The Bacteria Responsible for Dental Caries: Genetics versus Environment

Fiona Collins BDS, MBA, MA, FPFA, Ira Lamster DDS, MMSc, Editor-in-Chief

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The Bacteria Responsible for Dental Caries: Genetics versus Environment

Dental caries is a multifactorial, polymicrobial disease with environmental, behavioral and host risk factors.1Pitts NB, Zero DT, Marsh PD, Ekstrand K, Weintraub JA, Ramos-Gomez F, Tagami J, Twetman S, Tsakos G, Ismail A. Dental caries. Nat Rev Dis Primers 2017;25(3):17030. The presence of cariogenic bacteria and fermentable carbohydrates are prerequisites for dental caries, with bacterial metabolic activity resulting in the production of acid that can demineralize dental hard tissues.1Pitts NB, Zero DT, Marsh PD, Ekstrand K, Weintraub JA, Ramos-Gomez F, Tagami J, Twetman S, Tsakos G, Ismail A. Dental caries. Nat Rev Dis Primers 2017;25(3):17030.

The initiation and progression depends on the balance between destructive and protective factors, and whether demineralization outpaces remineralization.1Pitts NB, Zero DT, Marsh PD, Ekstrand K, Weintraub JA, Ramos-Gomez F, Tagami J, Twetman S, Tsakos G, Ismail A. Dental caries. Nat Rev Dis Primers 2017;25(3):17030.,2Featherstone JD. The caries balance: the basis for caries management by risk assessment. Oral Health Prev Dent 2004;2(Suppl 1):259-64. Genetics also plays a role and may influence host susceptibility by influencing tooth structure, salivary status, taste perception and host response to cariogenic bacteria.3Shuler CF. Inherited risks for susceptibility to dental caries. J Dent Educ 2001;65(10):1038-45.,4Opal S, Garg S, Jain J, Walia I. Genetic factors affecting dental caries risk. Aust Dent J 2015;60:2-11.,5Bretz WA, Corby PM, Melo MR, Coelho MQ, Costa SM, Robinson M, Schork NJ, Drewnowski A, Hart TC. Heritability estimates for dental caries and sucrose sweetness preference. Arch Oral Biol 2006;51(12):1156-60.,6Nibali L, Di Iorio A, Tu YK, Vieira A. Host genetics role in the pathogenesis of periodontal disease and caries. J Clin Periodontol 2017;44:S18:52-78.,7Lips A, Antunes LS, Pintor AVB, dos Santos DAB, Bachinski R, Küchler EC, Alves GG. Salivary protein polymorphisms and risk of dental caries: a systematic review. Braz Oral Res 2017;31:e41. Recent research has resulted in a better understanding of the influence of environmental factors and host genetics on the microbial risk for dental caries.

Genetics and microbial risk

A review of studies published between 1959 and 2013 examined genetic factors that may influence risk for dental caries.4Opal S, Garg S, Jain J, Walia I. Genetic factors affecting dental caries risk. Aust Dent J 2015;60:2-11. It was concluded that both genetics and environmental factors contribute to the development of dental caries in a complex manner, with the environment and interplay of genes determining the nature of the tooth surface, salivary constituents, and the immune response. In a study of more than 200 twins with and without dental caries, the abundance of microbial species in dental biofilm was heritable (i.e., influenced by genetics after adjusting for age and gender8Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, McNeil DW, Marazita ML. Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 2010;44:277-84.).9Corby PM, Bretz WA, Hart TC, Schork NJ, Wessel J, Lyons-Weiler J, Paster BJ. Heritability of oral microbial species in caries-active and caries-free twins. Twin Res Hum Genet 2007;10(6):821-8. In comparing children with and without dental caries, differences were found for 10 types of bacteria (p˂0.0001). It was concluded that this was due to familial and/or genetic factors. Other twin studies have found only a minor/no role for the genetic influence on the microbial components of dental biofilm or saliva, with one study concluding that the microbial communities associated with a caries-free status were similar in monozygotic and dizygotic twins.10Papapostolou A, Kroffke B, Tatakis DN, Nagaraja HN, Kumar PS. Contribution of host genotype to the composition of health-associated supragingival and subgingival microbiomes. J Clin Periodontol 2011;38:517-24.

In comparing children with and without dental caries, it was concluded that differences found for some bacteria were due to familial and/or genetic factors.

A recent cohort study with almost 500 individuals 5 to 11 years-of-age examined the influence of genetic and environmental factors on cariogenic bacteria in supragingival dental biofilm.11Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 2017;22:269-78 e263. The oral microbiome was similar for monozygotic (identical) and dizygotic (fraternal) twins, independent of the presence of caries. However, some differences were observed. Dental biofilm variations were usually similar for both identical twins, and less frequently similar for fraternal twins or unrelated individuals. The greatest genetic influence was found for Veillonella spp., while Prevotella pallens and Leptotrichia spp., which are also associated with a caries-free state, were also found to be heritable. Cariogenic bacteria, including Streptococcus mutans, were found to be largely influenced by environmental factors. These findings were in contrast to earlier studies in which S. mutans was determined to be significantly heritable, and this finding was attributed to the use of more advanced techniques that could assess microbial diversity.11Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 2017;22:269-78 e263.

Cariogenic bacteria, including Streptococcus mutans, were found in a recent cohort study to be largely influenced by environmental factors.

Gender and genetics

Genetics was found in one study to be a greater influence on dental caries in the primary detention in males, and different genes were important determinants of caries risk in the permanent dentition of males and females.12Shaffer JR, Wang X, McNeil DW, Weyant RJ, Crout R, Marazita ML. Genetic susceptibility to dental caries differs between the sexes: a family-based study. Caries Res 2015;49:133-40. In a twin study, the effect of gender on bacterial abundance was unclear, and the quantity of some microorganisms varied with age, including Veillonella and Streptococcus.13Stahringer SS, Clemente JC, Corley RP, Hewitt J, Knights D, Walters WA, Knight R, Krauter KS. Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood. Genome Res 2012;22:2146-52. A further assessment of the influence of genetics and gender included 2,600 children and adults. Fifty-four to 70% of the variation in caries experience in the primary dentition, and 35% to 55% of the variation in the permanent dentition, respectively, was attributed to genetics.8Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, McNeil DW, Marazita ML. Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 2010;44:277-84.

In a twin study, the effect of gender on bacterial abundance was unclear.

Microbial transmission and the environment

Colonization by Streptococcus mutans, the bacteria of primary concern in the development of caries, was determined in one study to be the result of transmission from those closest to the individual.14Momeni SS, Whiddon J, Cheon K, Ghazal T, Moser SA, Childers NK. Genetic diversity and evidence for transmission of streptococcus mutans by DiversiLab rep-PCR. J Microbiol Methods 2016;128:108-17. The children’s bacterial genotypes were shared with mothers (54%), siblings (46%) and cousins (23%; Figure 1). Further, 34 different genotypes of S. mutans were found, demonstrating bacterial diversity.

Figure 1. Sources/sharing of oral bacteria found in children


Further, a lack of vitamin D during pregnancy can result in enamel hypoplasia in offspring.16Kong Y-Y, Zheng J-M, Zhang W-J, Jiang Q-Z, Yang X-C, Yu M, Zeng SuJ. The relationship between vitamin D receptor gene polymorphism and deciduous tooth decay in Chinese children. BMC Oral Health 2017;17:111. Enamel hypoplasia is associated with ECC, and considered a prerequisite for severe ECC.17American Dental Association. Symposium on Early Childhood Caries in American Indian and Alaska Native Children, 2010. Vitamin D deficiency also negatively impacts the immune response to cariogenic bacteria in persons with untreated caries.16Kong Y-Y, Zheng J-M, Zhang W-J, Jiang Q-Z, Yang X-C, Yu M, Zeng SuJ. The relationship between vitamin D receptor gene polymorphism and deciduous tooth decay in Chinese children. BMC Oral Health 2017;17:111. Interestingly, a polymorphism for the vitamin D receptor was found to be associated with high caries rates and is one example of the complexity of environmental and genetic caries risk factors.16Kong Y-Y, Zheng J-M, Zhang W-J, Jiang Q-Z, Yang X-C, Yu M, Zeng SuJ. The relationship between vitamin D receptor gene polymorphism and deciduous tooth decay in Chinese children. BMC Oral Health 2017;17:111. In addition, a systematic review of 16 studies on the influence of genetics on salivary proteins found evidence in 11 of these for several salivary protein polymorphisms that increased or decreased caries risk.7Lips A, Antunes LS, Pintor AVB, dos Santos DAB, Bachinski R, Küchler EC, Alves GG. Salivary protein polymorphisms and risk of dental caries: a systematic review. Braz Oral Res 2017;31:e41. Identified polymorphisms increased or decreased salivary antimicrobial activity, decreased bacterial adhesion, increased colonization and aggregation, or decreased buffering capacity. Recent genome-wide research has also found genetic loci that may influence salivary flow and diet.18Vieira AR, Marazita ML, Goldstein-McHenry T. Genome-wide scan finds suggestive caries loci. J Dent Res 2008;87(5):435-9.

A systematic review found evidence of salivary protein polymorphisms that increased caries risk.

Immune response to cariogenic bacteria

A number of studies have investigated the role of genetics in the host response to cariogenic bacteria. Individual studies researching potential immune response genes have found that individuals with active carious lesions were missing the salivary CD14 molecule that is part of the immune response to bacterial lipopolysaccharides. Further, distinct beta defensin 1 subsets influenced caries rates, and lactotransferrin genotype variants influenced caries experience.19Vieira AR, Modesto A, Marazita ML. Caries: review of human genetics research. Caries Res 2014;48:491-506. Human leukocyte antigen (HLA) genes may also influence risk for dental caries.19Vieira AR, Modesto A, Marazita ML. Caries: review of human genetics research. Caries Res 2014;48:491-506. In a study of HLA alleles in African-American females, two alleles were associated with high levels of Streptococcus mutans (p≤0.005), and two others were associated with higher and lower levels of lactobacilli, respectively.20Acton RT, Dasanayake AP, Harrison RA, Li Y, Roseman JM, Go RCP, Wiener H, Caufield PW. Association of MHC genes with levels of caries-inducing organisms and caries severity in African-American women. Human Immunol 1999;60:984-9. In another study, the HLA-DRB1*04 allele was significantly associated with ECC.21Bagherian A, Nematollahi H, Afshari JT, Moheghi N. Comparison of allele frequency for hla-dr and hla-dq between patients with ecc and caries-free children. J Indian Soc Pedod Prev Dent 2008;26:18-21.

Conclusions

Genetics is a promising area of cariology research. However, future research will be required to examine the oral microbiome, host genetic make-up and environment to determine how these factors influence caries development. Longitudinal studies of individuals across the life course are necessary.11Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 2017;22:269-78 e263. If specific genes and markers can be identified that increase inherited risk, in the future simple testing may help clinicians provide targeted care for patients with a genetic predisposition for caries.

In the meantime, the roles of cariogenic bacteria and fermentable carbohydrates in dental caries are unequivocal, and colonization by cariogenic bacteria is primarily influenced by environmental factors. It is also well-recognized that a healthy diet, adequate salivary buffering capacity, proper oral hygiene, and exposure to fluoride, protective antimicrobials and ions in saliva are beneficial. In addition, it has been suggested that the oral microbial community associated with a disease state may be due to a lack of host genomic adaptation.11Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 2017;22:269-78 e263. This further emphasizes the importance of environmental factors, and interventions that modify the environment, and thereby the caries risk. In conclusion, since environmental factors are modifiable, strategies designed to modify the environment currently represent the best approach for prevention/early intervention of dental caries.

References

  • 1.Pitts NB, Zero DT, Marsh PD, Ekstrand K, Weintraub JA, Ramos-Gomez F, Tagami J, Twetman S, Tsakos G, Ismail A. Dental caries. Nat Rev Dis Primers 2017;25(3):17030.
  • 2.Featherstone JD. The caries balance: the basis for caries management by risk assessment. Oral Health Prev Dent 2004;2(Suppl 1):259-64.
  • 3.Shuler CF. Inherited risks for susceptibility to dental caries. J Dent Educ 2001;65(10):1038-45.
  • 4.Opal S, Garg S, Jain J, Walia I. Genetic factors affecting dental caries risk. Aust Dent J 2015;60:2-11.
  • 5.Bretz WA, Corby PM, Melo MR, Coelho MQ, Costa SM, Robinson M, Schork NJ, Drewnowski A, Hart TC. Heritability estimates for dental caries and sucrose sweetness preference. Arch Oral Biol 2006;51(12):1156-60.
  • 6.Nibali L, Di Iorio A, Tu YK, Vieira A. Host genetics role in the pathogenesis of periodontal disease and caries. J Clin Periodontol 2017;44:S18:52-78.
  • 7.Lips A, Antunes LS, Pintor AVB, dos Santos DAB, Bachinski R, Küchler EC, Alves GG. Salivary protein polymorphisms and risk of dental caries: a systematic review. Braz Oral Res 2017;31:e41.
  • 8.Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, McNeil DW, Marazita ML. Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 2010;44:277-84.
  • 9.Corby PM, Bretz WA, Hart TC, Schork NJ, Wessel J, Lyons-Weiler J, Paster BJ. Heritability of oral microbial species in caries-active and caries-free twins. Twin Res Hum Genet 2007;10(6):821-8.
  • 10.Papapostolou A, Kroffke B, Tatakis DN, Nagaraja HN, Kumar PS. Contribution of host genotype to the composition of health-associated supragingival and subgingival microbiomes. J Clin Periodontol 2011;38:517-24.
  • 11.Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 2017;22:269-78 e263.
  • 12.Shaffer JR, Wang X, McNeil DW, Weyant RJ, Crout R, Marazita ML. Genetic susceptibility to dental caries differs between the sexes: a family-based study. Caries Res 2015;49:133-40.
  • 13.Stahringer SS, Clemente JC, Corley RP, Hewitt J, Knights D, Walters WA, Knight R, Krauter KS. Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood. Genome Res 2012;22:2146-52.
  • 14.Momeni SS, Whiddon J, Cheon K, Ghazal T, Moser SA, Childers NK. Genetic diversity and evidence for transmission of streptococcus mutans by DiversiLab rep-PCR. J Microbiol Methods 2016;128:108-17.