The pros and cons of oral bacteria(需要翻译)
By Rosemary Frei, MSc, DrBicuspid.com contributing writer
www.researchgate.net 科研资料共享
Philip D. Marsh 口腔生物学专家 出书《Oral Microbiology, 5e》
http://dental.case.edu/ Western Reserve University School of Dental Medicine
Nutri-Health Supplements and Life Extension, Designs for Health生态保健品公司，销售益生菌
http://www.dentistry.ucla.edu/about-us/faculty/shi Wenyuan Shi, PhD,个人网站
专业数据：人体稳态中，人与细菌共存，细菌分为有益菌和有害菌，部分细菌即有害又有利；某些疾病和特定细菌病毒有关；如果人体稳态中元数据发生急剧改变（例如ph值），致病菌可能占据主导地位，随后引发疾病。单纯用抗生素杀死致病菌对于某些疾病效果不好，如果找不到稳态改变的元数据，疾病反复发作
The mouth provides a hospitable environment for many microorganisms. It is warm, nutrient-rich, continuously bathed with saliva, and has a pH of between 6.75 and 7.25. Hence the oral cavity is home to a rich microbiota, most of which are beneficial organisms and live in harmony with each other and the host.
口腔 是一个适合许多微生物生长环境。温暖，营养丰富，唾液淋浴，ph值适中。大多数细菌是有益的，并和平共处。
The presence of microbes is in fact essential for maintaining the normal physiology of the oral cavity. While this symbiosis is usually stable and mutually beneficial, if some external force changes the balance, the result can be gingivitis, dental caries, or periodontal disease.
微生菌存在是为了维持口腔正常生理功能。 如果这个共生互惠平衡被外力破坏，结果可能是牙龈炎，牙周炎等等。
A significant body of knowledge is now available on how to maintain a healthy ecology of microbiota and keep diseases at bay. There is also a growing number of oral health products, from lozenges to mouthwashes, designed to optimize the balance of bacteria in the mouth, retain their beneficial characteristics, and suppress their potentially harmful impact.
Denizens of the oral cavity
Philip D. Marsh, PhD, is one of the leaders in this area and has been publishing papers on oral microbes for more than 35 years. He advises caution when seeking to interfere with the microbiological balance in the mouth in a bid to stem oral diseases.
Philip D. Marsh,指出，在抑制口腔疾病方面，干预口腔生态平衡要谨慎。
"What we‘ve been brought up with is ‘Plaque is bad -- get rid of it.‘ But it‘s actually too much plaque and plaque in the wrong places that are bad for us. We want to prevent the buildup of levels of organisms, particularly in hard-to-reach places of the mouth, that could lead to disease," said Marsh, a professor of oral microbiology at Leeds Dental Institute. "Pushing to have an ultraclean mouth isn‘t beneficial to us; we should be trying to maintain our natural microbiota at levels compatible with oral health in order to preserve their beneficial activities."
通常我们概念是牙斑是坏的，但太多牙斑和牙斑长在错误地方才是坏的。我们想要阻止微生物建立水平，特别是很难到达的口腔位置，这可能引起灾难。非常干净的口腔对我们不利。我们应该保持口腔中天然微生物，让他们进行有益人体生理功能。
Aaron Weinberg, DMD, PhD, agrees that trying to sterilize the mouth may lead the way for exogenous, deleterious organisms to colonize it instead
口腔消毒可能会引起外生，有害细菌入侵
"You don‘t want a sterile mouth; you want a mouth that has primarily good bacteria in it, in order to keep exogenous microorganisms out and prevent them from colonizing the mouth," said Dr. Weinberg, the associate dean for research at the Case Western Reserve University School of Dental Medicine.
Another faculty member at the Case Western Reserve University dental school who specializes in oral bacteria has a similar view. Yiping Weng Han, PhD, a professor of periodontics, pathology, and reproductive biology, focuses onFusobacterium nucleatum, as does Dr. Weinberg.
According to Dr. Han, the ultimate research goal is not to "search out and destroy" all cells of F. nucleatum, although the microbe is associated with serious diseases in the oral cavity and throughout the body.
"First of all, to eliminate all the bacteria is impractical, and it‘s also not ideal because then you have a surface that exogenous bacteria can colonize," she said. "Also, if we eliminate one species, we don‘t yet know the effects because there is a lot of interdependence among different species."
The importance of homeostasis
Biofilms form in a rapid sequence of events and mature into a complex, interacting community of microorganisms that have different properties than when they are present in isolation. The resulting community is more resistant to antimicrobial agents, stress, and host defenses, for example. Biofilms act as a barrier to organisms in the air, water, and food with which people constantly come into contact.
Among the main bacteria residing in the mouth -- including in biofilms -- in both health and disease are species that have traditionally been considered to be "bad," such as Streptococcus mutans, Tannerella forsythia, Porphyromonas gingivalis, and F. nucleatum. The bacteria that have been picked for the "good" team include S. sanguinis, S. oralis, Actinomyces naeslundii, Neisseria subflava, and Veillonella dispar.
However, it is now acknowledged that this is an artificial distinction. For example, F. nucleatum has been shown by the teams led by Drs. Weinberg and Han to have properties that can be exploited to benefit human health. ButF. nucleatum is also associated with gingivitis and a raft of serious diseases elsewhere in the body.
F. nucleatum 对人体健康有利也有害，但这种细菌被人为区分开，在口腔领域被认为是有益菌或有害菌，但在人体其它器官可能发挥好的作用，所以对它评价仍有争议
"While it is debatable whether F. nucleatum is a ‘good‘ or ‘bad‘ bug in the oral cavity, as soon as this fastidious anaerobe leaves its natural habitat -- that is, the mouth -- it becomes a bona fide ‘bad‘ bug," Dr. Han noted.
Several decades ago, researchers likened the interactions in the mouth to ecological systems in nature. Breakdowns in the normal balance between species on the planet can result from a number of causes and hence do not have one exclusive etiology. Similarly, Dr. Marsh believes, in the mouth, the key steps in the descent into disease relate to particular shifts in environmental circumstances rather than the actions of specific sets of microorganisms.
Dr. Marsh 人为在口腔中，得病的关键原因在于转换到一个特殊环境，而不是一个特殊微生物行为。
"If you take 100 examples of an organism that is implicated in dental caries -- S. mutans, for example -- you can find some that are very good at making acid and some that are not quite as good," Dr. Marsh explained. "We‘re not dealing with bacteria that produce toxins. We‘re dealing with bacteria whose metabolic end products can be deleterious and which grow best in the presence of those end products."
Dr. Weinberg has a similar view.
"This concept of ‘pathogenic organisms‘ is really overutilized,过度使用" he said. "Because when you say ‘pathogenic organism,‘ you‘re equating it to something that shouldn‘t be in the body. But in oral disease, these are organisms that have evolved over the millennia to grow and coexist with the host, albeit in low numbers."
致病微生物概念被过度使用，当用到 致病微生物时，我们想到是有害的，不应该存在体内，但在口腔中，这些微生物已经进化了千年，并与寄生体共存，即使数量非常少。
Dr. Weinberg‘s own research with F. nucleatum indicates that when the bacterium comes into contact with oral epithelial cells, the cells produce small proteins, which he has dubbed human beta-defensins. These are a group of antimicrobial peptides that kill bacteria, fungi, and encapsulated viruses, and represent the first line of defense for the mouth‘s lining. Dr. Weinberg‘s team has also isolated and characterized, from the outer membrane of F. nucleatum, the F. nucleatum-associated defensin inducer (FAD-I), which promotes the expression of human beta-defensins (Journal of Biological Chemistry, November 19, 2010, Vol. 285:47, pp. 36523-36531).
The team now is working to identify the "hot spots" of FAD-I that are directly responsible for this activity. The goal is eventually to be able to control and direct the production of endogenous antimicrobial peptides肽 in the oral mucosa and other vulnerable mucosal sites of the body.
"The idea is to use FAD-I in certain situations in the oral cavity where you want a particular site to be more sterile than others," Dr. Weinberg explained. "If you can induce the production of these peptides -- which are nature‘s own antibiotics -- we could possibly change the microflora of that particular site. And if we could use the peptides as an adjunct附属的 to conventional antibiotics, we may be able to reduce the antibiotic resistance that is prevalent in a number of bacteria."
For their part, Dr. Han and her co-investigators have begun identifying the mechanisms that allow F. nucleatum to move from the mouth into the bloodstream and thence throughout the body -- taking other bacteria with it and leaving destruction in their path (Molecular Microbiology, December 2011, Vol. 82:6, pp. 1468-1480). Her team has shown that F. nucleatum can induce preterm birth 早产and stillbirth 流产in animals and humans (see, for example, Obstetrics & Gynecology, February 2010, Vol. 115:suppl 2, part 2, pp. 442-445). Other researchers have linked it to colorectal 结肠直肠的cancer (Genome Research, October 18, 2011) and infections and abscesses 浓重in all the internal organs, including the brain and lungs.
F. nucleatum虽然引起牙周炎，但可以引诱早产。 F. nucleatum和直肠癌，内部器官浓重，肺炎，脑炎有关
A fine balance -- that can be destroyed
In a healthy mouth, biofilms perform many positive functions. As just one example, 25% of nitrates 硝酸盐from vegetables re-emerge i再次出现n the saliva. In the mouth, the nitrates are converted to nitrites, which in turn are converted to nitric oxide in the stomach (Free Radical Biology & Medicine, April 2009, Vol. 46:8, pp. 1068-1075). Nitric oxide has many important functions in maintaining good health, including helping control blood pressure.
在健康口腔中，生物膜起到很多积极作用。
In addition, some beneficial bacteria are now recognized as being capable of signaling to their hosts -- us -- that they are not harmful.
一些有益细菌能传递信号给宿主---他们没有害
"It has been shown -- first in the gut and now there are a couple of papers in dental journals on this relating to oral bacteria -- that the bacteria ‘talk‘ to the host to indicate they are beneficial: ‘Don‘t overreact to us, because we‘re doing you good.‘ That allows the host to focus, instead, on searching for microorganisms that are actually potential threats," said Dr. Marsh, citing one of several papers on the topic (Infection and Immunity, September 2008, Vol. 76:9, pp. 4163-4175).
When the natural balance in the mouth shifts significantly, bacteria with harmful effects can begin to dominate. pH and nutrient status are believed to be two of the main drivers of the descent into disease. For example, in people who have a diet high in simple carbohydrates or sugars, the pH of the mouth will drop more frequently and to lower levels than in people with a more healthful diet. This in turn leads to a significant increase in acid-tolerating bacteria such as S. mutans and the displacement of oral-health-associated, neutral-pH-loving bacteria.
当口腔自然平衡被突然转换，细菌有害性占据主动。ph值和营养状态被认为是引起疾病主要因素。 如果饮食中，单一含糖碳酸饮料过多，引起口腔ph值经常低于正常值。随后能忍受酸性细菌迅速繁殖，代替ph中性为主的细菌。
Another example is the increase in gram-negative proteolytic 格兰阴式蛋白质水解的bacteria in the presence of the inflammatory response that accompanies periodontal disease. These proteolytic bacteria can further exacerbate the inflammatory response, leading in turn to even worse damage to the teeth and surrounding tissues, as well as greater proliferation of damaging bacteria.
牙周炎会引起 格兰阴式蛋白质水解细菌增加进一步破坏口腔
"So it‘s a change in environment that selects for the more pathogenic organisms," Dr. Marsh explained. "Therefore, to deal with disease, it‘s not the best approach to only try to develop an agent that is ‘antiorganism X‘ or ‘antiorganism Y,‘ but rather to also try to deal with the pressures that cause the selection. Otherwise, it‘ll just happen over and over again."
所以是环境变化引起致病细菌增多，如果致病细菌占据主导地位，就会引发疾病。 如果不明病因而滥用抗生素，只会头痛医头，起不到根治效果.因此，为了解决疾病，我们不要开发抗生素杀灭细有害菌A或有害菌B，还要找到环境选择引起有害菌原因。否则会反复发生。
Other researchers have uncovered some interesting potential twists in this view of the oral microorganism-disease interaction. George Hajishengallis, DDS, PhD -- who recently moved from the University of Louisville to the University of Pennsylvania -- and his colleagues are challenging the traditional view of P. gingivalis‘ role in periodontitis (Cell Host & Microbe, November 2011, Vol. 10:5, pp. 497-506).
They hypothesize that P. gingivalis acts as a "keystone pathogen" and co-opts other bacteria into the destruction of bone. The scientists have shown that P. gingivalis is able to induce an inflammatory response to its presence without itself being attacked by inflammatory cells. The result is a flood of exudate into the periodontal space, which feeds both P. gingivalis and other bacterial species in the biofilm. The well-fed miniature army then proceeds to induce even more inflammation, which destroys the bone and surrounding tissue.
"So it‘s actually the altered microbiota that are causing the bone loss, notP. gingivalis itself, which remains at low concentrations," Dr. Hajishengallis said.
The key to this process is the ability of P. gingivalis to subvert the function of a key receptor on the surface of some inflammatory cells that recognizes a molecule known as complement component 5. Complement component 5 plays a crucial role in the inflammatory cascade. The result is the inflammatory cells are incapacitated. The researchers hope that the use of an antagonist that blocks the receptor can stop this action on the part of P. gingivalis.
"This is promising, and we are testing the possibility in animals," Dr. Hajishengallis said. "If we get encouraging results, we will start on human studies."
Dr. Hajishengallis‘ excitement at gaining new insights into the ancient relationship between humans and our tiny fellow travelers is shared by every researcher in the field -- including those who use the expanding knowledge to design products that optimize oral health.
New research yields new products
It isn‘t possible to fully summarize in a few words the wide array of products that is springing from rapidly advancing research. A sampling will provide at least an inkling of the breadth and power of what is available.
One of the major categories of offerings提议 is probiotics. Some companies, such as Nutri-Health Supplements and Life Extension, sell mints that pack a probiotic punch. Life Extension‘s Advanced Oral Hygiene vegetarian mint lozenges contain both Bacillus coagulans and S. salivarius. The company‘s website cites studies indicating that in vitro S. salivarius inhibits biofilm formation by S. mutans. Regular use of the lozenges "could make a significant impact in protecting oral health," due to the beneficial bacteria‘s ability to "help block harmful bacteria ... in the mouth," according to the company.
益生菌是一个很好提议 （稳态元数据才是key，益生菌只能改善效果，不能根治）
Toothpaste is another popular probiotic delivery vehicle. Designs for Health‘s PerioBiotic toothpaste, for example, contains the Lactobacillus paracasei strain ADP-1 -- dubbed Dental-Lac -- as well as xylitol and calcium glycerophosphate.
Mouthwashes that contain antibacterial agents and/or probiotics also have been developed. For example, a team led by Wenyuan Shi, PhD, the chair of oral biology at the University of California, Los Angeles, School of Dentistry and founder of C3-Jian, has produced a mouthwash that contains a specifically targeted antimicrobial peptide (STAMP) called C16G2. Like other STAMPs, C16G2 is designed to selectively kill S. mutans while leaving the rest of the microbiota intact, according to information on C3-Jian‘s website (the company has exclusive patent rights to the mouthwash). A phase I trial with 12 healthy adult volunteers showed the mouthwash lowered concentrations of S. mutans, and also reduced the plaque burden and amount of demineralization (Caries Research, November 2011, Vol. 45:5, pp. 415-428).
"I like to explain it in terms of the ecology of a lawn," Shi said. "When you use a broad-spectrum herbicide除草剂
, all of the plants in the lawn get knocked down for a little while, but they also grow back first. It‘s better to specifically kill the weeds, or bad bacteria."
如果采用光谱除草剂，所有植物立即死亡，但会很快长回来，最好精确杀死有害菌。
The ProBiora3 mouthwash from Oragenics contains a mix of three probiotic bacterial strains: S. oralis KJ3, S. rattus JH145, and S. uberis KJ2. The results of a phase I clinical trial involving 20 healthy 21- to 35-year-old volunteers suggested the product is well-tolerated and produced large but not statistically significant drops in S. mutans titers and significant decreases in concentrations of Campylobacter rectus and P. gingivalis (Journal of Applied Microbiology, August 2009, Vol. 107:2, pp. 682-690).
"The science behind the product is fairly definitive, I would say," said Oragenics‘ co-founder Jeffrey Hillman, DDS, who recently retired as the company‘s chief scientific officer and director. "And it‘s been well-received by everyone who‘s used it. The strains in the mouthwash not only outcompete the ‘bad‘ bacteria, they also produce small amounts of hydrogen peroxide that gradually whiten teeth. So there are cosmetic benefits as well as the benefits to oral health."
When it comes to finding balance in the oral cavity, it‘s a good time to be a dentist and a patient, it seems. The new avenues 途径of research opening up with every passing day are making the match more even between human ingenuity 足智多谋and bacteria‘s ancient craftiness狡猾.
“It’s actually too much plaque and plaque in the wrong places that are bad for us.”
– Philip D. Marsh, PhD,
Leeds Dental Institute
“To eliminate all the bacteria is impractical.”
– Yiping Weng Han, PhD,
Case Western University
“If we could use the peptides as an adjunct to conventional antibiotics, we may be able to reduce the antibiotic resistance that is prevalent in a number of bacteria.”
– Aaron Weinberg, DMD, PhD,
Case Western University
“It’s actually the altered microbiota that are causing the bone loss, notP. gingivalis.”
– George Hajishengallis, DDS,
PhD, University of Pennsylvania