certainty and direct clinical translatability of the current evidence.

Study main outcome

For clarity, the findings from the 14 included studies were categorized into three thematic subgroups based on their primary area of investigation: PD, SGD and OSCC.

Types of dietary interventions identified

Across the 14 studies, different dietary patterns and fasting modalities were tested to explore the potential effects on the oral cavity.

Caloric restriction

This diet is defined explicitly as a reduction in energy intake well below the number of calories that would be consumed ad libitum (meaning without restriction), between 10% and 40%, without malnutrition [2, 3, 13, 17, 24, 26, 27, 33, 34].

Short-term fasting

This dietary pattern is defined as a 48-hour period of glucose restriction (0.5 g/L) designed to mimic the metabolic state of fasting and reduced nutrient availability before chemotherapy [4]. Subjects abstain from food before and after treatment for a total of 24–120 h [5].

Ketogenic diet

This diet consists of a high intake of fats, a moderate intake of proteins, and a low intake of carbohydrates. The maximum carbohydrate intake is 50 g per day, which induces a state of physiological ketosis, whereby the digested fats are converted into ketone bodies that are used as an energy source. A classical KD consists of approximately 90% fat, 8% protein and 2% carbohydrate [6–9, 23, 26, 27].

Fasting-mimicking diet

FMD consists of a low-calorie diet, low in protein and sugar but rich in healthy fats, designed to reproduce the physiological effects of fasting while ensuring a minimal supply of essential nutrients. This diet mimics the effects of fasting by decreasing insulin/glucose signaling pathway activation, while avoiding the potential side effects of lack of essential nutrients [13, 20, 32].

Alternate-day fasting

This dietary approach constitutes a form of IF, whereby individuals alternate between periods of CR and unrestricted eating [13, 14, 30].

Intermittent fasting

IF consists of eating during a well-defined period and fasting for the remaining time (16:8, a 16-­hour fast with an 8-­hour eating window; 5:2 diet, eating normally for 5 days per week then restricting calorie intake to 500—600 calories on the other 2 days). There are no specific restrictions regarding the types of food consumed [13, 18, 19, 24, 27, 28, 30, 31].

Periodontal disease and oral microbiota

A total of six studies have investigated the impact of DI on PD and oral microbiota. Of these, three were clinical trials [9, 28, 31] and three were preclinical studies [3, 21, 34].

In 2008, a three-month comparative preclinical study involving 55 healthy adult rhesus macaques examined the effects of a 30% CR on the development and progression of PD. Clinical parameters were assessed at baseline and at 1, 2, and 3 months, including PPD, clinical attachment level, BOP, modified gingival index, and plaque index. No significant differences in plaque accumulation were observed between groups, as plaque index remained comparable from baseline (control: 1.11 vs. CR: 1.01) to 3 months (control: 1.36 vs. CR: 1.42), indicating that the effects of CR were not due to changes in oral biofilm. Levels of BOP were consistently lower in the CR group throughout the study, with significant differences observed between groups (p < 0.0015). At baseline, BOP was similar between groups (control: 1.35 vs. CR: 1.29), whereas at 3 months, the CR group exhibited markedly lower levels compared with controls (control: 2.46 vs. CR: 1.84). Similarly, the modified gingival index was significantly reduced in the CR group at all time points (p < 0.0001), with baseline values of 0.70 in controls versus 0.67 in CR animals, increasing to 4.02 in controls compared with 3.20 in the CR group at 3 months. Pocket depth was also consistently lower in the CR group (p < 0.0016), remaining more stable over time (baseline: control: 2.19 vs. CR: 2.15; 3 months: control: 3.48 vs. CR: 3.10). Clinical attachment loss was significantly lower in the CR group (p < 0.0038). Although attachment loss increased in both groups from 1 to 3 months (control: 1.28 → 1.68; CR: 1.06 → 1.27), a statistically significant progression of periodontal destruction from baseline was observed only in the control group (p < 0.01). These findings suggest that CR attenuates gingival inflammation and periodontal tissue destruction primarily through modulation of the host immune response rather than by altering oral microbiota composition [21].

A preclinical study by Soares et al. evaluated whether a 12-week 30% CR could mitigate alveolar bone loss in the context of experimental PD, following obesity induction via a high-fat, high-sugar “cafeteria diet” in 48 Wistar rats. Periodontal outcomes, including BOP, biofilm, tooth mobility, and gingival index, were assessed before euthanasia, while alveolar bone loss was evaluated post-mortem through photographs of the processed and stained mandibles. PPD was not measured, as clinical assessment requires live tissue. The authors reported that CR reduced alveolar bone loss and improved periodontal clinical indices. Specifically, CR significantly decreased BOP, with approximately 70% of CR-treated rats showing no BOP compared to 0% in the non-CR groups. CR also had a significant beneficial effect on gingival index (p < 0.001) and tooth mobility (p = 0.001), while no significant differences were observed for the biofilm parameter, which was present in all animals regardless of intervention. Furthermore, CR significantly reduced alveolar bone loss in rats subjected to ligature-induced experimental PD (p < 0.01), whereas no significant changes were observed in rats without PD induction (p > 0.05). Additionally, CR lowered blood glucose levels, body weight, and adiposity, and the blood collected showed no significant changes in calcium and alkaline phosphatase levels when comparing the experimental groups, indicating that the intervention did not induce malnutrition [34].

In another preclinical study, Soares et al. investigated whether a 30% CR could influence the progression of alveolar bone loss induced by experimental PD in 48 non-obese Wistar rats. The study design was comparable to their previous study, with the exception of the obesity induction procedure.The results showed that CR led to reductions in body weight, fat mass and blood glucose levels, while serum lipid levels remained unchanged. CR also significantly decreased alveolar bone loss and gingival inflammation compared with the control group (which is an ad libitum group). Bone biomarkers such as calcium and alkaline phosphatase remained stable, suggesting that CR did not adversely impact bone metabolism [3].

A single-blind, controlled clinical trial conducted by Pappe et al. in 66 healthy adults evaluated the effects of Bahá’í dry fasting -a 19-day annual practice during which food and drink are abstained from sunrise to sunset for spiritual reflection and self-discipline- and IF (16 h fasting, 8-hour feeding window) on periodontal parameters (BOP and gingival crevicular fluid (GCF)) during experimentally induced local gingivitis, compared with a standard diet. The Bahá’í fasting group showed a significantly lower increase in BOP (5,42%) than both IF group (14,61%) and control group (14,9%), and no rise in GCF. In the IF group, BOP increased similarly to the control group, but without a significant rise in GCF. In contrast, the control group showed increases in BOP, GCF (0.14µL at T1 and 0.23µL at T2) and plaque accumulation [31].

A six-month pilot study by Lira-Junior et al. involving 18 obese adults evaluated the effects of 5:2 IF on periodontal parameters (plaque index, BOP and PPD). The results showed no significant changes in the plaque index or in the composition and diversity of the microbiota. However, significant improvements were observed in BOP and PPD [28].

In a six-week pilot study involving 20 healthy adults, the effects of a KD on periodontal health were evaluated. No significant changes were observed in periodontal parameters or dental plaque accumulation [9].

Overall, based on the limited studies available, DI such as CR or IF may have beneficial effects on both periodontal and metabolic parameters. In contrast, KD does not appear to improve periodontal outcomes and is associated with increased LDL cholesterol levels. Furthermore, none of these dietary approaches seem to significantly affect the composition or diversity of the oral microbiota.

Salivary glands and Sjögren’s disease

Four preclinical in vivo studies have investigated the effects of various diets on SG function [8, 14, 30, 35].

Among them, a recent preclinical study on 20 healthy Wistar rats investigated the effects of ADF on the function, histological structure, and oxidative stress of the parotid and submandibular SG. Their findings showed that ADF preserved both glandular function and histological integrity despite inducing moderate oxidative stress, characterized by significant alterations in antioxidant defenses (p < 0.05 to p < 0.0001) without evidence of lipid or protein oxidative damage. Additionally, ADF led to significant reductions in body weight loss and adipose tissue reserves (p < 0.01 to p < 0.0001) [30].

Another preclinical study, involving 18 rats assessed the impact of a KD and a chitosan-supplemented diet on the submandibular SG. Chitosan, a dietary fiber derived from crustacean shells such as shrimp and lobster, is a relatively new nutritional supplement with emerging interest. It has been reported to exhibit multiple potential biological activities, including antibacterial, anticancer, antioxidant and hepatoprotective effects, and may contribute to SG tissue regeneration. The KD was associated with cellular degeneration, amyloid deposition, and structural alterations, indicating detrimental effects on gland morphology. In contrast, chitosan supplementation attenuated these alterations, suggesting a potential protective and regenerative effect [8].

A three-week preclinical study on 24 Non-Obese-Diabetic (NOD) mice -a well established model for type 1 diabetes- evaluated the effects of ADF in a murine model of Sjögren’s disease and investigated the underlying cellular and molecular mechanisms. ADF improved salivary flow and glandular function (p < 0.05), reduced inflammation and immune cell infiltration (p < 0.05), and attenuation of Th1 (p < 0.01) and Th17 (p < 0.05) responses, without affecting autoantibody production [14].

Li et al. subsequently conducted another preclinical study to determine how ADF influences salivary gland stem cells (SGSCs) in the same murine model of Sjögren’s disease. After three weeks, ADF increased the proportion of SGSCs, reduced cellular senescence and inflammation, and remodeled cellular metabolism, indicating a beneficial effect on SG function [35].

Together, these preclinical studies suggest that different dietary patterns -such as ADF- may significantly influence SG function, structure and cellular mechanisms. While IF appears to preserve glandular integrity and enhance stem cell populations, certain diets, such as the KD, may exert detrimental effects that can be mitigated by specific supplements like chitosan.

Oral squamous cell carcinoma and its therapies

Four studies have investigated the impact of DI on OSCC and its treatments. Among them, one was a preclinical in vitro study [4], one combined preclinical in vitro and in vivo experiments [32], one was a preclinical in vivo study [33], and one included both in vivo experiments and a phase I clinical trial [7].

In Ma et al. study, mice bearing HNSCC xenografts treated with radiotherapy and KD showed -compared to mice receiving radiation alone- reduced tumor glutathione levels (reflecting increased oxidative stress), slower tumor growth, and a modest improvement in survival. The accompanying phase I clinical trial involved twelve patients with locally advanced HNSCC who received radiotherapy, chemotherapy, and KD. However, eight patients discontinued the diet prematurely due to adverse effects including nausea, fatigue, acute pancreatitis and severe hyperuricemia. Among the four patients who tolerated the diet, biological monitoring confirmed the achievement of ketosis (elevated blood ketone levels) with stable blood glucose and no ketoacidosis was observed. Systemic oxidative stress markers remained unchanged. Nevertheless, the feasibility of this intervention appears to be very limited [7].

In a recent chinese preclinical study, both in vitro and in vivo experiments showed that FMD directly sensitizes tumor cells to gefitinib, leading to a significant reduction in tumor growth, cell proliferation, and macrophage infiltration [32].

The preclinical in vitro study by Sheykhbahaei et al. investigated the effects of STF on tumor cells and healthy keratinocytes during chemotherapy. The results showed a significant decrease in cell viability and an increase in apoptosis and necrosis in HN5 tumor cells treated with cisplatin combined with fasting, whereas the effect on healthy keratinocytes was less pronounced and not statistically significant. STF (48 h before and after chemotherapy) appeared to enhance the pro-apoptotic effects of cisplatin on HNSCC cells, although no protective effect was observed in normal cells [4].

In their preclinical in vivo study, Thurman et al. demonstrated that a 40% CR in rats significantly reduced the incidence of SCC, despite increasing the animals’ lifespan compared to those fed ad libitum. The authors also identified a genetic component, as SCC cases tended to cluster within certain litters and lineages, suggesting a hereditary predisposition. Moreover, litter size appeared to influence cancer incidence, which was higher in litters of 7–9 pups than in those of 3–6 [33].

A global overview of the effects of the different DI on PD, SG, and OSCC is summarized in Fig. 2.

Fig. 2.

Impact of six different diets on the Periodontal Disease (PD), Salivary Glands (SG), and Oral Squamous Cell Carcinoma (OSCC)

Discussion

This systematic review is, to our knowledge, the first to comprehensively synthesize preclinical and clinical evidence on DI across the entire oral cavity, including PD, SG and OSCC. By integrating metabolic, inflammatory and regenerative mechanisms, this work highlights both the experimental findings and the current translational limitations of dietary strategies in oral health.

A comprehensive analysis of the included studies reveals that they emanated from a diverse array of geographical regions, encompassing Europe [9, 28, 31], the Americas [3, 7, 14, 21, 30, 33–35], the Middle East [4, 8], and Asia [32, 35]. Notably, the majority of these studies were published between 2021 and 2025 [3, 4, 7–9, 14, 28, 30–32, 34, 35], reflecting a recent and growing scientific interest in fasting and DI, with only two earlier studies from 1997 [33] and 2008 [21]. This geographical and temporal diversity reflects a growing global interest in fasting and DI, practices deeply rooted in various cultural and religious traditions, and their potential impact on periodontal health, SG physiology, and OSCC. The involvement of research teams from different biological and environmental contexts also underscores the broad relevance of dietary strategies as experimental or adjunctive approaches in oral health and oncology.

As summarized in Fig. 2, the findings of this systematic review indicate that DI such as IF and CR are associated with oral and metabolic changes. These approaches appear to promote periodontal health [3, 21, 28, 31, 34], preserve SG integrity [14, 30, 35], and may enhance therapeutic response in OSCC experimental models [4, 7, 32]. However, KD did not improve periodontal parameters or SG function [8, 9], and findings remain inconsistent.

Periodontal disease and oral microbiota

PD is a chronic, multifactorial, inflammatory disease affecting approximately 20–50% of the global population and represents one of the leading causes of tooth loss [2, 3, 16, 36]. Its etiology is multifactorial, involving microbial, immunological, environmental and lifestyle-related factors such as oral hygiene, smoking, stress, and diet [3, 36]. Emerging evidence suggests that nutrition plays a role in modulating periodontal inflammation [2, 36]. Diets rich in refined sugars and saturated fats promote dysbiosis and inflammatory responses, whereas antioxidant nutrients-such as vitamins A, C, D, and E, polyphenols, and omega-3 fatty acids-have been shown to exert protective effects against gingival inflammation [36].

Malnutrition does not directly induce PD but increases both its susceptibility and clinical severity [6]. Oxidative stress, which arises from an imbalance between reactive oxygen species production and antioxidant defense mechanisms, plays a central role in periodontal tissue destruction and disease progression [2, 6]. Pro-inflammatory diets high in refined sugars and saturated fats exacerbate this imbalance, while polyunsaturated fatty acids and antioxidant-rich foods support redox homeostasis [6].

CR has been shown to attenuate both systemic and local hyperinflammatory states associated with PD, potentially slowing disease progression [2, 10]. Proposed mechanisms include reduced oxidative stress, downregulation of insulin and IGF-1 signaling, and enhanced cellular repair and autophagy [10]. Similarly, IF appears to confer biological effects in experimental studies by being associated with oxidative stress reduction and modulation of inflammatory mediators, as well as by activating AMPK and sirtuin signaling pathways (SIRT1, SIRT3, SIRT6), inhibiting mTOR, and improving insulin sensitivity [29]. The available literature supports these findings, consistent with the results reported by Branch-Mays et al. [21], Soares et al. [3, 34], Pappe et al. [31] and Lira-Junior et al. [28] in this review. Although these mechanisms are supported by experimental studies, most evidence remains preclinical or derived from small pilot clinical studies, highlighting the need for robust clinical validation.

KD has been proposed as another nutritional approach with potential anti-inflammatory and immunomodulatory properties, characterized by reductions in IL-1β, IL-6, TNF-α, and CRP, and increased regulatory T-cell activity [36]. In PD, bacterial biofilm induces recruitment of neutrophils, macrophages, and T lymphocytes, which release pro-inflammatory cytokines [36]. These mediators activate osteoclasts, promote bone resorption, and impair fibroblast regeneration, leading to periodontal tissue destruction [36]. KD may mitigate this inflammatory cascade by lowering the expression of IL-1β, TNF-α, cyclooxygenase-2, NF-κB, and macrophage inflammatory protein 2 [36]. Reducing systemic and local CRP and other inflammatory mediators could limit osteoclast activation, suggesting a protective effect of KD on periodontal tissues and alveolar bone integrity [36]. Nevertheless, current findings are inconsistent. Shaw et al. [37] observed elevated regulatory T-cell counts and reduced salivary IgA levels following short-term KD adaptation in a randomized trial (n = 8), indicating possible immune modulation. In contrast, Woelber et al. [9] found no significant improvement in periodontal parameters in a six-week pilot study involving 20 patients. These discrepancies highlight the heterogeneity of available studies and emphasizes the necessity for standardized, well-controlled clinical trials.

Overall, current evidence supports possible beneficial associations of CR and IF on periodontal health. In contrast, data regarding KD remain inconsistent and inconclusive.

Salivary glands and Sjögren’s disease

Sjögren’s disease is a chronic systemic autoimmune disorder characterized by lymphocytic infiltration and progressive destruction of the salivary and lacrimal glands, resulting in impaired secretory function and autoantibody production [14]. Clinically, Sjögren’s disease manifests with xerostomia and keratoconjunctivitis sicca as its most prevalent symptoms. Histopathologically, leukocytic infiltration, tissue destruction, and the accumulation of senescent cells are frequently observed within the SGSC/progenitor cell compartments, which compromise regenerative capacity and exacerbate glandular dysfunction [35].

IF, particularly ADF, has been shown to induce a metabolic shift from glucose to fatty acid utilization, modulate immune responses, eliminate senescent cells, and promote tissue regeneration [35]. The underlying mechanisms involve multiple interconnected pathways. Fasting promotes apoptosis-mediated clearance of senescent cells [35], thereby reducing tissue dysfunction [35], and inhibits activation of the NLRP3 inflammasome [35], a key mediator of chronic inflammation. Metabolic reprogramming toward lipid oxidation improves cellular energy efficiency and reduces oxidative stress. Additionally, fasting decreases effector T-cell trafficking through modulation of the CXCR3/CXCL9/11 chemokine axis [14], and downregulates proinflammatory cytokines such as IFN-γ, IL-17, and TNF-α [14]. Anti-inflammatory pathways are activated, including PPARγ signaling, which contributes to immune regulation [14]. Finally, fasting upregulates epithelial markers AQP5 and Claudin-1, supporting both secretory function and epithelial barrier integrity in affected tissues [14].

The main immunometabolic and anti-inflammatory pathways underlying the effects of IF on SG are summarized in Fig. 3.

Fig. 3.

Immunometabolic and anti-inflammatory effects of IF in SG. The arrows represent proposed mechanistic associations based on experimental observations and do not imply direct causality

Collectively, ADF appears to induce beneficial physiological and immunometabolic changes in experimental models, including increased salivary flow and glandular function, reduced inflammation and immune infiltration, downregulation of Th1/Th17 responses, and partial restoration of epithelial homeostasis without affecting autoantibody production [14]. These findings provide an experimental rationale for considering IF as a potential investigative DI in Sjögren’s disease and other autoimmune exocrinopathies.

Nevertheless, the available evidence remains scarce and partially inconsistent. Barzotti et al., reported that although ADF preserved glandular structure and function, it failed to improve salivary output or connective tissue composition and even induced moderate oxidative stress, suggesting a potential imbalance in antioxidant defenses [30].

KD has also been investigated for its effects on SG. Aboulfotoh [8] demonstrated, for the first time, that KD significantly alters the morphology of submandibular SG, leading to cellular vacuolization, amyloid deposition, and α-SMA overexpression. Conversely, chitosan, a natural polysaccharide derived from crustacean shells, exerted protective effects by promoting tissue regeneration, modulating extracellular matrix remodeling, and preventing pathological deposits [8]. Consistent with these experimental findings, recent clinical observations suggest that KD may be associated with reduced salivary flow. Al Taher et al. reported that KD may lead to decreased saliva production, thereby impairing its essential cleansing and buffering functions. Reduced salivary secretion has been associated with xerostomia, increased erosive activity, and a higher susceptibility to PD and other oral health complications [36].

All currently available studies on the impact of DI on SG were included in this review, indicating that this field is still in an early stage of investigation. Most of the available evidence derives from short-term, preclinical experiments with small sample sizes, which limits the generalizability of the findings. Therefore, large-scale, well-controlled clinical trials are necessary to clarify the effects of DI in exocrine gland disorders such as Sjögren’s disease.

Oral squamous cell carcinoma and its therapies

OSCC is a severe and relatively frequent malignancy with poor prognosis at advanced stages [4, 7, 11, 38]. The current standard of care-combining radiotherapy with platinum-based chemotherapy, particularly cisplatin, is limited by substantial toxicity and is not suitable for all patients [7].

Preclinical studies have demonstrated that fasting exerts antiproliferative effects in experimental cancer models and can potentiate the efficacy of anticancer therapies [4, 5, 26]. In vitro and in vivo models across various cancer types have shown that fasting may enhance the cytotoxic effects of chemotherapy while reducing oxidative stress in normal cells [5, 17, 22]. In murine models, fasting or FMD were reported to delay tumor progression in experimental setting [5, 25], improve responses to chemotherapy, radiotherapy, and immunotherapy [25], reduce systemic toxicity, and strengthen antitumor immunity by activating dendritic cells and cytotoxic CD8⁺ T cells while decreasing regulatory T-cell populations [22].

These effects are largely attributed to the metabolic differences between cancer and normal cells, where cancer cells are often highly dependent on continuous glucose and amino acid supply [4]. In contrast, normal cells may activate adaptive stress responses and reduce proliferation under nutrient deprivation [4, 13, 15].

Fasting induces reductions in glucose and IGF-1 levels [4, 5, 17, 25, 26], leading to the inhibition of growth-promoting signaling pathways and activation of cytoprotective mechanisms [4, 20]. This metabolic shift toward ketosis, characterized by elevated β-hydroxybutyrate levels, can also be mimicked through KD [23]. Based on the preferential glucose utilization of cancer cells, KD has been proposed to suppress tumor growth and enhance the effects of PI3K-targeted therapies. However, emerging evidence suggests that certain tumor types may use β-hydroxybutyrate as an alternative energy substrate, challenging the universality of these findings [22].

Despite these preclinical insights, clinical translation remains limited and challenging. Implementation of diets in cancer patients is hindered by poor adherence, risk of malnutrition, and treatment-related fatigue. In the clinical study by Ma et al. [7], only one-third of patients were able to maintain KD despite enteral feeding support. Adverse events such as nausea, fatigue, hyperuricemia, and acute pancreatitis were reported, highlighting significant feasibility and tolerability issues when combined with standard chemoradiotherapy [7]. Therefore, while DI show preclinical rationale, their clinical evidence remains insufficient to support routine clinical application [7]. However, these limitations are not uniform across all dietary strategies. Vernieri et al. [20] reported that a cyclic FMD administered alongside standard antitumor treatments may be feasible under controlled conditions, with good adherence and a low incidence of severe adverse events when strict eligibility criteria and close clinical monitoring were applied [20].

Collectively, these preclinical and early clinical studies suggest that fasting and CR may influence tumor biology and treatment response in experimental models of HNSCC. However, the current level of clinical evidence remains insufficient, and these interventions should currently be considered experimental rather than therapeutic strategies. The limited tolerability observed in KD-based interventions underscores the need for safer, more feasible, and better standardized nutritional strategies in oncology.

Methodological limitations

While this review highlights the potential effects of DI on PD, SG function and OSCC therapy response, several limitations must be acknowledged.

First, risk-of-bias assessment identified important methodological shortcomings across the included studies, particularly in preclinical in vivo research. These included insufficient reporting of randomization and allocation procedures, lack of blinding in outcome assessment, and small sample sizes, all of which increase the risk of selection, performance, and detection bias and may have led to an overestimation of effects.

In addition, the predominance of animal and in vitro studies limits the direct translatability of the findings to humans. Although experimental models provide important mechanistic insights, physiological differences between rodents, non-human primates, and humans must be considered when interpreting the potential clinical relevance of DI in oral health.

Clinical studies are also limited by small sample sizes, short follow-up periods, lack of randomization, highly specific populations, absence of long-term monitoring, and, in some cases, the lack of a control group. Nevertheless, this broad inclusion strategy was intentionally adopted because of the current scarcity of clinical evidence available in this emerging field.

Regarding SG, all currently available studies were included in this review, indicating that this field of research remains at an early stage of development. The scarcity of data, predominance of animal models, and lack of standardized outcome measures limit the extrapolation of these findings to clinical settings.

Furthermore, substantial methodological heterogeneity was observed across studies, particularly in terms of dietary duration, dietary composition, and outcome assessment methods. There is no consensus on the optimal DI, or target population, particularly in the context of PD, autoimmune glandular diseases and OSCC.

Finally, although a comprehensive database search was performed, publication bias cannot be excluded, and studies not published in English or in French, or not indexed in selected databases may have been overlooked.

Taken together, these limitations emphasize the need for large-scale, well-designed clinical trials to better evaluate the therapeutic potential of DI in oral health.

Conclusion

This systematic review highlights the emerging role of CR and IF as potential modulators of inflammation, tissue regeneration, and metabolic adaptation in various fields of oral health, including PD, SG disorders, and OSCC. Although current evidence is promising, it remains predominantly preclinical, heterogeneous, and limited by small sample sizes, short follow-up periods, and the lack of standardized DI protocols.

Future research should aim to overcome current methodological limitations by conducting large, well-designed clinical trials to further evaluate the effects of CR and IF on PD, SG disorders, and OSCC. Standardisation of DI, outcome measures, and follow-up duration is imperative to enhance the comparability and reproducibility of research findings across studies.

Moreover, mechanistic studies in human populations are urgently needed to elucidate the metabolic, immunological, and microbiota-related pathways that may mediate these effects. Such progress is necessary before considering any clinical translation and could ultimately clarify the potential role of nutritional interventions in oral disease management.

At present, these approaches should be considered experimental and not established therapeutic strategies, pending robust clinical validation.

Abbreviations

PD

Periodontal disease

SG

Salivary gland

OSCC

Oral squamous cell carcinoma

DI

Dietary intervention

IF

Intermittent fasting

CR

Caloric restriction

FMD

Fasting-mimicking diet

KD

Ketogenic diet

IGF1

Insulin-like growth factor 1

BOP

Bleeding on probing

PPD

Periodontal probing depth

STF

Short-term fasting

HNSCC

Head and neck squamous cell carcinoma

ADF

Alternate-day fasting

GCF

Gingival crevicular fluid

NOD

Non obese diabetic

SGSC

Salivary gland stem cells

SCC

Squamous cell carcinoma

Authors’ contributions

Conceptualization, M.P. and S.B. ; methodology, M.P ; validation, M.P. and S.B.; investigation, M.P. ; resources, M.P. ; data curation, M.P. ; writing—original draft preparation, M.P. ; writing—review and editing, M.P., A.Q., KJ.F., S.J., M.O. and S.B. ; visualization, M.P. ; supervision, S.B. ; project administration, S.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data availability

Data are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.