Associations between dental caries and systemic diseases: a scoping review

The objective of this study was to evaluate and present evidence from animal and human clinical studies on associations between dental caries and systemic diseases, and to suggest potential mechanisms that might explain such associations. An electronic search was conducted of PubMed, Embase and Cochrane Central Register of Controlled Trials for articles published from 2010 to 2020 in the English language. From the initial search, 404 full-text studies were assessed for eligibility. After excluding studies for technical and study limitations, a total of 67 studies were included in the summary tables and additional studies were included in the review to support evidence. Few systemic disease and conditions were found to be clinically meaningfully associated with caries experience. Best evidence from human and animal studies described association between metabolic diseases and dental caries. Several interesting animal studies were noted that could generate clinical hypotheses and further investigations in rodent models for cardiovascular injury and hyperglycemia. Inadequate data was found to suggest any modifications to current clinical practice or prevention guidelines. Limited clinical evidence was found connecting several systemic diseases and dental caries. Inadequate data was found to suggest any modifications to current clinical practice or prevention guidelines. Understanding of associations between dental caries and systemic diseases play a crucial role in the treatment planning and education of the dental patient.


Background
Dental caries is one of the most prevalent conditions worldwide [1] and accounts for significant morbidity [2]. Importantly, the prevalence of untreated dental caries has increased [1,2]. While there is a direct effect of untreated dental caries on oral health and associated quality of life, identification of indirect associations between dental caries (including untreated dental caries) and systemic health are of potential interest but have received little attention [3].
Associations have been more studied between periodontitis and systemic diseases and the contribution of oral inflammation and microbiota to diseases such as atherosclerosis, diabetes mellitus, pneumonia, chronic obstructive pulmonary disease, rheumatoid arthritis (RA) and Alzheimer disease (AD) [4][5][6]. In addition to epidemiologic evidence, laboratory and animal studies provide biological plausibility for periodontal-systemic associations [7,8].
While both dental caries and periodontitis are biofilm-mediated diseases, the pathogenesis of dental caries is complex and multifactorial and differs from periodontal disease. Dental caries is a biofilm-mediated disease with multiple contributing factors that drives net localized demineralization of the teeth [9]. The plausibility of systemic consequences from untreated dental caries and mechanistic role of the associated oral microbial-inflammatory process in these associations requires further inquiry through human and animal studies. The ability of oral microbiome to spread into systemic circulation from dental caries is plausible and would parallel mechanisms already studied for periodontal disease. In dental caries, involvement of root canal space or marginal periodontium are the most likely pathways for direct systemic extension of oral microbiota [10]. Host factors and pathogenic traits in oral microbiota can promote dental caries and increase the likelihood of oral-systemic spread. Such factors would include diseases [11] and medications [12] that result in reduced saliva production, adhesin expression in S.mutans for collagen binding [13][14][15], dysbiosis of the oral microbiota [16,17], genetic factors that predispose to dental caries and share common mechanistic underpinnings with systemic diseases [18].
The hypothesis of systemic spread of oral microbiota from carious lesions is reasonable but mechanisms by which systemic diseases exacerbate dental caries requires considerable future research. Metabolic diseases such as diabetes and obesity share various common environmental determinants with dental caries, including hyperglycemic state and high-carbohydrate/ sugar-rich diet [19]. Our current understanding of metabolic disease-dental caries associations and use of animal models [20][21][22][23][24][25][26][27] can serve to expand understanding of associations between dental caries and other systemic diseases. Animal models allow for study of systemic variables in dental caries due to the ability to longitudinally study disease phenotype within a reasonably short time frame.
This scoping review compiled and evaluated recent evidence from animal and clinical human studies that assessed associations between dental caries and systemic diseases and potential mechanisms for such associations. Specifically, a scoping review was undertaken to establish areas in which evidence on associations between dental caries and systemic diseases is available [28].

Data sources
An electronic search was conducted by a health sciences librarian (ES) in June 2021 in PubMed, Embase and Cochrane Central Register for Controlled Trials. Results were limited to articles published from 2010 to 2020 in the English language.

Search strategy
The following search strategy in PubMed utilized both keyword terms in the title and abstract fields as well as Medical Subject Headings (MeSH) to identify possible qualifying articles: ((((("dental caries" [ This search was translated and updated for Embase and Cochrane Central Register of Controlled Trials accordingly.

Data filtering
The results obtained using search strategy described above were deduplicated and further managed in an online workflow management system for scientific reviews (https:// www. covid ence. org/). After removal of duplicates, titles were examined by one author (AS) and articles unrelated to dental caries were removed. For retained articles, after title-based filtering, their eligibility was assessed by abstract-based filtering by two authors (AS and FAS). If articles were considered unrelated to scope of this review using criteria identified below, they were excluded. Articles were removed for various       varied inversely to body weight and the differences between groups for DT and FT were statistically significant; reduced prevalence of dental decay in obese children was significant for both primary and permanent dentition but was comparably less in permanent teeth than in primary teeth Conclusion: An inverse relationship between obesity and dental caries argues against the hypothesis that sugar is necessary and sufficient for dental decay and is a leading co-factor in obesity. The reasons for the inverse relationship noted in this study are not entirely clear Hall-Sculin et al. [47] Evaluate association between caries (DMFT) in late childhood (7-9 years) and obesity (BMI) in adolescence (   waist circumference (p < 0.001) and waist-hip ratio (p < 0.001) than girls; children brushing less than once daily had significantly higher BMI, waist circumference and waist-hip ratio than those brushing at least once daily (p < 0.05); parental education was associated with prevalence of dental caries (p < 0.01), SiC index prevalence (p < 0.05) and mean DMFT (p < 0.01); dental caries experience was associated with adiposity and there was a significant correlation between DMFT and waist-hip ratio (p = 0.03); regression models identified that dental caries was associated with    Swaminathan et al. [62] Determine correlation between BMI (overweight and underweight) and dental caries (DMFT/DEFT) in 3-12-year-old schoolchildren (2 subgroups by age: 3-5; 6-12).
Cross sectional 2200 India Outcomes: No significant differences were found for dental caries between overweight and underweight groups (by BMI) Conclusion: No association between BMI and dental caries was found in children in both primary and mixed dentition stages.

Location of study Outcomes and conclusions
Nakahara et al. [22] Animal study to evaluate if hyperglycemia induces periodontal inflammation by comparing results between T1DM diabetic rats (n=30, 10 each in 3 groups) and non-diabetic rats (n=30, 10 in each group) administered variable concentrations of fluoride. Also, a T2DM mouse model (n=30, 10 in each group) was compared with non-diabetic mice (n=30, 10 in each group).
Outcomes: In T1DM rat model, fluoride treatment significantly reduced dental caries, gingivitis and marginal periodontitis in 10 and 50ppm fluoride groups when compared to no fluoride group (p < 0.01); the T2DM mouse model, similar results were noted; in fluoride-untreated diabetic rats and mice, marginal periodontitis was always accompanied by moderate caries and alveolar bone resorption or marginal periodontitis was not noted in the absence of caries, regardless of diabetic status Conclusion: Long-term hyperglycemia induces dental caries but not periodontal disease in type 1 and 2 diabetic rodent models Nakahara et al. [23] Animal study to evaluate dental caries and periodontal disease in an alloxan induced hyperglycemia (T1DM) rat model (n=30) compared with nondiabetic group (n=17) Outcomes: Caries score was worse in diabetic group when compared to non-diabetic group; caries severity worsened with age with significantly higher scores at 26 weeks for maxillary (p < 0.05) and mandibular (p < 0.01) teeth when compared to 13 weeks; mean caries score was significantly higher in mandibular molars when compared to maxillary molars at 13 and 26 weeks (p < 0.05 and p < 0.01 respectively); alveolar bone resorption was significantly higher in mandible compared to maxilla after 26 weeks (p < 0.01) in diabetic group and alveolar bone resorption was noted adjacent to carious molars only; positive correlation was noted between alveolar bone resorption and caries score for both maxilla and mandible (p < 0.01 each) Conclusion: Alloxan-induced severe hyperglycemia can cause rapid and progressive dental caries and periodontitis in diabetic rat models

Location of study Outcomes and conclusions
Nakahara et al. [24] Animal study (n=60, 15 in each group) to evaluate relationship between hyperglycemia and dental caries and preventive effect of glycemic control on progression of caries in diabetic rat model by comparing four groups [spontaneous diabetes-with (INS) and without (C) insulin intervention, alloxan induced diabetes with (AL+INS) and without insulin intervention (AL)] Outcomes: Mean caries score and mean bone resorption of the maxilla were significantly lower (p < 0.01 each) in the INS group when compared to C group; mean caries score and mean bone resorption were significantly lower (p < 0.01 each) in the AL+INS group when compared to AL group; positive correlation was noted between alveolar bone resorption and caries scores (p < 0.01 for both maxilla and mandible); incidence of marginal periodontitis was significantly lower in INS and AL+INS groups when compared to C and AL groups (p < 0.05 and p < 0.01 respectively); no periodontal lesions were noted adjacent to a non-carious molar and non-carious molars were comparable in C and INS groups Conclusion: Glycemic control by insulin prevented occurrence and progression of dental caries and caries-related periodontitis in spontaneously and alloxan induced rodent diabetes model, suggesting that hyperglycemia may be a major factor influencing the development of dental caries Nishimoto et al. [25] Animal study (n=23, n=13 in diabetic group and n=10 in non-diabetic group) to evaluate relationship between hyperglycemia and early dental caries (7 weeks after alloxan administration) and the role of saliva and salivary glands in a rat diabetes model Outcomes: Mean weight of saliva (after pilocarpine administration) was significantly lower in diabetic group when compared to non-diabetic group at all time points of sample collection (p < 0.01); mean cusp height of molars (a measure of wear) in the diabetic group was approximately half that of nondiabetic group and that difference was significant (p < 0.01) as was the incidence and severity of caries; the incidence and severity of histologic change in diabetic group was significantly more than non-diabetic group (p < 0.01) and this change was predominantly in terms of vacuolation of acinar cells Conclusion: In this rodent diabetic model, hyperglycemia induces initial caries development and enhances occlusal wear. Also, parotid gland dysfunction may be involved in pathogenesis of occlusal wear and caries

Location of study Outcomes and conclusions
Sano et al. [26] Animal study to determine if diabetes affects onset and progression of dental caries and periodontal disease over long follow up (20 to 50 weeks). Also, clinical presentation of caries and periodontal disease in a rodent diabetic model were studied by comparing diabetic and non-diabetic mice Outcomes: Significantly higher incidence and severity of dental caries was noted in diabetic mice at 30 to 50 weeks of follow ups when compared to non-diabetic mice (p < 0.05 at 30 and 40 weeks and p < 0.001 at 50 weeks); mean caries score was significantly higher (p < 0.001) in diabetic mice when compared to non-diabetic mice; severity of gingivitis was positively correlated with severity of molar caries (p < 0.001 for both genders and both jaws) Conclusion: There is a strong relationship between diabetes and dental caries in this rodent diabetes model. It is possible that onset of periodontal disease was secondary to dental caries Yeh et al. [27] Animal study to elucidate mechanisms of dental caries by studying type 1 diabetic mice model with point mutation in Ins2 gene and clinically demonstrates hyperglycemia and xerostomia. The disease model mice were compared with wild-type littermates Outcomes: Mouse model for type 1 diabetes showed progressive changes in tooth appearance and wear when compared to wild type mice. No differences were noted in tooth development, suggesting these changes occurred due to hyperglycemia and xerostomia. In salivary glands, saliva production was little to none in type 1 diabetic mice after pilocarpine stimulation demonstrating significant xerostomia. Conclusion: Hyperglycemia and xerostomia in type 1 diabetes mouse model leads to excessive dental wear and demineralization.     technical reasons such as wrong outcome measures, inadequate statistical information, narrow participant enrollment such as studies with one gender enrollment. Articles that were published in potentially predatory journals were also removed if the corresponding journal was listed in Beall's list (https:// beall slist. net/) and was not listed in the Directory of Open Access Journals (https:// doaj. org/). When articles were on the topic of associations between dental caries and systemic diseases, systematic and retrospective reviews and data analysis of health records were excluded. Studies were also excluded if dental caries was not the primary variable and was studied as a subset of oral health and/or systemic disease was studied as a subset of overall health. In addition, infective endocarditis was removed from our search criteria as it has been extensively reviewed previously.
Clinical human and animal studies were included where associations between dental caries and a systemic disease were explored or a potential mechanism was elucidated and they did not meet any of the aforementioned exclusion criteria. Using the filtering criteria above and after full-text screening by two authors (AS and FAS) studies were included in the summary tables and additional studies were included in the review to support evidence. If one author agreed to inclusion after full-text screening, the corresponding article was included.
Individual studies were tabulated and brief description of the following parameters were provided: name of first author, year of publication, number of participants, country of study participants, study groups (treatment and control), study population (human or animal), objective of the study, study design, outcomes including statistical parameters and conclusions (Tables 1, 2, 3, 4, 5 and 6).

Results
After deduplication, the initial search yielded 4817 results. 404 full-text articles were assessed for eligibility and further 133 studies were excluded for various technical reasons described above. The remaining 271 full-text articles were assessed, and after excluding studies where dental caries and/or systemic disease was not the primary variable of interest, and excluding literature reviews and data analysis of health records, 67 studies were included in the summary tables.
Studies were included on the following systemic diseases: coronary artery disease (Table 1), congenital heart disease (Table 1), peripheral artery disease (Table 1), hypertension (Table 1), diabetes (type I and II) ( Table 2), obesity (Table 2), metabolic syndrome (Table 2), cystic fibrosis (Table 3), asthma (Table 3), ulcerative colitis (Table 4), Crohn's disease (Table 4), cerebral palsy (Table 5), attention deficit hyperactivity disorder (Table 5), rheumatoid arthritis (Table 6), systemic lupus erythematosus (Table 6) and chronic kidney disease (Table 6). A total of 56 human studies and 11 animal studies were included in the summary tables. Relatively, more studies on metabolic diseases (type I diabetes, type II diabetes, obesity and metabolic syndrome) were included in this review (40 total, 32 human and 8 animal) when compared to evidence found in other disease groups. Within 56 human studies included, 29 studies were case-control, 17 were cross sectional and 10 were longitudinal studies.

Cardiovascular diseases and caries
Dental caries experience was not significantly different when compared to controls in human studies of coronary and peripheral arterial disease, but overall oral inflammatory burden was significantly higher in cases due to increased burden of periodontal disease [29,31]. Additionally, one study compared dental caries in patients with congenital heart disease with and without heart transplants, thus comparing the effect of immunocompromised status on dental caries [30]. Interestingly, transplant group had significantly lower caries experience when compared to group without heart transplant. The authors explained this difference based on the possibility of increased attention to dental care in children with heart transplants. While frequent antibiotic intake could explain this observation, in this study it was an exclusion criteria due to possible confounding of results.
Other studies have evaluated attitudes of dentists and of parents of children who are at high risk for infective endocarditis [87] including those with congenital heart disease [88][89][90]. These findings suggest that specialists in pediatric dentistry and general practitioners who regularly treat children are more informed about appropriate dental care for children with congenital heart disease. There needs to be a concerted effort between the dentists, medical providers and parents to encourage prevention to achieve favorable outcomes in children at high risk for infective endocarditis due to their cardiac conditions.
More atherosclerotic plaque and presence of genomic DNA from S.mutans was found in a group of ApoE null mice, infected by intravenous injection (tail vein) of S.mutans and subjected to balloon angioplasty injury compared to non-injured mice (controls) [33]. Immunohistochemically, sections of atherosclerotic plaque from injured group showed macrophage invasion in the tunica adventitia of aorta and upregulation of TLR4. Further studies demonstrated that collagen-binding protein (cnm) is important for invasive potential of S .mutans [13]. Specifically, it was found that serotype f strain OMZ175 of S. mutans has this capability [91]. These studies further explores the invasive nature of serotype f strain OMZ175 of S. mutans in a model of cellular injury.
While experimental data on the invasive potential for certain serotypes of S. mutans exists, expert panels do not recommend antibiotic prophylaxis prior to all dental procedures. The rationale behind such an approach is that the likelihood of developing infective endocarditis due to a bacteremia from dental procedure is significantly lower than bacteremia from routine at-home toothbrushing and flossing. Furthermore, it is not clear if antibiotic prophylaxis prior to dental procedures will prevent all potential for infective endocarditis secondary to dental procedures. In this scenario, the risk-benefit analysis appears to be of low benefit and high risk, taking into account the potential for antibiotic resistance. A recent meta-analysis of randomized controlled trials showed vesicoureteral reflux patients treated with antibiotic prophylaxis were 6.4 times more likely to develop a multidrug-resistant urinary tract infection [92]. It is reasonable to use conclusion from this study and exercise caution in frequent antibiotic prophylaxis for dental procedures till directly applicable results are available in the dental literature. While caution must be exercised, there are exceptions and it is thought that patients in certain high-risk categories may benefit from antibiotic prophylaxis [93].
Ostalska-Nowicka et al. found association of dental caries with primary hypertension in a case-control study [32]. Authors found significantly higher salivary evening cortisol levels, uric acid concentrations in participants with caries and also found correlation between dental caries and microalbuminuria. These biochemical parameters are of importance in pathophysiology of hypertension and indicative of activation of renin-angiotensin system and reorganization of endothelium [32]. Considering the multifactorial nature of dental caries and hypertension, future studies that evaluate social determinants, diet and systemic inflammation secondary to oral and gastrointestinal dysbiosis may provide valuable input into common mechanisms of dental caries and primary hypertension [94][95][96][97].

Metabolic disorders and caries Diabetes
Several human clinical studies and animal studies have addressed the connection between dental caries and diabetes. Outcomes other than caries were also studied, including salivary composition, microbiology and periodontal status. Hegde et al. found that caries active participants who were diabetic demonstrated significantly reduced salivary calcium and significantly increased alkaline phosphatase when compared to caries active non-diabetic participants [34]. Similarly, Al-Badr et al. demonstrated that children with type 1 diabetes had significantly lower salivary pH and higher counts of Lactobacilli. Reduced salivary pH and higher lactobacilli count are crucial factors for demineralization of teeth and exacerbation of dental caries [38]. Reduction in salivary pH and increase in counts of cariogenic microbiota can occur secondary to cariogenic diet and poor plaque control and was demonstrated as such by Kamran et al. [39] and therefore, it is important to emphasize the multifactorial and overlapping nature of dental caries and obesity before drawing conclusions from study of select variables. Furthermore, studies into the association of diabetic control and other parameters of diabetes phenotype with dental caries will increase our understanding of risk stratification and consequently, prevention of dental caries in diabetic patients [40,41]. Two other studies showed that lifestyle, dietary and oral care factors were significantly different between groups with controlled and uncontrolled diabetes measured by glycated Hb [35,36]. Similarly, when pediatric cohort with phenylketonuria and those with type 1 diabetes were compared, children with phenylketonuria had significantly higher caries experience [37].
Animal studies used rodent models of diabetes (primarily type 1 diabetes) and hyperglycemia to study its relationship with dental caries and other tooth-related changes [20][21][22][23][24][25][26][27]. Changes in enamel, dentin, pulp and salivary glands with alveolar bone loss were compared, both to control groups and groups with intervention using fluoride application and insulin administration. Consistent results from animal models demonstrated that hyperglycemia in diabetic rodents was associated with increased dental caries [22][23][24][25][26]. In addition, these studies showed that there were histological and morphometric changes in enamel, dentin and pulp in diabetic animals. There were reduction in volume of pulpal connective tissue and enamel and dentin, along with excessive wear of enamel [20,21,25,27]. Salivary histological change included vacuolization in acinar cells and functionally, reduction in saliva production that resulted in xerostomia [25,27]. Carious lesions positively correlated with gingivitis and periodontitis [23,26]. Lastly, both fluoride application and insulin administration interventions resulted in reduction of dental caries, marginal gingivitis and periodontitis [22,24].

Obesity
Of all systemic diseases, an association between obesity and caries was more robust than noted for other systemic conditions, as documented in twenty-two human clinical studies including eight longitudinal clinical studies. Data from longitudinal studies did not consistently find an association between obesity and dental caries and studies with larger samples sizes did not find association between dental caries and obesity [42, 43, 47, 48, 51-53, 57, 58, 60, 62, 63]. In studies where obesity and metabolic syndrome were found to be associated with caries, odds ratio ranged from 1.01 to 3.7 [42,43,49,52,[63][64][65]. Interestingly, a relationship between low BMI and dental caries was noted and an inverse relationship between overweight status and caries was seen in some studies [44,46,58]. Chala et al., through statistical modeling found a U-shaped relationship between BMI and caries, which means that caries was associated with both underweight and overweight status [44] and this U-shaped relationship between BMI and caries has been reproduced in two recent studies. Untreated dental caries can impact overall nutritional status and subsequently BMI. Further, reduction in masticatory efficiency can promote intake of softer foods and increase in dental caries burden [56,61]. Longitudinal studies are needed to examine relationship between onset and progression of dental caries and their effect on BMI. A study showed significant weight gain in children when teeth with severe dental caries and pulpal involvement were extracted [98]. Mixed results on the association of BMI and dental caries are also indicative of the complex etiologic nature of dental caries. Various factors including access and attitude to dental care, socio-economic status, maternal education, oral habits, diet, biological and microbiological factors interact in caries etiopathogenesis [99]. Additionally, variable definitions and surrogate markers used in association studies further complicate consensus and ability to synthesize reproducible conclusions [100]. An important implication of the mixed results observed for caries association with systemic conditions likely results in lack of reliable, reproducible risk prediction tools for dental caries [101]. It appears that past and current caries experience along with frequent follow ups and use of fluoride for caries prevention remain the most effective tools for caries prevention in clinical practice.

Respiratory diseases and caries Asthma
Most human clinical studies were undertaken in pediatric cohorts and were case-control in design, aimed at comparing groups with asthma and caries to groups with caries alone. Caries burden was typically measured using DMFT/dmft and DMFS/dmfs indices along with other variables, including microbiological (S. mutans and Lactobacilli counts, oral microbiota assessment using 16 S sequencing) [68,69,74], medications [70], sugary diet [71], salivary parameters [72,74] and genetics [18]. Results reinforced previously discovered etiological factors for dental caries in children; namely, consumption of sugary drinks [71], higher S. mutans counts, higher plaque index in caries active children [68], and lower salivary flow rate and pH [72,74]. Other factors related to dental caries activity included tablet delivery of asthma medication [70], the abundance of Veillonella sp. [69] and SNPs of the ameloblastin gene (AMBN rs4694075) [18].
Heidari et al. explained the association of higher caries burden with asthma to the use of tablet form of asthma medication on grounds that tablet formulation delivers a higher drug dose when compared to syrup and spray forms of medications [70]. It is possible that these patients presented with severe symptoms of asthma and therefore required higher drug dose, but that information was not clearly presented. Other studies have shown an association between inhaled corticosteroids for asthma and higher burden of dental caries [73,102,103]. Additionally, while the duration of intake of medication was not associated with severity of caries in this study, there are other studies that found contrary results [68,104]. Cherkasov et al. found an increased relative abundance of Veillonella from dental biofilm in caries-affected children when compared to caries-free children with asthma [69]. While Veillonella is not considered a cause of dental caries like S. mutans, these results are not surprising. Veillonella can metabolize lactate which is produced in abundance by cariogenic streptococci in dental biofilms [105], and various studies have previously demonstrated increased levels of Veillonella in carious lesions [106][107][108][109][110].
Ergöz et al. found an association between AMBN rs4694075 and dental caries in asthmatics, which is an interesting finding. It should be noted that other genome wide association studies (GWAS) studies and GWAS meta-analyses arrived at differing conclusions [111,112]. Additionally, Ergöz et al. did not mention any dental developmental defects in their cases and so the potential of these being confounding factors may not be applicable. However, it may be argued that since mutations in ameloblastin (AMBN) and other dental development genes are related to dental developmental defects [113], clinical information on absence of dental developmental defects may be considered when evaluating and reporting genetic association of dental development genes and asthma.
While it appears that nature of the association of asthma with dental caries is uncertain, it is prudent to employ prevention strategies for dental caries in asthma patients [114,115].

Cystic fibrosis (CF)
Two human studies described an association between dental caries and CF [66,67]. These studies evaluated caries, molar-incisor hypomineralization, oral hygiene, diet and salivary factors in groups with and without CF.
Peker et al. noted lower caries experience (DMF-T) in CF patients, and suggested this could be related to frequent use of antibiotics [67]. Salivary factors studied were not significantly different between the groups. Contrary to human clinical studies, a CF mouse model showed significantly higher caries experience and significantly reduced salivary bicarbonate concentration in CF mice [75]. Although human salivary studies of CF did not show significant differences between controls and cases, interest in exploring salivary biochemical composition in CF patients is practical. CF is caused by mutations in the CFTR gene (CF transmembrane conductance regulator) which is a chloride and bicarbonate channel [116] and CFTR mRNA has been localized in the ductal cells of salivary glands [117]. In a mouse model with deletion of phenylalanine 508, significantly increased counts of S.mutans along with increased caries incidence and severity were noted. In the same mouse model, salivary bicarbonate concentration was significantly reduced when compared to wildtype littermates [75]. However, human studies on salivary parameters in CF patients do not consistently show low pH and higher caries severity and systematic review on this data has shown limitations in study design and high risk of bias [118].

Gastrointestinal diseases and caries
Limited clinical studies were found assessing a connection between caries and gastrointestinal diseases, including studies of inflammatory gastrointestinal diseases [76][77][78]. A human clinical study (case-control) showed that pediatric participants with inflammatory bowel disease had significantly more caries and periodontal inflammation than healthy participants [76,77]. Similar results in an adult cohort has been shown previously [119]. In another study, CD patients who had resective surgery demonstrated a greater caries experience, cariogenic microbiota, oral hygiene and poor diet when compared to controls [78]. In other studies, CD patients have demonstrated increased caries prevalence [77,119,120], increased sugar intake [121,122] and increased levels of S. mutans [123], one of the bacterial species strongly linked to caries activity. The presence of these factors creates a conducive environment for accelerated caries activity. Patients with IBD have shown increased odds for dental caries in a recent study, confirming previous results in aforementioned studies (4.27 for CD and 2.21 for UC) [77]. Kojima et al. undertook an interesting study using a colitis mouse model to study effects of a serotype of S. mutans. Results showed that serotype k of S. mutans was able to evade host response in peripheral blood due to variation in glucose surface side chains. Also, uptake of S. mutans by hepatocytes, which was potentially facilitated by collagen binding protein, aggravated colitis due to production of IFN-γ by liver [79].
S. mutans can be divided into four serotypes (c, e, f, k) and serotypes f and k predominantly carry the cnm gene. The presence of cnm gene confers a collagen binding property to specific S. mutans serotypes and has been demonstrated to be essential for invasiveness into human coronary artery endothelium [13]. In the study by Kojima et al., significantly more IBD patients showed cnm encoding S. mutans (serotype k or f). Of note, this study showed hepatocyte involvement by S. mutans as a crucial step in the colitis mouse model while S. mutans was undetectable in samples from the gut [79]. This observation suggests that oral microbiota may affect a disease state in an organ that it does not invade directly by modulating the inflammatory environment. These authors have published follow up studies, investigating the relationship between S. mutans serotype k and liver disease in mouse models. These studies showed aggravation of nonalcoholic steatohepatitis by a specific strain of S.mutans through participation of cell surface proteins, including collagen-binding protein [124,125].

Neurologic diseases and caries
Cardoso et al. studied dental caries burden in patients with cerebral palsy and noted that these patients had high prevalence of dental caries and mean DMFT/dmft values of 1.71 and 2.22 respectively. Further, they found that caregiver awareness and education was associated with dental caries experience in these patients (PR = 1.439) [80]. Control of dental biofilm in patients who are limited in their physical and mental capability is challenging [126,127]and becomes the collective undertaking of caregiver and dentist and thus, education of the caregiver plays a crucial role in achieving this collective goal [80]. Similarly, enhanced preventive measures can be extended in the geriatric population where compromised motor control and masticatory efficiency results in a shift to a softer diet and that along with exposed root surfaces further increases possibility of dental caries [128,129].
Delwel et al. raised an important point about composite nature of DMFT index, wherein caries experience (decayed component of DMFT) should be evaluated separately to assess caries burden and for statistical comparison between groups [130]. Overall, standardization in dental indices and utilization of semantics and ontology frameworks should enhance our ability for data analysis and draw robust conclusions.
In a case-control study of participants with ADHD, Paszynska et al. found significantly higher BMI in test group and significantly higher ICDAS 5 and 6 scores (teeth with advanced caries) in the primary dentition. They also found that increased intake of sugary foods and drinks were significantly higher in ADHD group [81]. It appears that in studies determining associations of dental caries with neurological and behavioral disorders, standardized interviews for caretakers, food habits and other social determinants will be crucial in order to draw informed conclusions and not extrapolate mechanistic links between systemic diseases and dental caries.

Other diseases and caries
In our review of literature, we found a few articles that could not be categorized by organ system and/or were not adequate in number to warrant their own section in this review. These diseases included RA, chronic renal diseases and systemic lupus erythematosus.
DMFT/DMFS were associated with RA as assessed by disease activity score and serologic markers. Also, S.mutans was significantly higher in RA patients and indices for oral inflammatory burden and disease were associated with serologic markers for RA. Furthermore, the oral inflammatory burden was significantly higher in early untreated RA when compared to chronic RA [82]. RA is a risk factor for both caries and periodontal disease [3]. The plausible link between compromised plaque control and joint dysfunction is reasonable but the contribution of RA to overall inflammatory burden is also an important consideration [131]. Active SLE patients showed increased dental caries activity including smooth surface caries when compared to inactive SLE. Furthermore, salivary pH and flow were significantly reduced and high counts of S.mutans were noted [84]. Another study showed relationship between compromised biofilm control, SLE severity and dental caries [85]. These results raise the possibility of SLE being coincidental in the direct relationship between poor oral hygiene and dental caries. In one study that explored associations between dental caries and chronic kidney disease (CKD), disease group demonstrated significantly higher CFUs of S.mutans and IgA response but significantly lower filled teeth when compared to controls [86]. Importantly, in this study, plaque index was similar between the two groups. Other studies have demonstrated lower dental caries in CKD patients [132,133] and proposed the need for longitudinal studies exploring association between dental caries and CKD.
Although evidence of the association between SLE, RA and dental caries is limited, risk stratification of patients in consultation with rheumatologist may facilitate preventive dental care. Determination of xerostomia in patients with SLE or RA is advised since these patients often have associated Sjögren's syndrome (secondary Sjögren's syndrome) and may experience higher dental caries burden secondary to xerostomia, requiring preventive measures [134]. Sjögren's syndrome is a chronic inflammatory autoimmune disease that usually involves exocrine glands including salivary glands [135]. Additionally, other risk factors such as past caries experience, ability to maintain oral hygiene if limited by joint dysfunction and root exposure commonly noted in elderly patients may help with development of a customized dental caries preventive care plan. Similarly, diet in patients with CKD tend to be carbohydrate rich and that along with poor oral hygiene can increase risk for dental caries [132]. In the caries prevention plan for patients with CKD, oral hygiene should be maintained meticulously through proper home care and periodic dental appointments.
The oral cavity has evolved with a symbiotic and diverse microbiota which serves under some circumstances as a safeguard against numerous environmental challenges [136]. Conditions that disrupt this balance include breach in mucosal defenses and acquisition of pathogenic species, or pathogenic traits by certain commensal microbiota. Examples of acute local infections that occur secondary to breach of mucosal barriers and/or colonization by pathogenic microbiota include dental abscess and lymphadenopathy. Dental caries may also influence a systemic response through direct extension of pertinent microbiota or resulting inflammation. A systemic exposure to effects of caries is also plausible through marginal caries that extends to the periodontium or by pulpal involvement. The systemic influence of dental caries both by direct extension of oral microbiota and creation of a pro-inflammatory state are reasonable hypotheses. However, the obvious challenge is to prove such hypothetical mechanisms by human studies. The chronicity of caries as a disease and the ethical challenges imposed by not treating dental caries are significant challenges for future studies.
We expect that mechanistic explanations of dental caries-systemic disease associations in future studies will likely come from animal models. Also, animal models can inform human studies on variables of interest. In this regard, longitudinal studies that are aimed at evaluating oral and systemic variables of interest in periods of accelerated dental caries in the human host will prove useful. This study is a scoping review and provides an overview of available evidence on the topic of associations between dental caries and systemic diseases. It has a wider scope and does not limit the analysis to one systemic disease. This analysis is not as rigorous as that offered by systematic reviews and meta-analyses and the information presented should be used in complement to systematic reviews and meta-analyses on this topic.

Conclusions
Limited clinical evidence was found connecting several systemic diseases and dental caries. When adequate clinical results were available, it offered mixed evidence of such associations. Interesting animal studies were noted that could generate clinical hypotheses and further investigations in rodent models for cardiovascular injury and hyperglycemia. Best evidence from human and animal studies described the association between metabolic diseases and dental caries. Animal studies using rodent models demonstrated significant changes in dental tissues following hyperglycemia. Also, an association between hyperglycemia and dental caries was consistently noted in animal studies. Inadequate data was found to suggest any modifications to current clinical practice or prevention guidelines.