Retrospective Review of Oral Probiotic Therapy

Retrospective Review of Oral Probiotic Therapy
Mark L Cannon*/Ashlee Vorachek **/Catherine Le ***/Kevin White ****
Purpose: There have been many in vitro studies reporting on the efficacy of probiotic bacteria in inhibiting
pathogens, and there have been published studies reporting on the inhibitor effects of probiotic bacteria on
the salivary levels of bacterial pathogens. However, there have not been but a few studies on the clinical
benefits of oral probiotic therapy. Study design: Dental records of 60 patients that were enrolled
in an Institutional Review Board approved study were reviewed as to current caries activity status with
measurement of the Decayed Missing Filled Teeth index and by Caries Management By Risk Assessment
(CAMBRA) determination. The current oral health status was compared to the prior-to-study enrollment
status and then analyzed in respect to published national norms.
The data (without any identifiers) had a statistical analysis by a blinded biostatistician. The data was
subjected to statistical analysis (Statsgraphic) before and after the probiotic therapy. Results: Of the 53
subjects available for follow up, only 4 had remained caries active with a grand total of 27 carious lesions
being detected and subsequently restored in this group. Of the original total of 60 patients with 292 initial
carious lesions, after probiotic therapy and dental restoration, 78 total restorations were placed in the subject
group over the following three years. Approximately half of these restorations were required in teeth that had
initially presented with smaller lesions and had been placed in a “watch” category. Two of the patients that
developed further carious lesions had been randomly assigned to the probiotic PerioBalance, while the other
two caries active patients were assigned EvoraKids probiotic.
Of the original group of caries active patients, 24 did not present with any further carious involvement.
Another 25 could be categorized as caries static, as the restorations required were substantially less than
before probiotic therapy had been begun. The F-ratio, which in this case equals 51.3313, is a ratio of the
between-group estimate to the within-group estimate. Since the P-value of the F-test is less than 0.05, there
is a statistically significant difference between the means of the 4 variables at the 95.0% confidence level.
Conclusion: The tested probiotic supplements had a statistically significant effect on the caries experience
of the enrolled subjects.
From Northwestern University and Ann and Robert Lurie Children’s
Hospital, Chicago, IL. USA
*Mark L. Cannon, DDS MS.
**Ashlee Vorachek, DDS.
*** Catherine Le, DDS.
****Kevin White DDS.
Send all correspondence to:
Cannon M. L.,
Northwestern University and Ann and Robert Lurie Children’s Hospital,
Chicago, IL. USA
Contact: drmarkcannon@outlook.com, markcannon@northwestern.edu
Phone: +(847)8996720
E-mail: drmarkcannon@outlook.com, markcannon@northwestern.edu
INTRODUCTION
D ental caries in the primary teeth of children ages 2 to 11
declined from the early 1970’s until the mid 1990’s. From
the mid 1990’s until the 1999-2004 National Health and
Nutrition Examination Survey, this trend has reversed. A small, but
significant, increase in primary tooth decay was found. This trend
reversal was reportedly more severe in younger children 1
. Dental
caries remains the most common disease of childhood in spite of
many highly touted dental prevention innovations 2. The addition
of fluoride to water supplies and to toothpaste was heralded as a
cure for dental decay. In addition, the application of pit and fissure
sealants also was optimistically trumpeted as another preventative
procedure of significant stature. Unfortunately, fluoride addition
to water supplies only reduces decay by up to25% and the addi-
tive effect of fluoride toothpaste is only 10-23% 3- 6. In fact, by age
65, 98% of all US citizens have experienced dental decay 7, 8. The
concept that fluoride simply delays carious involvement has been
suggested and all practitioners have seen previously sealed molars
eventually need restorations9- 11. Therein lies the rub, if decay is
Retrospective Review of Oral Probiotic Therapy
2 doi 10.17796/1053-4625-43.6.1 The Journal of Clinical Pediatric Dentistry Volume 43, Number 6/2019
delayed long enough, “short” five or even ten-year public health
studies will show a positive effect, even when there is no actual long
term benefit. However, patients appear to be keeping their denti-
tion healthy and longer, as the number of full and partial dentures
have significantly decreased over time. But at the same time, more
implants are being placed along with an increase in the number of
endodontically treated teeth which leads to fewer extractions being
treatment planned 1
.
Streptococcus mutans remains the main pathogen in the initia-
tion of dental decay, although other microorganisms have now been
implicated 12-19 .
To date there have been no long-term studies of any potential
benefits from probiotic therapy in improving oral health. There have
been many in vitro studies reported on the efficacy of probiotic
bacteria on inhibiting pathogens. Also there have been a number
of studies reported on the inhibitor effects of probiotic bacteria on
the salivary levels of pathogens. Still, there have not been but a
few studies on the clinical benefits of probiotic therapy 20-25
. Most
published research includes the use of probiotics in cheese, milk or
yogurt 26–32. A study of children with a low caries rate demonstrated
a significant decrease in new carious lesions, with a reduction from
0.8 new carious lesions to 0.2. This was a surprising result, as the
subjects already were at low caries risk, which should indicate a
“normal” microbiome 33. The caveat being that perhaps any carious
lesions indicate an unhealthy situation, in which case, virtually none
of us have a healthy microbiome. Interestingly, research studies have
revealed that even avulsed teeth will have a periodontal ligament
that survives better in a probiotic solution 34 and 35. Many such similar
studies suggest that a healthy microbiome create a healthy patient.
This present study was to determine what clinical effect, if any, a
probiotic course had on long term caries rate of high caries risk
subjects. A retrospective Institutional Review Board permission was
obtained to look at the blinded data from a previously approved IRB
study, three years later, and the current oral health of the subjects.
The subjects had been randomly assigned to either the PerioBalance
Group- Lactobacillus reuteri Prodentis®/™ (L. reuteri DSM 17938
and L. reuteri ATCC PTA 5289) or the EvoraKids Group- Evora-
Plus, Oragenics, now Probiora Health (ProBiora3 is a proprietary
blend of three naturally occurring strains of beneficial bacteria,
including Streptococcus oralis KJ3®, Streptococcus uberis KJ2®,
and Streptococcus rattus JH145®). Thirty subjects were randomly
assigned by randomizer software to each group.
MATERIALS AND METHOD
Dental records of 60 patients that were enrolled in the Institu-
tional Review Board approved study, “A clinical trial to evaluate
the effectiveness of DNA-PCR and CRT at measuring the salivary
level of bacteria in caries prone children with PerioBalance or
EvoraKids Plus therapy” were reviewed as to current caries activity
status with measurement of the Decayed Missing Filled Teeth
index and Caries Management By Risk Assessment (CAMBRA)
determination. The current oral health status was compared to the
prior-to-study enrollment status and then analyzed in respect to
published national norms.
The dental records of patients that were enrolled in the original
study were reviewed three years since they last participated. The
dental charts were analyzed and data collected on the number of
teeth that had been treated since the subjects first enrolled. The data
collected was compared to published national norms to determine
if the patients remained cavity prone, became more cavity prone
or developed fewer cavities than average for their age, race and
gender. The data (without any identifiers) had a statistical analysis
by a biostatistician. The data was subjected to the ANOVA (analysis
of variance) to determine if there is any statistical difference before
and after the probiotic therapy. The difference between the two
probiotic groups was also analyzed with the Wilcoxon Two Sample
test and Kruskal Wallis comparison. Of the 64 original probiotic
enrolled subjects, clinical data existed for follow up on 60 subjects.
The remaining 4 original subjects did participate in the probiotic
regimen, but did not complete the salivary sampling. Out of the 60
remaining, fifty-three patients were available for follow up at the
three-year review.
RESULTS
Of the 53 subjects available for follow up, only 4 had remained
caries active with a grand total of 27 carious lesions being detected
and subsequently restored in this group. Of the original 64 patients
with 628 initial carious lesions, after probiotic therapy and dental
restoration, 78 total restorations were placed in the subject group
over the following three years. Approximately half of these resto-
rations were required in teeth that had initially presented with
smaller lesions and had been placed in a “watch” category. It is very
important to note that for I.R.B. approval, only carious lesions that
were clearly involving dentin could be restored. Hence, a number of
carious lesions that penetrated to the Dentin Enamel Junction were
placed in a “watch” category. Two of the patients that developed
further carious lesions had been randomly assigned to the probi-
otic PerioBalance, while the other two caries active patients were
assigned EvoraKids probiotic.
Of the original group of caries active patients, 24 did not present
with any further carious involvement. Another 25 could be catego-
rized as caries static, as the restorations required were substantially
less than before probiotic therapy had been begun.
Table 1. Caries active, Caries resistant and Caries static
patients.
Caries Active Caries Resistant Caries Static
PerioBalance 2 11 13
EvoraKids 2 13 12
Caries Count 27 0 51
Table 2. Caries History Compared to Nationally Reported
Values.
Caries
Experience
Pre
Probiotic
National
Average
Post
Probiotic
Per patient- 3 years 5.51 1.84 0.75
Statistical Analysis
Kruskal-Wallis Test: Test statistic = 59.9423 P-Value = 0
The StatAdvisor
The Kruskal-Wallis test tests the null hypothesis that the
median within each of the 4 columns is the same. The data from
all the columns is first combined and ranked from smallest to
largest. The average rank is then computed for the data in each
Retrospective Review of Oral Probiotic Therapy
The Journal of Clinical Pediatric Dentistry Volume 43, Number 6/2019 doi 10.17796/1053-4625-43.6.1 3
column. Since the P-value is less than 0.05, there is a statistically
significant difference among each median at the 95.0% confi-
dence level.
Summary Statistics
ANOVA Table
Source Sum of
Squares
Df Mean
Square
F-Ratio P-Value
Between
groups
52.6751 3 17.5584 51.33 0.0000
Within
groups
28.733 84 0.34206
Total
(Corr.)
81.4082 87
The ANOVA table decomposes the variance of the data into
two components: a between-group component and a within-group
component. The F-ratio, which in this case equals 51.3313, is a ratio
of the between-group estimate to the within-group estimate. Since
the P-value of the F-test is less than 0.05, there is a statistically
significant difference between the means of the 4 variables at the
95.0% confidence level.
DISCUSSION
There has been a genuine concern that probiotic therapy is at best
effective for a short time and would require substantial investment in
resources, time and commitment to be a long term therapeutic. This
argument assumes that, all things considered, that the microbiome is
rather stagnant and fails to respond to an outside stimulus. This has
been demonstrated to be completely untrue, with research proving
that any use of antibiotics, anti-microbials, change in diet or loca-
tion, will quickly influence the microbiome36-38. Another concern is
that probiotic therapy won’t have any long-term effect that can be
measured in a patient population. The results of this study would
indicate that probiotic therapy was of benefit in managing caries
active patients and reducing future risk of dental disease after use for
just one month. More importantly, this study proves that the effects
were measurable even three years later. This means that the oral
microbiome was shifted to being less pathogenic, and that probiotic
therapy may indeed be more economical than other, less effective
measures. It is very important to note that at least half of the carious
lesions that were restored in the subjects were present at the first
evaluation but had been arbitrarily placed in the “watch” category
as a condition of the Institutional Review Board approval. Only very
obvious carious lesions penetrating well into dentin were initially
restored. This essentially means that the probiotics both arrested
a number of carious lesions, or greatly slowed their progression.
This would not be unlike the reported effect of fluoride, and the end
result would be that many carious primary teeth could be allowed
to exfoliate without needing restorative treatment39. Indeed, probi-
otics simply reduce the pathogens that modern, high sugar diets,
feed. Ideally, the clinician should determine the status of the oral
microbiome by appropriate testing, institute a preventive protocol
with polyols and probiotics, then re-test at perhaps an annual
session, depending on patient compliance. Oral disease is totally
preventable, and oral disease leads to systemic disease.
Although there have been numerous research publications with
probiotic therapy demonstrated as effective and safe, there has been
a great reluctance amongst many health care professionals to adopt
probiotic protocols into their daily practice. Over one hundred
articles on probiotics are published every month, in many of the
most prestigious journals, and yet there is still this reluctance 40
.
Unfortunately, some of this reluctance is due to simple economics,
as there is no insurance nor governmental reimbursement for probi-
otic therapy. Indeed, a number of practitioners have expressed
concern that if probiotics work and their use becomes common-
place, their economic position would deteriorate. In addition, there
is an occasional article/ research publication that denigrates the
use of probiotics to preserve health. Review of these articles often
disclose a flawed protocol, or even more basic, a misunderstanding
of the mechanisms that probiotics employ for obtaining health.
For instance, two articles recently published in the New England
Journal of Medicine reported that a probiotic “disappointed” in
the treatment of acute gastroenteritis of pediatric subjects seen in
Emergency Departments 41-42
. Unfortunately, these studies were
designed to fail as probiotics are not a treatment for a viral acute
gastroenteritis, but instead they boost the immune system to prevent
the disease or to ameliorate the symptoms 43-45. Sick children that
are seen in ED’s are not the best subjects, they are already ill and
it was totally unclear that anything was done to insure the probi-
otics survival. Most likely the child was on a diet of clear soda and
crackers, void of any prebiotics necessary to aid in the probiotics
success. Research into the mechanisms of probiotic actions would
seem to suggest that at least 28 days would be required to develop
the appropriate immune response. Certainly 5 days of probiotic use
in an already ill pediatric subject would not be sufficient, so the
results were very predictable 46 . On the other hand, it may be stated
that a historical precedent for use of a viral “probiotic” would be
the cowpox inoculation by Edward Jenner to prevent the mortality
seen with the scourge of smallpox 47. In this sense, cowpox may be
considered a probiotic as it contributed to the health (actually even
survivability) of the individual.
The importance of re-establishing a normal microbiome cannot
be overemphasized. The connection of oral health to systemic
health is now well established. Indeed, there is no real disease such
as periodontal disease, it is simply a symptom of a global disease,
that may best be described as Neural Arterial Gingival Simplex (or
NAGS). Porphyromonas gingivalis, has been found to be a caus-
ative agent of periodontal disease, arteriosclerosis and inflammatory
Alzheimer’s 48. Porphyromonas gingivalis has been long linked in
numerous published studies to both periodontal disease and athero-
sclerosis. Because there is a sole pathogen associated with all these
pathologies, it is most logical to describe all the pathologies asso-
ciated with it as a singular disease but caused by several pathogens
with Porphyromonas gingivalis being foremost 49 and 50
. Such is the
case for any other disease, for instance, viral acute gastroenteritis
due to rotavirus may cause fever, chills, muscle aches, fatigue and
nausea, each component is not considered a separate disease 51 and
52 . Changing the microbiome may very well become the preventive
technique of choice. For example, oral and systemic preventive
protocols may include probiotic supplementation with possibly
overlapping beneficial bacterial, archaeon, viral or yeast probiotics.
Retrospective Review of Oral Probiotic Therapy
4 doi 10.17796/1053-4625-43.6.1 The Journal of Clinical Pediatric Dentistry Volume 43, Number 6/2019
CONCLUSION
Probiotics significantly reduced the caries rate of high caries
prone pediatric subjects without any reported side effects. The
reduction was not only significant statistically, it was very signifi-
cant clinically with only four subjects (out of fifty-three) remaining
caries prone. Dental professionals should adopt probiotic therapy
as one of the most effective caries preventive measures in children.
REFERENCES
1. Dye BA, Xianfen L, Beltrán-Aguilar ED. Selected Oral Health Indicators
in the United States 2005–2008. NCHS Data Brief, no. 96. Hyattsville,
MD: National Center for Health Statistics, Centers for Disease Control
and Prevention; 2012.
2. National Institute of Health- National Institute of Dental and Craniofacial
Research- online March 2019.
3. U.S. Department of Health and Human Services Federal Panel on
Community Water Fluoridation. U.S. Public Health Service recommen-
dation for fluoride concentration in drinking water for the prevention of
dental caries. Public Health Rep;130:318–31. 2015.
4. Community Preventive Services Task Force. Preventing Dental Caries:
Community Water Fluoridation website. https://www.thecommuni-
tyguide.org/findings/dental-caries-cavities-community-water-fluorida-
tionExternal. Accessed October 23, 2014.
5. Griffin SO, Jones K, Tomar SL. An economic evaluation of community
water fluoridation. J Public Health Dent;61:78–86. 2001.
6. Marinho VCC, Higgins JPT, Logan S, Sheiham A. Fluoride toothpastes
for preventing dental caries in children and adolescents. Cochrane Data-
base of Systematic Reviews. 2003; Issue 1. Art. No.: CD002278. DOI:
10.1002/14651858.CD002278.
7. Griffin SO, Regnier E, Griffin PM, Huntley V. Effectiveness of fluoride in
preventing caries in adults. J Dent Res;86:410–5. 2007.
8. Thomson WM. Epidemiology of oral health conditions in older people.
Gerodontology 31 Suppl 1:9–16. 2014.
9. Ahovuo-Saloranta A, Forss H, Walsh T, Hiiri A, Nordblad A, Mäkelä M,
Worthington HV. Sealants for preventing dental decay in the permanent
teeth. Cochrane Database of Systematic Reviews. 2013; Issue 3. Art. No.:
CD001830. DOI: 10.1002/14651858.CD001830.pub4.
10. Mejàre I., Lingström P., Petersson L.G., Holm A.K., Twetman S.,
Källestål C., Nordenram G., Lagerlöf F., Söder B., Norlund A., Axelsson
S., Dahlgren H. ,Caries-preventive effect of fissure sealants: a systematic
review. Acta Odontol Scand. Dec;61(6):321-30. 2003.
11. Simecek J. W., Diefenderfer K. E., Ahlf R. L. , Ragain J. C. Jr. Dental
sealant longevity in a cohort of young U.S. naval personnel. J Am Dent
Assoc. Feb;136(2):171-8; quiz 230. 2005.
12. Loesche W.J. Role of Streptococcus mutans in human dental decay.
Microbiol Rev; 50(4):353-380 .1986.
13. Loesche W.J. Nutrition and dental decay in infants. Am J Clin Nutr;
41:423-35 .1985.
14. Hamada S. and Slade H.D. Biology, immunology, and cariogenicity of
Streptococcus mutans. Microbiol Rev. 1980; 44(2):331-84.
15. Sanchez-Perez L. and Acosta-Gıo A.E. Caries risk assessment from
dental plaque and salivary Streptococcus mutans counts on two culture
media. Arch Oral Biol;46:49–55.2001.
16. Koga T., Oho T., Shimazaki Y. and Nakano Y. Immunization against
dental caries. Vaccine; 20:2027–2044. 2002.
17. Loesche W.J., Rowan J., Straffon L.H. and Loos P.J. Association of Strep-
tococcus mutans with human dental decay. Infect Immun; 11:1252- 60.
1975.
18. van Houte J. and Duchin S. Streptococcus mutans in the mouths of chil-
dren with congenital sucrose deficiency. Arch Oral Biol; 20:771-73. 1975.
19. Islam B., Khan S.N. and Khan A.U. Dental caries: From infection to
prevention. Med Sci Monit,; 13(11):RA196-203. 2007.
20. Guarner F., Perdigon G., Coerthier G., Salminen S., Koletzko B. and
Morelli L. Should yoghurt cultures be considered probiotic? Br J Nutr;
93:783–786.2005.
21. Koornhof H.J. Probiotics — how functional are they? SAMJ; 94(4):272-
273. 2004.
22. Sheiham A. Dietary effects on dental diseases. Public Health Nutr.
Apr;4(2B):569-91. 2001.
23. Silva M., Jacobus N.V., Deneke C. and Gorbach S.L. Antimicrobial
substance from a human lactobacillus strain. Antimicrob Agents Chemo-
ther; 31:1231–1233. 1987.
24. Isolauri E., Sutas Y., Kankaanpaa P., Arvilommi H. and Salminen S.
Probiotics: effects on immunity. Am J Clin Nutr; 73(Suppl. 2): S444–
S450. 2001.
Retrospective Review of Oral Probiotic Therapy
The Journal of Clinical Pediatric Dentistry Volume 43, Number 6/2019 doi 10.17796/1053-4625-43.6.1 5
25. Meurman J.H. and Stamatova I. Probiotics: contributions to oral health.
Oral Diseases; 13:443–451. 2007.
26. Meurman J.H., Antila H. and Salminen S. Recovery of Lactobacillus
strain GG (ATCC 53103) from saliva of healthy volunteers after
consumption of yoghurt prepared with the bacterium. Microb Ecol Health
Dis; 7:295–298.1994.
27. Nase L., Hatakka K., Savilahti E., Saxelin M., Ponka A., Poussa T.,
Korpela R. and Meurman J.H. Effect of long-term consumption of a
probiotic bacterium, Lactobacillus rhamnosus GG, in milk on dental
caries and caries risk in children. Caries Res; 35:412–420.2001.
28. Ahola A.J., Yli-Knuuttila H., Suomalainen T., Poussa T., Ahlström A.,
Meurmanb J.H. and Korpela R. Short-term consumption of probiot-
ic-containing cheese and its effect on dental caries risk factors. Arch. Oral
Biol; 47:799–804.2002.
29. Nikawa H., Makihira S., Fukushima H., Nishimura H., Ozaki Y. and
Ishida K. Lactobacillus reuteri in bovine milk fermented decreases the oral
carriage of mutans streptococci. Int J Food Microbiol; 95:219–223.2004.
30. Busscher H.J., Mulder A.F. and van der Mei C.H. In vitro adhesion to
enamel and in vivo colonization of tooth surfaces by lactobacilli from a
bio-yogurt. Caries Res; 33:403–404.1999.
31. Cildir S. K., Germec D., Sandalli N., Ozdemir F. I., Arun T., Twetman
S., Caglar E., Reduction of salivary mutans streptococci in orthodontic
patients during daily consumption of yoghurt containing probiotic
bacteria. Eur J Orthod. 2009 Aug;31(4):407-11. doi: 10.1093/ejo/cjn108.
Epub 2009 Feb 4.
32. Caglar E., Kuscu O. O., Selvi Kuvvetli S., Kavaloglu Cildir S., Sandalli
N., Twetman S., Short-term effect of ice-cream containing Bifidobac-
terium lactis Bb-12 on the number of salivary mutans streptococci and
lactobacilli. Acta Odontol Scand. Jun;66(3):154-8. 2008.
33. Hedayati-Hajikand, T., Lundberg, U., Eldh, C., & Twetman, S. (2015).
Effect of probiotic chewing tablets on early childhood caries—a
randomized controlled trial. BMC oral health, 15(1), 112. doi:10.1186/
s12903-015-0096-5.
34. Caglar E., Sandalli N., Kuscu O.O., Durhan M.A., Pisiriciler R., Caliskan
E. A., Kargul B. Viability of fibroblasts in a novel probiotic storage
media. Dent Traumatol. Oct;26(5):383-7. 2010.
35. Saini D., Gadicherla P., Chandra P., Anandakrishna L., Coconut milk and
probiotic milk as storage media to maintain periodontal ligament cell
viability: an in vitro study. Dent Traumatol. 2017 Jun;33(3):160-164. doi:
10.1111/edt.12310. Epub 2016 Dec 12.
36. Trasande, L. et al. Infant antibiotic exposures and early-life body mass.
Int. J. Obes. 37, 16–23 2013.
37. Virta, L., Auvinen, A., Helenius, H., Huovinen, P. & Kolho, K. Associa-
tion of repeated exposure to antibiotics with the development of pediatric
Crohn’s disease-a nationwide, register-based Finnish Case-Control Study.
Am. J. Epidemiol. 175, 775–784 .2012.
38. Honda K., Littman, D. R. The microbiota in adaptive immune homeostasis
and disease. Nature 535, 75–84, https://doi.org/10.1038/nature18848
.2016.
39. Sheiham A., James W. P. A new understanding of the relationship
between sugars, dental caries and fluoride use: implications for limits on
sugars consumption. Public Health Nutr. 2014 Oct;17(10):2176-84. doi:
10.1017/S136898001400113X. Epub 2014 Jun 3.
40. Pubmed search, March 2019. 2530 clinical trials and 26072 articles.
41. Schnadower D. et al. Lactobacillus rhamnosus GG versus Placebo for
Acute Gastroenteritis in Children. N Engl J Med. Nov 22;379(21):2002-
2014. 2018.
42. Freedman S. B., et al. Multicenter Trial of a Combination Probiotic for
Children with Gastroenteritis. N Engl J Med. Nov 22;379(21):2015-2026.
2018.
43. Licciardi P. V., Tang ML.Vaccine adjuvant properties of probiotic
bacteria. Discov. Med. 12 525–533. 2011-
44. Schnadower D., Finkelstein Y., Freedman SB;Ondansetron and probiotics
in the management of pediatric acute gastroenteritis in developed coun-
tries. Curr. Opin. Gastroenterol. 31 1–6. 10. 2015.
45. Sindhu K. N., Sowmyanarayanan T. V., Paul A., Babji S., Ajjampur S. S.,
Priyadarshini S., et al. Immune response and intestinal permeability in
children with acute gastroenteritis treated with Lactobacillus rhamnosus
GG: a randomized, double-blind, placebo-controlled trial. Clin. Infect.
Dis. 58 1107–1115. 2014.
46. Lei, S., Ramesh, A., Twitchell, E., Wen, K., Bui, T., Weiss, M., Yuan,
L. (2016). High Protective Efficacy of Probiotics and Rice Bran against
Human Norovirus Infection and Diarrhea in Gnotobiotic Pigs. Frontiers
in microbiology, 7, 1699. doi:10.3389/fmicb.2016.01699
47. Riedel S. (2005). Edward Jenner and the history of smallpox and vaccina-
tion. Proceedings (Baylor University. Medical Center), 18(1), 21-5.
48. Dominy, S. S. et al. Porphyromonas gingivalis in Alzheimer’s disease
brains: Evidence for disease causation and treatment with small-mol-
ecule inhibitors, Science advances vol. 5,1 eaau3333. 23 Jan. 2019,
doi:10.1126/sciadv.aau3333.
49. Kim, H. J., Cha, G. S., Kim, H. J., Kwon, E. Y., Lee, J. Y., Choi, J., &
Joo, J. Y. (2018). Porphyromonas gingivalis accelerates atherosclerosis
through oxidation of high-density lipoprotein. Journal of periodontal &
implant science, 48(1), 60-68. doi:10.5051/jpis.2018.48.1.60
50. Hussain M., Stover C. M., Dupont A., P. gingivalis in Periodontal Disease
and Atherosclerosis–Scenes of Action for Antimicrobial Peptides and
Complement. Front Immunol. Feb 10;6:45. 2015.
51. Rotavirus: vaccination. Centers for Disease Control and Prevention
website. https://www.cdc.gov/rotavirus/vaccination.html . Updated
August 12, 2016.
52. Preventing norovirus infection. Centers for Disease Control and Preven-
tion website. https://www.cdc.gov/norovirus/preventing-infection.html .
Updated July 15, 2016.