Review Article :
Neural
Arterial Gingival Simplex is a common systemic disease linked to an invasive
periodontal pathogen, Porphyromonas gingivalis as the key initiator. Instead of
considering separate pathologic conditions as separate diseases, the health
community should view this disease as a single entity, to diagnose and treat
accordingly. We discuss the evidence for this hypothesis and the need for
definitive research. A strategy to maintain a healthy, resilient microbiome
with adjunctive support by probiotics and polyols is warranted. Newer
diagnostic and monitoring technologies along with many possible therapeutic
agents and protocols are readily available to prevent and treat Neural Arterial
Gingival Simplex. The importance of re-establishing
a normal microbiome
cannot be overemphasized [1,2]. Modern diet and the overuse of antimicrobials
have resulted with a tremendous increase in autoimmune diseases that were
virtually unheard of in the past [3-5]. This shift in diet occurred first in
the Neolithic period, followed by another shift in the Industrial Era, and
finally now with the combined effects of fast food and antimicrobials [6]. Even
a number of common food preservatives and additives have been shown to exert
negative health effects [7]. As a result, it is estimated that almost half of
all middle-aged Americans have metabolic syndrome [8-10]. In short, the costs
of western diet and life style have been significant, and unless a paradigm
shift urgently occurs, we could be a society devoted only to extending the life
span of the chronically ill, incapable of achieving the accomplishments of
prior generations [11,12]. Fortunately, advances in scientific study of the
microbiome provide hope that wellness can be restored and productive health
span increased. The
connection of oral health to systemic health is now well established [13].
Indeed, there is no isolated disease such as periodontal disease; it is simply
a symptom of a systemic disease that may best be described as Neural
Arterial Gingival Simplex (NAGS). Porphyromonas gingivalis,
has been found to be a causative agent of periodontal disease, arteriosclerosis
and inflammatory Alzheimers [14-16]. Because P. gingivalis can be considered the foremost or “keystone”
initiator of periodontal
disease, it is reasonable to describe P. gingivalis as a causal agent of NAGS,
a single disease with all of its downstream comorbidities [17]. 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, and each
component is not considered a separate disease [19,20]. Addressing the microbiome may
very well become the preventive technique of choice. Oral and systemic
preventive protocols would include probiotic supplementation, possibly with
overlapping beneficial bacterial, archaeon, viral or yeast probiotics. For
example, it may be stated that an historical precedent for use of a viral
“probiotic” would be the cowpox inoculation by Jenner to prevent the mortality
seen with the scourge of smallpox [21]. In this sense, cowpox may be considered
a viral probiotic as it contributed to the health and even survivability of the
individual. P.
gingivalis has been called a “guerilla”
for its notable tactics of slowly subverting the hosts defense mechanisms [22].
The hosts immunity is bypassed by the ability of P. gingivalis fimbriae to attach to hosts cells, such as gingival
epithelial cells or endothelial cells, and then to invade the cell itself [23].
The ability of P. gingivalis to shift
genomes in different strains to specifically target different host cells makes
it particularly virulent [24]. In addition, the epigenetic influence of P. gingivalis allows it to open the
tight junctions between cells and to modulate the immune response [25]. All
told, P. gingivalis subverts a
massive host immune response, and does not normally overwhelm the host because
that would effectively limit the spread of the pathogen. A dead host does not
propagate a pathogen. P.
gingivalis is a perfect pathogen. It spreads from
the older members of the host population to the younger members [26]. P. gingivalis is seen in children as
young as 7-8 years of age, however, gingival
pathology is not usually detected until age 17
[27,28]. The majority of young adults already have more than a millimeter of
attachment loss [29]. It should be noted that in autopsy studies 20% of 2-15
year old children demonstrate atherosclerosis,
and by age 21 50% will have calcified aortic deposits [30-32]. This too
perfectly coincides with the development of “periodontal disease”. In addition,
research at Northwestern University revealed that in their early 20s subjects
were already developing beta
amyloid plaque and tau protein deposits [33]. With
recent publications demonstrating the correlation between gingipain from P. gingivalis and Alzheimers disease,
this should not be the least surprising [14]. With the new concept of P. gingivalis infection causing a single
disease with multiple symptoms, it is now easy to understand the modes
involved. The oral component is the initial infection where the immune system
is alerted and subverted, creating an inflammatory environment. Circulating leukocytes
carry P. gingivalis and associated Lipo
Poly Saccharide (LPS), affecting the endothelial cells
of arteries, and passing into the neural component, eventually reducing the
cognitive ability of the host, which would reduce the oral hygiene of the host,
further spreading the pathogen amongst all contacts [34]. The key to prevention will always
lie with having the healthiest microbiome [35]. A “healthy non- western
microbiome” will trigger the more robust response to pathogens with the least
autoimmune consequences. Unfortunately for the civilized world, we have brought
upon ourselves the epidemic of autoimmune disease, while decreasing our innate
response to common pathogens [36]. Much has been said of the hygiene
hypothesis, and of us all being “too clean” [37]. But it is extremely doubtful
that as a society, we will all return to our hunter-gatherer roots (barring
some natural catastrophe). Probiotic supplementation appears to be the
essential to re-establish a healthy resilient microbiome [38-42]. This option
alone, without appropriate diet and lifestyle modification, is severely limited
[43]. The appropriate diet is necessary to provide the required prebiotics that
beneficial organisms need to thrive and to favorably influence the entire
microbiome [44]. The microbiome metabolites then exert an epigenetic effect
upon the host, either producing health, or illness [45]. Dysbiosis not only
directly produces disease, but also the metabolites of the microbiome are
messengers to the brain and the rest of the body [46]. The immune system
responds, as does the behavior of the host [47]. Depression has been linked to
the presence of a specific bacterial species, and also the lack of one species
[48,49]. Schizophrenia is also an epigenetic disease and Autism Spectrum
Disorder (ASD) has been linked to propionic acid producing bacterial species,
such as, Clostridia bolteae
and Clostridia histolyticum
[50-54]. Conversely the presence of Clostridia sporogenes
could help protect against ASD by combining propionic acid with indole to
produce 3-Indole Propionate, a neural protective metabolite, thereby
neutralizing the epigenetic effect of propionic acid [55,56]. It has been
theorized that the absence of C.
sporogenes is related to the use of glyphosate, known by the trade name
Roundup [57]. Possibly the increase risk of non-Hodgkins Lymphoma seen in
chronic exposure to individuals exposed to Roundup is due to its effect on the
hosts microbiome, by removing or reducing the level of a protective
bacterial species. With dysbiosis, the existence of
disease always means not just an increase in the presence of a pathogen, but
normally always a decrease in the level of commensals, allowing the pathogen to
generate the pathological response [58]. In a perfectly balanced system, the
host should always survive, at least long enough for the pathogen to spread.
The host should, by evolution, develop a robust response to the pathogen,
increasing the chance of the host species survival [59]. If this does not
happen, the host species will disappear and the pathogen can only survive by
becoming a zoonotic disease pathogen, jumping species, such as, bird flu or
swine flu [60]. There is a canine version of P. gingivalis,Porphyromonas cangingivalis,
and periodontal pathogens typically seen in human hosts have been detected in
canines [61-62]. Whether this is by co-evolution or zoonotic origin is of
interest, as it should explain the disease process with greater clarity. Gingipain-deficient mutant P. gingivalis may prove to be a
precursor to an Alzheimers preventive probiotic. After all, this mutant strain
could and should compete with the “wild type” strains producing gingipain. A
further example of this would be the strains of Fusobacterium nucleatum
that do not have the FADA gene. These strains could occupy that ecological
niche of F. nucleatum and possibly
decrease miscarriages (spontaneous abortions) and colorectal cancer.
Development of these less virulent strains is similar to Jeffrey Hillmans
research into a low or non-lactic acid producing strain of Streptococcus mutans
[63]. Colonization of the population with this safe probiotic could greatly
decrease the most common disease of childhood, dental caries. It is estimated
that over 98% of the human population suffers from dental caries, a totally
preventable disease that is strictly due to dietary habits and dysbiosis [64].
Oddly enough, dentistry totally ignores this and concentrates only on
fluoridation, limiting the effectiveness of prevention programs [65-72]. Erythritol and xylitol are
polyols that have been extensively researched and demonstrated to have notable
anti-cariogenic and anti-periodontal disease properties [73]. Polyols
(particularly the non-hexitol alditols or “sugar alcohols” erythritol and
xylitol) have been found effective in inhibiting the transition to and
maturation of biofilms from planktonic cells [74]. Xylitol clearly inhibited
the formation of mixed species biofilms, which included P. gingivalis in vitro [75].
Erythritol
suppressed the maturation of gingivitis biofilms, and contributed to a
healthier oral ecosystem [76]. P.
gingivalis takes advantage of early colonizers (Streptococci
and Candida) to provide attachment and protection within the biofilm matrix. Polyols
can reduce extracellular polysaccharide production and interfere with biofilm
matrix elaboration, thereby reducing adherence and biofilm development [77-79]. Streptococci and Candida utilize
common dietary sugars sucrose and D-glucose for preferred energy sources, as
well as for polysaccharide production. Higher glucose concentrations stimulate
Candida growth. Compared with common D-sugars, xylitol induced the lowest
adhesion and biofilm formation on either S.
mutans or Candida albicans [80]. Candida facilitates the
colonization and proliferation of periopathic biofilm by co-aggregating with P. gingivalis and adhering to epithelial
cells [81]. Patients with severe periodontitis have a higher rate of Candida
colonization [82]. In diabetes, high levels of glucose in the gingival sulcus
coupled with immunosuppression enhance Candida growth [83]. Glucose, fructose
and mannose are the preferred sugars used for energy and biosynthesis by
Candida, whereas polyols
such as xylitol are poorly utilized. Sugar sensing drives virulence attributes,
including adhesion, oxidative stress resistance, biofilm formation,
morphogenesis, invasion, and antifungal drug tolerance in fungal pathogens
[84,85]. In dual species biofilm Candida helps provide P. gingivalis adherence and protection against oxygen, allowing it
to organize in shallower gingival pockets [86]. The hydroxyl groups of polyols
may interfere with the hydrogen bonding between hydroxyl groups of
polysaccharides and allow greater penetration of antimicrobials. Polyols,
especially erythritol, enhanced the fungicidal effect of benzethonium chloride
toward in vitro candidal biofilms [87]. Xylitol and sorbitol at the
concentrations used in commercial oral health care products had some levels of
candidacidal activities [88]. Polyols can penetrate biofilms to deliver
probiotics [89]. Erythritol delivered zinc chloride deeper into the protective
three-dimensional matrix of extracellular polymeric substances of mature
biofilm [90]. Although P. gingivalis utilizes peptides for its main energy source, sugars
are used by P. gingivalis for
biosynthesis of macromolecules [91]. Polyols can interfere with these
processes. As a result, polyols reduce the growth and the virulence factors of P. gingivalis. Xylitol was found to
inhibit the inflammatory
cytokine expression provoked by LPS remnants of P. gingivalis [92]. Further, xylitol interferes
with P. gingivalis phagocytosis by
macrophages. In macrophages that are infected with live P. gingivalis, xylitol significantly decreased the production of
cytokines, NO and chemokines such as TNF-α, IL-1β, IL-12p40, eotaxin, IP-10,
MCP-1, and MIP-1α. Such potent anti-inflammatory activities recommend use of
polyols for prevention and mitigation of periodontal conditions [93]. Plaque
grown in the presence of polyols has consistently been shown to be less
inflammatory and less irritating to tissues than sucrose-grown
plaque [94-99]. Polyols can suppress the growth
and virulence expression of mixed bacterial biofilms. Erythritol was the most
effective polyol in suppressing the growth and organization of P. gingivalis grown on a Streptococcus
gordonii biofilm. Erythritol exerted inhibitory effects on several pathways-reduced
growths through DNA and RNA depletion, attenuated extracellular matrix
production, and alterations of dipeptide acquisition and amino acid metabolism
[100]. Recognition of NAGS corresponds
with newer enhancements in the diagnosis, prevention and treatment of
periodontal diseases. Periodontal diagnosis goes beyond gross visual,
radiographic and mechanical probing to include Polymerase
Chain Reaction (PCR), DNA determination of specific
pathogenic entities and quantities-the overall pathogenic burden. Genetic and
inflammatory markers are also included to help construct an overall assessment
of individual patient risk and assign targeted treatment plans. Improved
salivary and inflammatory diagnostics can help with monitoring treatment
progress in achieving and maintaining therapeutic end points. Awareness of NAGS likewise calls
for prevention, treatment and maintenance that extend beyond localized
mechanical strategies. Presence of P.
gingivalis is not limited to those with bleeding gums and deep pockets
[101]. P. gingivalis in dental biofilms
is associated with expression of virulence factors leading to progression of periodontal
disease [102]. P. gingivalis biofilms are not easily controlled by purely
mechanical means and are more resistant to antimicrobials than planktonic cells
[74]. Treatment of Periodontal disease and the prevention of dental caries
should include a very strong polyol component [103- 108]. This therapy would
not only prevent the oral disease, but should also help prevent the development
of systemic disease, atherosclerosis and the scourge of the elderly, Alzheimers
disease [109,110]. Certainly, it would be
advantageous to prevent NAGS, as the cost to society is enormous, and the cost
to the individual can be devastating. Polyols are available in many forms such
as tabletop sweeteners and as ingredients in commercial foods and beverages. More
direct “polyol delivery systems” for oral care include toothpaste, lozenges,
chewing gum, mouth rinses and oral sprays. Further research is warranted and
necessary to reduce the burden of this devastating disease on modern society.
We should first perform a number of retrospective review of patients who have been
diligent users of polyol products, especially the reviewing the childrens
health records of those that were subjects in the early Finnish studies of
xylitol and erythritol supplements. Unfortunately, this may be difficult due to
human subject privacy rules. On a positive note, there are apparently studies
that have already been started that are long term in scope, such as the
Pussinen et al study [111]. Prospective studies could take many decades to
irrefutably prove the long term positive effects of polyol and probiotic
supplementation. Due to the documented early onset of atherosclerosis in
children, newer diagnostic technologies should be utilized to identify and
monitor risk. With the now available non-invasive testing for the presence of P. gingivalis and use of ultrasound for
atherosclerosis detection, the research may be accomplished sooner rather than
later. A disease of neural, arterial and
gingival involvement resulting from an infection by P. gingivalis has since prehistoric times inflicted severe pathological
effects on the homo genus. The disease is now of an epidemic nature and should
be prevented by probiotic therapy, dietary changes, and life style adjustments.
Treatment should include supplemental polyol support. 1.
Sommer
F and Bäckhed F. The gut microbiota-masters of host development and physiology
(2013) Nat Rev Microbiol 11: 227-238. https://doi.org/10.1038/nrmicro2974 2.
Rosenberg
E and Zilber-Rosenberg I. Microbes Drive Evolution of Animals and Plants: the
Hologenome Concept (2016) MBio 7: 2. https://doi.org/10.1128/mBio.01395-15 3.
Szylit
O and Andrieux C. Physiological and pathophysiological effects of carbohydrate
fermentation (1993) World Rev Nutr Diet 74: 88-122. 4.
Trasande
J, Blustein M, Liu E, Corwin L, M Cox, et al. Infant antibiotic exposures and
early-life body mass (2013) Int J Obes 37: 16-23. https://doi.org/10.1038/ijo.2012.132 5.
Virta
L, Auvinen A, Helenius H, Huovinen P and Kolho K. Association of repeated
exposure to antibiotics with the development of pediatric Crohns disease-a
nationwide, register-based Finnish Case-Control Study (2012) Am J Epidemiol
175: 775-784. https://doi.org/10.1093/aje/kwr400 6.
Honda
K and Littman DR. The microbiota in adaptive immune homeostasis and disease
(2016) Nature 535: 75-84. https://doi.org/10.1038/nature18848 7. Mummert
A, Esche E, Robinson J and Armelagos GJ. Stature and robusticity during the
agricultural transition: Evidence from the bioarchaeological record (2011) Eco
Hum Biol 9: 284-301. https://doi.org/10.1016/j.ehb.2011.03.004 8.
Dengate
S and Ruben A. Controlled trial of cumulative behavioural effects of a common
bread preservative (2002) J Paediatr Child Health 38: 373-376. https://doi.org/10.1046/j.1440-1754.2002.00009.x 9. Castro
AV, Kolka CM, Kim SP and Bergman RN. Obesity, insulin resistance and comorbidities?
Mechanisms of association (2014) Arq Bras Endocrinol Metabol 58: 600-609.
http://dx.doi.org/10.1590/0004-2730000003223 10. Stears
A, ORahilly S, Semple RK and Savage DB. Metabolic insights from extreme human
insulin resistance phenotypes (2012) Best Pract Res Clin Endocrinol Metab 26:145-157.
https://doi.org/10.1016/j.beem.2011.09.003 11.
Mendrick
DL, Diehl AM, Topor LS, Dietert RR, Will Y, et al. Metabolic Syndrome and
Associated Diseases: From the Bench to the Clinic (2017) Toxicol Sci 162: 36-42.
12.
Kanherkar
RR, Bhatia-Dey N and Csoka AB. Epigenetics across the human lifespan (2014)
Front Cell Dev Biol 2: 49. https://dx.doi.org/10.3389%2Ffcell.2014.00049 13.
Li
Y and Tollefsbol TO. Age-related epigenetic drift and phenotypic plasticity
loss: implications in prevention of age-related human diseases (2018)
Epigenomics 8:1637-1651. https://doi.org/10.2217/epi-2016-0078 14.
Kim
J and Amar S. Periodontal disease and systemic conditions: a bidirectional
relationship (2006) Odontology 94: 10-21. https://dx.doi.org/10.1007%2Fs10266-006-0060-6 15.
Dominy
SS, Lynch C, Ermini F, Benedyk M, Marczyk A, et al. Porphyromonas gingivalis in Alzheimers disease brains: Evidence for
disease causation and treatment with small-molecule inhibitors (2019) Sci adv
5: eaau3333. https://doi.org/10.1126/sciadv.aau3333 16. Kim
HJ, Cha GS, Kim HJ, Kwon EY, LeeJY, et al. Porphyromonas
gingivalis accelerates atherosclerosis through oxidation of high-density
lipoprotein (2018) J periodontal implant sci 48: 60-68. https://doi.org/10.5051/jpis.2018.48.1.60 17.
Bale
BF, Doneen AD and Vigerust DJ. High-risk periodontal pathogens contribute to
the pathogenesis of atherosclerosis (2016) Postgrad Med J 93: 215-220. https://doi.org/10.1136/postgradmedj-2016-134279 18. Hussain
M, Stover CM and Dupont AP. Gingivalis in Periodontal Disease and
Atherosclerosis - Scenes of Action for Antimicrobial Peptides and Complement (2015)
Front Immunol 6: 45. https://doi.org/10.3389/fimmu.2015.00045 19.
Hajishengallis
G, Darveau RP and Curtis MA. The keystone-pathogen hypothesis (2012) Nat Rev Microbiol
10: 717-725. https://dx.doi.org/10.1038%2Fnrmicro2873 20.
Rotavirus: vaccination. Centers
for Disease Control and Prevention 21.
Preventing
norovirus infection. Centers for Disease Control and Prevention 22.
Riedel
S. Edward Jenner and the history of smallpox and vaccination (2005) Baylor
University Medical Center Proceedings, USA, 18: 21-25. https://doi.org/10.1080/08998280.2005.11928028 23.
Hajishengallis
G. Porphyromonas gingivalis-host
interactions: open war or intelligent guerilla tactics? (2009) Microbes infect
11: 637-645. https://doi.org/10.1016/j.micinf.2009.03.009 24.
Moreno
S and Contreras A. Functional differences of Porphyromonas gingivalis Fimbriae in determining periodontal
disease pathogenesis: a literature review (2013) Colombia medica 44: 48-56. 25. Tribble
GD, Kerr J E, and Wang BY. Genetic diversity in the oral pathogen Porphyromonas gingivalis: molecular
mechanisms and biological consequences (2013) Future microbial 8: 607-620. https://doi.org/10.2217/fmb.13.30 26.
Guo
W, Wang P, Liu ZH, and Ye P. Analysis of differential expression of tight
junction proteins in cultured oral epithelial cells altered by Porphyromonas gingivalis, Porphyromonas
gingivalis lipopolysaccharide, and extracellular adenosine triphosphate
(2018) Int J oral sci 10: e8. https://doi.org/10.1038/ijos.2017.51 27.
Hajishengallis
G and Lamont RJ. Breaking bad: manipulation of the host response by Porphyromonas gingivalis (2014) Eur J Immunol,
44: 328-338. https://doi.org/10.1002/eji.201344202 28.
Lamell
CW, Griffen AL, McClellan DL and Leys EJ. Acquisition and colonization
stability of Actinobacillus
actinomycetemcomitans and Porphyromonas
gingivalis in children (2000) J Clin Microbi0l 38: 1196-1199. 29. Liu
Y, Zhang Y, Wang, L, Guo Y, and Xiao S. Prevalence of Porphyromonas gingivalis four rag locus genotypes in patients of
orthodontic gingivitis and periodontitis (2013) PloS one 8: e61028. https://dx.doi.org/10.1371%2Fjournal.pone.0061028 30.
Toledo
BE, Barroso EM, Martins AT and Zuza, EP. Prevalence of Periodontal Bone Loss in
Brazilian Adolescents through Interproximal Radiography (2012) Int J Dent 2012:
357056. https://doi.org/10.1155/2012/357056 31.
Rao
D, Sood D, Pathak P, and Dongre SD. A cause of Sudden Cardiac Deaths on Autopsy
Findings; a Four-Year Report (2014) Emergency 2: 12-17. 32.
Hong
YM. Atherosclerotic cardiovascular disease beginning in childhood (2010) Korean
Circ J 40: 1-9. https://doi.org/10.4070/kcj.2010.40.1.1 33.
Berenson
GS, Srinivasan SR, Bao W, Newman WP and Tracy RE. Association between Multiple
Cardiovascular Risk Factors and Atherosclerosis in Children and Young Adults (1998)
Engl J Med 338: 1650-1656 https://doi.org/10.1056/NEJM199806043382302 34. Baker-Nigh
A, Vahedi S, Davis EG, Weintraub S, Bigio EH, et al. Neuronal amyloid-β
accumulation within cholinergic basal forebrain in ageing and Alzheimers
disease (2015) Brain 138: 1722-1737. https://doi.org/10.1093/brain/awv024 35.
Hajishengallis
G. Periodontitis: from microbial immune subversion to systemic inflammation (2015)
Nat Rev Immunol 15: 30-44. https://doi.org/10.1038/nri3785 36.
Marques
TM, Cryan JF, Shanahan F, Fitzgerald GF, Ross RP, et al. Gut microbiota
modulation and implications for host health: dietary strategies to influence
the gut-brain axis (2014) Innov Food Sci Emerg Technol 22: 239-47. https://doi.org/10.1016/j.ifset.2013.10.016 37.
Walsh
CJ, Guinane CM, OToole PW and Cotter PD. Beneficial modulation of the gut
microbiota (2014) FEBS Lett 588: 4120-4130. https://doi.org/10.1016/j.febslet.2014.03.035 38.
Okada
H, Kuhn C, Feillet H and Bach JF. The hygiene hypothesis for autoimmune and
allergic diseases: an update (2010) Clin Exp Immunol 160: 1-9. https://doi.org/10.1111/j.1365-2249.2010.04139.x 39.
Thomas
S, Izard J, Walsh E, Batich K, Chongsathidkiet P, et al. The Host Microbiome
Regulates and Maintains Human Health: A Primer and Perspective for
Non-Microbiologists (2017) Cancer Res 77: 1783-1812. https://doi.org/10.1158/0008-5472.CAN-16-2929 40. Barengolts
E. Gut Microbiota, Prebiotics, Probiotics, And Synbiotics In Management Of
Obesity And Prediabetes: Review Of Randomized Controlled Trials (2016) Endoc
Prac 22: 1224-1234. https://doi.org/10.4158/EP151157.RA 41.
Kang
DW, Adams JB, Gregory AC, Borody T, Chittick L, et al. Microbiota Transfer
Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms:
an open-label study (2017) Microbiome 5: 10. https://doi.org/10.1186/s40168-016-0225-7 42.
Swartwout
B and Luo XM. Implications of Probiotics on the Maternal-Neonatal Interface:
Gut Microbiota, Immunomodulation, and Autoimmunity (2018) Front Immunol 9:
2840. https://doi.org/10.3389/fimmu.2018.02840 43.
Tsai
YL, Lin TL, Chang CJ, Wu TR, Lai WF, et al. Probiotics, prebiotics and
amelioration of diseases (2019) J biomed sci 26: 3. https://doi.org/10.1186/s12929-018-0493-6 44.
Singh
RK, Chang HW, Yan D, Lee KM, Ucmak D, et al. Influence of diet on the gut
microbiome and implications for human health (2017) J Transl Med 15: 73 https://doi.org/10.1186/s12967-017-1175-y 45.
Mach
N and Fuster-Botella D. Endurance exercise and gut microbiota: A review (2016) J
Sport Health Sci 6: 179-197. https://doi.org/10.1016/j.jshs.2016.05.001 46.
Qi
Y and Wade PA. Crosstalk between the microbiome and epigenome: messages from
bugs (2017) J Biochem1 63: 105-112. https://doi.org/10.1093/jb/mvx080 47.
Kelly
JR, Minuto C, Cryan JF, Clarke G and Dinan, TG. Cross Talk: The Microbiota and
Neurodevelopmental Disorders (2017) Front Neurosci 11: 490. https://doi.org/10.3389/fnins.2017.00490 48.
Lach
G, Schellekens H, Dinan TG and Cryan JF. Anxiety, Depression, and the
Microbiome: A Role for Gut Peptides (2017) Neurotherapeutics 15: 36-59. https://doi.org/10.1007/s13311-017-0585-0 49.
Strandwitz
P, Kim KH, Terekhova D, Liu JK, Anukriti Sharmaet, et al. GABA-modulating
bacteria of the human gut microbiota (2019) Nature Microbiol 4: 396-403.
https://www.nature.com/articles/s41564-018-0307-3 50.
Föcking
M, Doyle B, Munawar N, Dillon ET, Cotter D, et al. Epigenetic Factors in
Schizophrenia: Mechanisms and Experimental Approaches (2019) Mol
Neuropsychiatry. 5:6-12. https://doi.org/10.1159/000495063 51.
MacFabe
DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, et al.
Neurobiological effects of intraventricular propionic acid in rats: possible
role of short chain fatty acids on the pathogenesis and characteristics of
autism spectrum disorders (2007) Behav Brain Res 176: 149-69. https://doi.org/10.1016/j.bbr.2006.07.025 52.
Shultz
SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, et al. Intracerebroventricular
injection of propionic acid, an enteric bacterial metabolic end-product,
impairs social behavior in the rat: implications for an animal model of autism
(2008) Neuropharmacology 54: 901-911. https://doi.org/10.1016/j.neuropharm.2008.01.013 53.
Shultz
SR, Macfabe DF, Martin S, Jackson J, Taylor R, et al. Intracerebroventricular
injections of the enteric bacterial metabolic product propionic acid impairs
cognition and sensorimotor ability in the Long-Evans rat: further development
of a rodent model of autism (2009) Behav Brain Res 200: 33-34. https://doi.org/10.1016/j.bbr.2008.12.023 54.
MacFabe
DF, Cain NE, Boon F, Ossenkopp KP and Cain DP. Effects of the enteric bacterial
metabolic product propionic acid on object-directed behavior, social behavior,
cognition, and neuroinflammation in adolescent rats: Relevance to autism
spectrum disorder (2011) Behav Brain Res 217: 47-54. https://doi.org/10.1016/j.bbr.2010.10.005 55.
Rose
S, Bennuri SC, Davis JE, Wynne R, Slattery JC, et al. Butyrate enhances
mitochondrial function during oxidative stress in cell lines from boys with
autism (2018) Translational Psychiatry 8: 42. https://doi.org/10.1038/s41398-017-0089-z 56.
Wikoff
WR, Anfora AT, Liu J, Schultz PG, Lesley SA, et al. Metabolomics analysis
reveals large effects of gut microflora on mammalian blood metabolites (2009) Proceedings
of the National Academy of Sciences of the United States of America, USA 106:
3698-3703. https://doi.org/10.1073/pnas.0812874106 57.
Parthasarathy
A, Cross PJ, Dobson R, Adams LE, Savka MA, et al. A Three-Ring Circus:
Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the
Health of Plants and Animals (2018) Front Mol Biosci 5: 29. https://doi.org/10.3389/fmolb.2018.00029 58.
Argou-Cardozo
I and Zeidán-Chuliá F. Clostridium Bacteria and Autism Spectrum Conditions: A
Systematic Review and Hypothetical Contribution of Environmental Glyphosate
Levels (2018) Med Sci (Basel) 6: 29. https://doi.org/10.3390/medsci6020029 59.
Hooks
KB and OMalley MA. Dysbiosis and Its Discontents (2017) mBio 8: e01492-1517. https://doi.org/10.1128/mbio.01492-17 60.
Park
M, Loverdo C, Schreiber SJ and Lloyd-Smith JO. Multiple scales of selection
influence the evolutionary emergence of novel pathogens (2013) Philo Transac
Roy Soc London Series B Biol Sci 368: 20120333. https://doi.org/10.1098/rstb.2012.0333 61.
Han
BA, Kramer AM and Drake JM. Global Patterns of Zoonotic Disease in Mammals
(2016) Trends Parasitol 32:565-577. https://doi.org/10.1016/j.pt.2016.04.007 62.
Davis
IJ, Wallis C, Deusch O, Colyer A, Milella L, et al. A cross-sectional survey of
bacterial species in plaque from client owned dogs with healthy gingiva,
gingivitis or mild periodontitis (2013) PloS one 8: e83158. https://doi.org/10.1371/journal.pone.0083158 63.
Yamasaki
Y, Nomura R, Nakano K, Naka S, Matsumoto-Nakano M, et al. Distribution of
periodontopathic bacterial species in dogs and their owners (2012) Arch Oral
Biol 57: 1183-1188. https://doi.org/10.1016/j.archoralbio.2012.02.015 64.
Hillman
JD, McDonell E, Hillman CH, Zahradnik RT and Soni MG. Safety assessment of
probiora3, a probiotic mouthwash: subchronic toxicity study in rats (2009) Int
J Toxicol 28: 357-367. https://doi.org/10.1177/1091581809340705 65.
Dye
BA, Thornton-Evans G, Xianfen L and Iafolla TJ. Dental caries and tooth loss in
adults in the United States, 2011-2012 (2015) NCHS Data Brief 197. 66.
Islam
B, Khan SN and Khan AU. Dental caries: from infection to prevention (2007) Med
Sci Monit 13: RA196-203. 67.
Meurman
JH and Stamatova I. Probiotics: contributions to oral health (2007) Oral
Diseases 13: 443-451. https://doi.org/10.1111/j.1601-0825.2007.01386.x 68.
Meurman
JH, 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 (1994) Microb Ecol Health Dis 7: 295-298. https://doi.org/10.3109/08910609409141368 69.
Nase
L, Hatakka K, Savilahti E, Saxelin M, Ponka A, et al. Effect of long-term
consumption of a probiotic bacterium, Lactobacillus rhamnosus GG, in milk on
dental caries and caries risk in children (2001) Caries Res35: 412-420. https://doi.org/10.1159/000047484 70.
Ahola
AJ, Yli-Knuuttila H, Suomalainen T, Poussa T, Ahlström A, et al. Short-term
consumption of probiotic-containing cheese and its effect on dental caries risk
factors (2002)Arch Oral Biol 47: 799-804. 71.
Nikawa
H, Makihira S, Fukushima H, Nishimura H, Ozaki Y, et al. Lactobacillus reuteri
in bovine milk fermented decreases the oral carriage of mutans streptococci
(2004)Int J Food Microbiol 95: 219-223. https://doi.org/10.1016/j.ijfoodmicro.2004.03.006 72.
Cildir
SK, Germec D, Sandalli N, Ozdemir FI, Arun T, et al. Reduction of salivary
mutans streptococci in orthodontic patients during daily consumption of yoghurt
containing probiotic bacteria (2009) Eur J Orthod 31: 407-411. https://doi.org/10.1093/ejo/cjn108 73.
Hedayati-Hajikand
T, Lundberg U, Eldh C and Twetman. Effect of probiotic chewing tablets on early
childhood caries-a randomized controlled trial (2015) BMC oral health 15: 112. https://doi.org/10.1186/s12903-015-0096-5 74.
Janakiram
C, Deepan Kumar CV and Joseph J. Xylitol in preventing dental caries: a
systematic review and meta-analyses (2017) J Nat Sci Biol Med 8: 16-21. https://doi.org/10.4103/0976-9668.198344 75.
Sánchez
MC, Romero-Lastra P, Ribeiro-Vidal H, Llama-Palacios A and Figuero E.
Comparative gene expression analysis of planktonic Porphyromonas gingivalis ATCC 33277 in the presence of a growing
biofilm versus planktonic cells (2019) BMC Microbiol 19: 58. https://doi.org/10.1186/s12866-019-1423-9 76.
Badet
C, Furiga A and Thébaud N.Effect of xylitol on an in vitro model of oral
biofilm (2008) Oral Health Prev Dent 6: 337-341. 77.
Janus
MM, Volgenant CMC, Brandt BW, Buijs MJ, Keijser BJF, et al. Effect of
erythritol on microbial ecology of in vitro gingivitis biofilms (2017)J Oral
Microbiol 9: 1. https://doi.org/10.1080/20002297.2017.1337477 78.
Söderling
E, Hietala and Lenkkeri AM. Xylitol and erythritol decrease adherence of
polysaccharide-producing oral streptococci (2010) Curr Microbiol 60: 22-29. https://doi.org/10.1007/s00284-009-9496-6 79.
Ferreira
AS, Silva-Paes-Leme AF, Raposo NR and da Silva SS.By passing microbial
resistance: xylitol controls microorganisms growth by means of its
anti-adherence property (2015) Curr Pharm Biotechnol 16: 35-42. 80.
Ghezelbash
GR, Nahvi I and Rabbani M. Comparative inhibitory effect of xylitol and
erythritol on the growth and biofilm formation of oral Streptococci (2012) AJMR
6: 4404-4408. 81.
Brambilla
E, Ionescu AC, Cazzaniga G, Ottobelli M and Samaranayake LP. Levorotatory
carbohydrates and xylitol subdue Streptococcus
mutans and Candida albicans
adhesion and biofilm formation (2015) J Basic Microbiol 56: 480-492. https://doi.org/10.1002/jobm.201500329 82.
Sardi
JC, Duque C, Mariano FS, Peixoto IT, Höfling JF, et al. Candida spp. in
periodontal disease: a brief review (2010) J Oral Sci 52: 177-185.https://doi.org/10.2334/josnusd.52.177 83.
De-La-Torre
J, Quindós G, Marcos-Arias C, Marichalar-Mendia X, Gainza ML, et al. Oral
candida colonization in patients with chronic periodontitis. Is there any
relationship (2018) Rev Iberoam Micol 35: 134-139. https://doi.org/10.1016/j.riam.2018.03.005 84.
Rodrigues
CF, Rodrigues ME and Henriques M. Candida sp. infections in patients with
diabetes mellitus (2019) J Clin Med 8: 76. https://doi.org/10.3390/jcm8010076 85.
Vargas
SL, Patrick CC, Ayers GD and Hughes WT. Modulating effect of dietary
carbohydrate supplementation on Candida
albicans colonization and invasion in a neutropenic mouse model (1993)
Infect Immun 61: 619-626. 86.
Van
Ende M, Wijnants S and Van Dijck P. Sugar sensing and signaling in Candida albicans and Candida glabrata (2019) Front Microbiol
10: 99. https://doi.org/10.3389/fmicb.2019.00099 87.
Bartnicka
D, Karkowska-Kuleta J, Zawrotniak M, Satała D, Michalik K, et al. Adhesive
protein-mediated cross-talk between Candida
albicans and Porphyromonas gingivalis
in dual species biofilm protects the anaerobic bacterium in unfavorable oxic
environment (2019) Sci Rep 9: 4376. https://doi.org/10.1038/s41598-019-40771-8 88.
Ichikawa
T, Yano Y, Fujita Y, Kashiwabara T and Nagao K. The enhancement effect of three
sugar alcohols on the fungicidal effect of benzethonium chloride toward Candida
albicans (2008) J Dent 36: 965-968. https://doi.org/10.1016/j.jdent.2008.07.013 89.
Kim
J, Yoon-Young Kim, Ji-Youn Chang and Hong-Seop Kho. Candidacidal activity of
xylitol and sorbitol (2016) J Oral Med Pain 41: 155-160 https://doi.org/10.14476/jomp.2016.41.4.155 90.
Lipińska
L, Klewicki R, Sójka M, Bonikowski R, Żyżelewicz D, et al. Antifungal activity
of lactobacillus pentosus ŁOCK 0979 in the presence of polyols and
galactosyl-polyols (2017) Probiotics Antimicrob Proteins 10: 186-200. https://doi.org/10.1007/s12602-017-9344-0 91.
Lim
JH, Jeong Y, Song SH, Ahn JH, Lee JR, et al. Penetration of an antimicrobial
zinc-sugar alcohol complex into Streptococcus
mutans biofilms (2018) Scientific Reports 8: 16154. https://doi.org/10.1038/s41598-018-34366-y 92.
Arimoto
T, Ansai T, Yu W, Turner AJ and Takehara T. Kinetic analysis of PPi-dependent
phosphofructokinase from Porphyromonas
gingivalis (2002) FEMS Microbiology Letters 207:35-38.https://doi.org/10.1111/j.1574-6968.2002.tb11024.x 93.
Han
SJ, Jeong SY, Nam YJ, Yang KH, Lim HS, et al. Xylitol inhibits inflammatory
cytokine expression induced by lipopolysaccharide from Porphyromonas gingivalis (2005) Clin Diagn Lab Immunol 12: 1285-1291.
https://doi.org/10.1128/CDLI.12.11.1285-1291.2005 94.
Park
E, Na HS, Kim SM, Wallet S, Cha S, et al. Xylitol, an anticaries agent,
exhibits potent inhibition of inflammatory responses in human THP-1-derived
macrophages infected with Porphyromonas
gingivalis (2014) J Periodontol 85: e212-e223. https://doi.org/10.1902/jop.2014.130455 95.
Luostarinen
V, Paunio J, Varrela M, Rekola M, Luoma S, et al. Turku sugar studies, XV.
Vascular reactions in the hamster cheek pouch to human gingival exudate (1975)
Acta Odontologica Scandinavica 33: 287-291. 96.
Harjola
U and Liesmaa H. Effects of polyol and sucrose candies on plaque, gingivitis
and lactobacillus index scores (1978) Acta Odontologica Scandinavica 36:
237-242. 97.
Tenovuo
J, Mielityinen H and Paunio K.Effect of dental plaque grown in the presence of
xylitol or sucrose on bone resorption in vitro (1981) Pharmacol Ther Dent 6: 35-43. 98.
Mielityinen
H, Tenovuo J, Söderling E and Paunio K. Effect of xylitol and sucrose plaque on
release of lysosomal enzymes from bones and macrophages in vitro (1983) Acta
Odontol Scand 41: 173-180. 99.
Mäkinen
KK, Pemberton D, Cole J, Mäkinen PL, Chen CY, et al. Saliva stimulants and the
oral health of geriatric patients (1995) Adv Dental Research 9: 125-126.
https://doi.org/10.1177/08959374950090020901 100.
Shyama
M, Honkala E, Honkala S and Al-Mutawa SA.Effect of xylitol candies on plaque
and gingival indices in physically disabled school pupils (2006) Clin Dent 17: 17-21. 101.
Hashino
E, Kuboniwa M, Alghamdi SA, Yamaguchi M, Yamamoto R, et al. Erythritol alters
microstructure and metabolomic profiles of biofilm composed of Streptococcus gordonii and Porphyromonas gingivalis (2013) Mol
Oral Microbiol 28: 435-451. https://doi.org/10.1111/omi.12037 102.
How
KY, Song KP and Chan KG. Porphyromonas
gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line
(2016) Frontiers in microbiology 7: 53. https://doi.org/10.3389/fmicb.2016.00053 103.
Zenobia
C and Hajishengallis G. Porphyromonas
gingivalis virulence factors involved in subversion of leukocytes and microbial
dysbiosis (2015) Virulence 6: 236-243. https://doi.org/10.1080/21505594.2014.999567 104.
Boesten
DM, Berger A, De Cock P, Dong H, Hammock BD, et al. Multi-targeted mechanisms
underlying the endothelial protective effects of the diabetic-safe sweetener
erythritol (2013) PLoS One 8: e65741. https://doi.org/10.1371/journal.pone.0065741 105.
Park
E, Sam Na H, Min Kim S, Wallet S, Cha S, et al. Xylitol, an anticaries agent,
exhibits potent inhibition of inflammatory responses in human thp-1-derived
macrophages infected with porphyromonas
gingivalis (2014) J Periodontol 85: e212–e223. https://doi.org/10.1902/jop.2014.130455 106.
Nayak
PA, Nayak UA and Khandelwal V. The effect of xylitol on dental caries and oral
flora (2014) Clin Cosmet Investig Dent 6: 89-94. https://doi.org/10.2147/CCIDE.S55761 107.
Söderling
E, Isokangas P, Pienihäkkinen K and Tenovuo J. Influence of maternal xylitol
consumption on acquisition of mutans streptococci by infants (2000) J Dent Res
79: 882-887. https://doi.org/10.1177/00220345000790031601 108.
Falony
G, Honkala S, Runnel R, Olak J, Nõmmela R, et al. Long-term effect of
erythritol on dental caries development during childhood: a post-treatment
survival analysis (2016) Caries Res 50: 579-588. https://doi.org/10.1159/000450762 109.
Ur-Rehman
S, Mushtaq Z, Zahoor T, Jamil A and Murtaza MA. Xylitol: a review on
bioproduction, application, health benefits, and related safety issues (2015)
Crit Rev Food Sci Nutr 55: 1514-1528. https://doi.org/10.1080/10408398.2012.702288 110.
Cock PD. Erythritol functional roles in
oral-systemic health (2018) Advances in Dental Research 29: 104-109. https://doi.org/10.1177/0022034517736499 111. Pussinen
PJ, Paju S, Koponen J, Viikari JSA, Taittonen L, et al. Association of
Childhood Oral Infections With Cardiovascular Risk Factors and Subclinical Atherosclerosis in
Adulthood (2019) JAMA Netw Open 2: e192523. https://doi.org/10.1001/jamanetworkopen.2019.2523 Mark L Cannon,
Professor,
Division of Dentistry, Department of Otolaryngology, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois, USA,
Tel: 847-899-6720, E-mail: drmarkcannon@outlook.com
Cannon ML and Peldyak JN. The prevention and
treatment of neural arterial gingival simplex (2019) Dental Res Manag 3: 32-37 Neural arterial gingival simplex, Porphyromonas gingivalis, Alzheimer’s disease, Polyols.The Prevention and Treatment of Neural Arterial Gingival Simplex
Cannon L Mark and Peldyak N John
Abstract
Full-Text
Introduction
Evolution
Guerilla Tactics
Prevention
Treatment
Conclusion
References
*Corresponding author
Citation
Keywords