Review Article :
The Prevention and Treatment of Neural Arterial Gingival Simplex
Cannon L Mark and Peldyak N John
Abstract
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.
Full-Text
Introduction
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.
Evolution
Guerilla Tactics
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].
Prevention
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].
Treatment
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.
Conclusion
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.
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*Corresponding author
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
Citation
Cannon ML and Peldyak JN. The prevention and
treatment of neural arterial gingival simplex (2019) Dental Res Manag 3: 32-37
Keywords
Neural arterial gingival simplex, Porphyromonas gingivalis, Alzheimer’s disease, Polyols.
