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Citation: Cliff Shunsheng Han, Oral Probiotic Deficiency May Cause Common Allergies – Theory of Negative Trigger Marks the Interaction between Microbiota and Host Immune System. website: https://allerpops.com/oral-probiotic-deficiency-may-cause-common-allergies/, published by Knoze Jr Corp on 11/17/2019.

Prebiotic Lollipops Promote Oral Probiotics Resulting in Lasting Allergy Relief – Oral Probiotic Deficiency Is the Cause of Allergies

Cliff Shunsheng Han1*

1 Knoze Jr Corp., 1650 Trinity Dr., Suite 103, Los Alamos, NM 87544.

*Correspondence to Cliff S. Han, Knoze Jr Corp., 1650 Trinity Dr., Suite 103, Los Alamos, NM 87544. Email: cliffhan@allerpops.com

Abstract

This study seeks to identify causes for common allergies and to develop translational measures to treat common allergies (allergic rhinitis). For this reason, I performed a longitudinal, cross-sectional, and translational study of oral microbiota that lasted for three years. With the help of an unusual allergy case of an immigrant, I identified the cause of his allergies. And the attempt to correct the cause was a great success with lasting allergy relief.

The results of the study indicate that the direct mechanism behind common allergies may be an oral probiotic deficiency. In other words, the lack of beneficial bacteria, Streptococcus, and Veilonella, in the oral/nasal cavities causes allergies. These bacteria are mutualists. Together, they produce metabolites that pacify the nearby immune system. With this in mind, I developed a prebiotic mix to promote those probiotics. As a result, the subject reached long-term remission from his allergies.

In addition, the study led to the development of the Theory of Negative Trigger (TNT). TNT advocates that oral probiotics are a negative trigger that controls the immune system so that the host and hosted microbiota can make peace with each other. As a consequence of the theory, we may modulate the interaction between microbiota and the immune system to prevent, treat, and even cure allergies, autoimmune diseases, and potentially cancers.

List of abbreviations: TNT, Theory of Negative Trigger; OTU, operational taxonomic unit; QIIME, Quantitative Insights Into Microbial Ecology

Introduction

More than 30 years ago, Dr. Strachan proposed the hygiene hypothesis to explain the increase of allergy diseases (Strachan, 1989). Subsequently, many studies suggest that personal and social hygiene practices have an association with the epidemic of allergy diseases (von Mutius, 2007). The hypothesis currently emphasizes the exposure of diverse environmental bacteria rather than infection (Ege et al., 2012Jatzlauk et al., 2017). Allergic subjects are found to have microbiota dysbiosis (Chung, 2017). Indeed, certain bacteria interact with the immune system through metabolites or structural molecules produced by bacteria (Blacher et al., 2017Gensollen et al., 2016). However, attempts at using probiotics to cure or prevent allergy diseases have had limited success (West et al., 2016).

In all those trails, researchers used probiotics that live in the gut. Instead of focusing on the remote interaction between gut and airway, I examined the local interaction between microbiota living in the airway and the immune system residing around the respiratory tracts. As a result, this study illustrates that the restructuring of oral microbiota can lead to lasting remissions of common allergies (allergic rhinitis).

In this article, we use allergies as equivalent to common allergies and allergic rhinitis.

Results

An unusually immigrant allergy sufferer

The subject (CSH, the author) started to have allergies in spring 2014, 18 years after immigrating to the US in the late nineties. His symptoms included nasal congestion, rhinorrhea, red and itchy eyes, tearing, coughing, aches in the throat, and a tight chest. According to a study in Italy immigrants usually develop common allergies within 3-5 years after immigration (Lombardi et al., 2008). Unlike those typical cases, this 18-year lapse between immigration and the development of the symptoms is extremely long. In fact, this long lapse might indicate that the underlying cause was likely to be personal rather than environmental.

Intensified oral hygiene before the onset of allergies points to the potential cause of allergies to the mouth.

Prior to the appearance of the first symptoms, the subject intensified his oral hygiene routine. In his first ten years in the US, he brushed his teeth only once a day.  Gradually, he began introducing additional dental hygienic practices, such as dental cleaning, flossing, tongue scraping, and using mouthwash. Eventually, in the winter before allergy symptoms first appeared, CSH brushed and flossed his teeth once every day. He also scraped tongue several times a week and used mouthwash frequently. In addition, he took antibiotics for a week to treat a lasting cough. Researchers observed the association between allergy and antibiotic use (Foliaki et al., 2009).

After reflection of his life in the past 18 years, CSH suspected that changes in his oral microbiota might have contributed to the development of his allergies. So, he began to collect samples of his saliva and for a comparison fecal matter as well, periodically. Altogether, the sample collection continued until spring 2017 (Table 1). However, I present here only data from saliva samples as no positive result was found from fecal samples.

The unexpected change of CSH’s allergies makes the whole study possible.

The first episode of CSH’s allergic rhinitis lasted for a year and a half. It ended in the summer of 2015 and became seasonal afterward. During this time, CSH experimented to reduce his oral hygiene for several weeks. As a consequence, local moderate periodontitis developed as well as bleeding and gum recession, but his allergy symptoms persisted. Resuming brushing and flossing for two weeks healed the inflammation, while the allergy symptoms continued. After that time, his only oral hygiene practice was to brush his teeth once a day without toothpaste. His allergy symptoms alleviated during two 4-8 week trips abroad but never completely went away before the summer of 2015 (Timeline in Table 1 and Figure 1A).

For comparison, saliva samples of his family members were also collected (Table 1). Together the samples collected before 2017 were sequenced and analyzed using a commercial service (Supplemental material). Yet, the result did not show any significant difference between the fecal samples before and after summer 2015 (data not shown).

The changes in two groups of bacteria in the subject’s mouth before and after the end of yearlong allergies in the summer of 2016 hint what may cause the allergies.

The results of CSH’s saliva samples show that the relative abundance of Veillonella increased (p=0.042) in saliva samples collected after summer 2015 (Figure 1A & 1B). Besides that, an increase in Streptococcus was not significant. The initial analysis indicated that the difference in abundance of Veillonella in CSH and his family members is not significant. However, one family member also suffers from seasonal allergies. His saliva had Veillonella at a level of half of those of non-allergic family members. The average abundance of Veillonella in the two non-allergic family members was 5-6 times as high as those in the two subjects with allergies. Also, two of the three OTUs (operational taxonomic units) in the genus of Streptococcus had similar distribution patterns in the family as Veillonella (Figure 1C).

Table 1. Samples collected for this study.
The abundance of probiotics is associated with clinic progress of allergies. Promotion of those probiotics relieved allergies symptoms. Together, Longitudinal, cross-sectional, and translational studies point out that not having enough oral probiotics cause allergies.
Figure 1. Consistent changes of the genera Streptococcus and Veillonella along the clinic course and prebiotic intervention indicate their causal role in allergies.  A. The relative abundance of Veillonella in samples before and after the change of yearlong allergies to seasonal allergies. B. The relative abundance of genera that are significantly changed after the transition from a yearlong allergy to seasonal allergy. A double-sided t-test was used in the analysis. C. Two OTUs of Streptococcus and Veillonella are less abundant in the saliva samples from subjects with allergies than those from people without allergies. D. The abundance of two OTUs belongs to Streptococcus and that of genus Veillonella increased after prebiotic induction and remission of allergies.

The hypothesis for the cause of allergies

Numerous studies indicate that Streptococcus and Veillonella grow together in the oral cavity with a mutualistic relationship (Takei et al., 1968van der Hoeven et al., 1978). Streptococcus attaches itself to surfaces, and Veillonella metabolizes the cavity-inducing lactic acid from the Streptococcus and converts it into short-chain fatty acids (SCFA). SCFA not only is less toxic than lactic acid but also benefit the human host in many other ways. And one of them is especially relevant to this study: they interact with the immune system to reduce inflammation (Correa-Oliveira et al., 2016).

Like the gut, the respiratory tract is another vulnerable interface between humans and the outside world. The immune system, such as tonsil, surrounds the airway from the mouth/nose to the bronchi. Because the results show a reduction of probiotics when the allergies were severe, I formed a hypothesis as follows. Not having enough oral probiotics is the cause of allergic rhinitis. In other words, we may moderate or eliminate allergy symptoms if we use prebiotics to raise the level of those relevant bacteria in the oral cavity.

Prebiotic produced allergy relief

Given these findings, I developed a prebiotic mix (U.S.Pat. No. 9,795,579). The composition contains sugars and arginine. The ingredients promote the growth of selected bacteria. They are picked based on the fermentation profile of Streptococcus and Veillonella, both as individual species and as a community (Han, 2017Kolderman et al., 2015Willcox, 1996).

Both  CSH and the other family member with allergies took the prebiotic mix several times a day in the early/middle of March 2017 when their allergies were at their peak. Those attempts alleviated the allergy symptoms significantly. Both subjects did not have to take any other medication for their allergies. However, the relief from their symptoms was temporary. They had to take the oral prebiotic mix several times a day to have continued success.

Accidental illness suggested that cleaning of oral microbiota is necessary for promoting oral probiotics, the true cause of allergies.

Five days after taking the prebiotic composition, CSH developed a fever likely due to an infection of the bronchi. He possibly contracted the infection from another family member who had become sick a week before. His temperature was between 38-39०C, accompanied by a phlegmy cough. CSH stopped using the compound once the fever began.

On the second day of the illness, he noticed that his tongue was completely red and absent from the natural biofilm. Like a farmer facing a burned field, he suspected that his fever/infection had cleared the micro eco-space in his oral cavity. The fever produced a unique opportunity for restructuring his oral microbiota.

The miraculous relief

In response, CSH took two doses of the prebiotic mix as soon as his fever receded. Surprisingly, the next day, March 15 of 2017, he found his allergic symptoms gone without taking any medicines. To clear the oral micro eco-space for the other family member with allergies, he developed a hot-water-based method (Supplementary Figure 1). That was gargling hot water for 10 minutes after brushing the teeth with water and scraping the tongue with a wet washcloth. The family member took some of the prebiotic mixes immediately after the cleaning process. And his allergies went into remission as well. After that, both CSH and this family member no longer required allergy medicines for the rest of the 2017 spring season.

The results indicate that our hypothesis is correct: oral probiotic deficiency is very likely the underlying cause of allergies. To further confirm the theory, I wanted to see if the targeted bacteria increased after the treatments.

The hot water based method clean oral biofilm better and led to a better results in allergy relief from the AllerPops prebiotic miix.
Supplementary Figure 1. Rinsing the mouth with hot water is more effective in removing biofilm than with rinsing with cold water. H, rinsing the mouth with water with a temperature of 46-49०C. C, with water at room temperature. 0, the tongue before rinsing; 10, the tongue after 10 minutes continuous rinsing; and 20 a picture of the tongue after 20 minutes continuous rinsing.
The measure of microbiome confirms the cause of allergies is lacking oral probiotics.

Approximately three weeks after their remission, the last batch of saliva samples was collected. I sequenced the samples and analyzed the data together with the previous dataset using the same service provider. The results showed that the relative abundance of Streptococcus and Veillonella increased in the final samples from both allergy subjects. The ratios of change varied between subjects and genera (Figure 1D). Therefore, the results support my theory that a low abundance of oral probiotic is the cause of allergies. The differences between the NSA23 and NSA25 samples from the non-allergic family member were likely due to an unrelated cause (Figure 1 D).

Cross-sample diversity analysis confirms that prebiotic treatment likely caused structural changes in the oral microbial community. Sample CSA25 after the prebiotic treatment is significantly different from the samples collected before the prebiotic treatment (Figure 2). The samples after the treatment were closer to the ones from the non-allergic family members (Supplementary figure 2). These changes in oral microbiota are consistent with our theory on the cause of allergies.

The microbiome analysis indicate AllerPops prebiotic mix can change the oral microbiota structure that is relevant to allergies. This explains why we have allergies.
Figure 2. Non-metric multidimensional scaling shows that microbiota structures in the saliva are profoundly changed after prebiotic induction. CSA25, collected after induction, is much further away from the rest of the samples of the same subject.
Healthy oral microbiota reduce the odd to have allergies and support the theory that oral probiotic deficiency is the cause of allergies.
Supplementary Figure 2. Microbiota structures in the saliva are profoundly changed after prebiotic induction. A sample cluster analysis with Unifrac distance indicates that CSA25 and BSA25 are closer to samples from non-allergic subjects.

Discussions

Theory of Negative Trigger

The induced microbiota changes and immediate and lasting clinical responses to the intervention, though from a limited sample size, suggest a new theory for etiology of allergy rhinitis — the Theory of Negative Trigger (TNT), in which probiotics are the negative triggers that control the power of the immune system.

TNT recognizes that the local immune system next to the respiratory tract is the root of common allergies. This local influence is greater than that from the immune system in the gut. Metabolites, including SCFA, produced by local beneficial bacteria likely act as a continuous messenger/pacifier to the nearby immune system. Modern life events such as extreme oral hygiene or antibiotic usage, local pyrotherapy, or a fever, can remove/diminish trigger bacteria (Figure 3).

Under healthy conditions, responsible probiotics produce enough pacifying metabolites so that the immune system does not react to commensal bacteria and environmental allergens that do no harm (Figure 3A).

Figure 3. The Theory of Negative Trigger for interaction between oral probiotic bacteria that produce immune-pacifying metabolites and the immune system. A. The normal state, a proper dose of pacifying metabolites from probiotics calms the immune system so that it does not overreact to commensal microbiota and allergens. B. Allergic state, oral probiotics are suppressed, and an insufficient dose of pacifying metabolites results in an agitated immune system that overreacts to allergens. C. The acute infection leads to diminished pacifying metabolites and results in a strengthened immune system with more power to fight pathogens. D. An over-pacified immune system can lead to a vulnerability to infections. A solid line represents positive interaction; a dashed line represents negative interaction; the greyed line indicates minimal cooperation; the thickness of the line shows the relative scale of interaction.
What causes allergies

Figure 3B demonstrates how common allergies develop. Intensive oral hygiene causes the biofilm to become vulnerable and collapse under the assault of antibiotics (Abeles et al., 2016). This process suppresses oral probiotics. Species of bacteria that are less sensitive to antibiotics take over the ecospace occupied by previous probiotics. The immune system, without enough pacifying messengers from probiotics, then becomes hostile to allergens. Therefore, I propose a new name, oral probiotic deficiency, for not having enough good bacteria in the mouth. In this condition, reduced oral probiotics cannot produce enough peaceful messages to the immune system. The consequences of oral probiotic deficiency may include allergy and autoimmune conditions. In other words, the insufficiency of oral probiotics is the real cause of allergies.

In addition to allergies, the hypersensitive immune system may cause other inflammations in the airway. They include, for example, periodontitis, rhinosinusitis, and tonsillitis by attacking commensal bacteria (Figure 3B). Therefore, this theory can explain previously observed associations between oral “infectious” diseases and common allergies (Arbes and Matsui, 2011). In fact, taking the prebiotic composition relieved the allergic family member’s tonsillitis.

Activate the Immune system to fight infections

Figure 3C illustrates how the immune system regains its strength under pathogenic infection. First, the invading pathogen can directly out-compete probiotics that produce pacifying metabolites. Second, severe infection induces pyrogens that raise body temperature to inhibit or kill probiotics. Some probiotics, including Veillonella, are temperature-sensitive  (Carlier, 2015). Consequently, suppression of probiotics will cease or significantly reduce the production of relevant metabolites. That means restraints on, or brake of, the immune system disappear or loose.  Third, the pathogen causes damages to normal tissue and releases toxins that stimulate the immune system directly. The stimulation like an accelerator to the immune system. The immune system, without the brake and with the accelerator, will then regain its strength to fight pathogens. This mechanism could explain how fever increases immunity and helps the body fight diseases, even cancers (Atkinson, 1979).

Theoretically, too many immune pacifying metabolites from overgrowing probiotics may dampen the local immune system too much. When it happens, the immune system cannot fend off even the normal commensal bacteria. As a result, it leads to chronic or acute infection which would reshape the whole community structure (Figure 3D). Study on people under normal life conditions will help to verify that prediction, though.  The TNT hypothesis would benefit from further testing from many different perspectives: infection, allergy, and autoimmunity.

TNT has the following propositions:

First, to remove and reapply the triggers can be relatively easy and quick. Theoretically, the effects of the negative trigger should not last long after removing it. Many different cells in the human body can absorb and metabolize SCFAs. Otherwise, the power of the immune system cannot be released in time to protect the host. Several observations also support this proposition. First, the epidemic of common allergies progresses fairly quickly in a short time at a population level. Second, oral biofilm disappears in less than a day under moderate fever. Third, the prebiotic compound promotes oral probiotics and produces a fast and lasting allergy-relief.

Second, the gut has a less significant role in common allergies. This study indicates the interactions between probiotics and the immune system come primarily at the local level. Long-distance interaction or circulation of immune cells likely plays a secondary role.

Third, immune system programming is less important in this situation. Practically, this study showed that allergies started before two years of age can be reversed with the prebiotic mix. This result indicates that immune system programming may play a less important role in allergy development. The concept of a critical time for immune system development should be re-evaluated to determine what is programmed and what is impacted if critical time is missed.

Potential impact

This is all good news for many who have allergies, autoimmune diseases, inflammations, and other conditions (including cancer). Many people would benefit from releasing the power of the immune system or suppressing it. Developing a method to fine-tune the strength of the immune system temporally and spatially under these conditions would improve people’s health. For example, one may make the immune system more active by suppressing probiotics in the airway and gut with physical and chemical (include antibiotics) means and by adding immune stimulants (such as a vaccine). This may help to control chronic infection and cancers.

What are the critical components in a microbiota associated with a human host?

The theory also suggests the first critical component of a microbiota associated with a host should be the ones that can communicate with the host to make a peace agreement. Bacteria in this role should first not cause immediate harm to the host and second are able to send pacifying signals to the host immune system. In humans, this communication is likely achieved through bacteria producing short-chain fatty acids. They are Streptococcus and Veillonella in the mouth and airway, fiber digesting bacteria in the gut, C. Akney on the skin. It is not know how wide this mechanism exists cross animal/plant. The second component of healthy microbiota should be enough diversity to occupy all nutrient space with members not a harmful or even better benefit to the host.  The last components are guest members dropped in accidentally.

Conclusion

In short, we have discovered that the cause of allergies is an oral probiotic deficiency, which I have been verified with longitudinal, cross-sectional, and translational studies. Our new TNT suggests possible solutions to many practical issues. It explains why it is beneficial for parents to transfer their microbiota to their children by confinement of mother and newborn at the beginning of life, and fever should be kept if it is not too high. This theory also suggests what comprises healthy microbiota and whether it is possible to reshape microbiota for optimal immune status in other situations.

Declarations

Ethics approval and consent to participate: All Participates consented to participate.

Consent for publication: N/A

Availability of data and material: The sequence data is available upon request.

Competing interests: CSH is the owner of Knoze Jr Corp. that holds granted/pending patents covering the oral microbiota inducing method described here.

Funding: N/A

Author’s contributions: CSH is the sole author and responsible for the content of the manuscript.

Acknowledgments: I thank my family for giving their saliva samples. This study is impossible without their contribution. I am grateful for language editing by Shena Han and James Kennedy III. I thank the following people for reading and commenting on the manuscript: Armand Dichosa, Joe Alcock.

Materials and Methods & References