Summary Oral bacteria directly affect the disease status of dental caries and periodontal diseases. The dynamic oral microbiota cooperates with the host to reflect information and status of immunity and metabolism through bidirectional communication throughout the oral cavity and systemic organs. The oral cavity is one of the most important windows of interaction between the human body and the environment. The microenvironment at different sites in the oral cavity has different microbial compositions and is regulated by complex signals, hosts, and external environmental factors. These processes may affect or reflect human health because certain health states appear to be related to the composition of oral bacteria, and the destruction of the microbial community is related to systemic diseases. In this review, we discuss emerging and exciting evidence of complex and important connections between oral microbes and multiple human systemic diseases, and the possible contribution of oral microorganisms to systemic diseases. This review aims to increase interest in oral microbes throughout the human body and also improve understanding about the role of oral microbes in systemic diseases. Microbial research in dentistry potentially improves our knowledge of the pathogenetic mechanisms of oral diseases, and at the same time, continued advances in this frontier field can have a tangible impact on human health. |
Changes of the oral microbiota in the state of systemic diseases are gradual and repeatable. Therefore, oral microbes can reflect human health and disease status in real time and have important value in early warning of disease risk and prediction of curative effect.
More than 700 types of microorganisms are colonized in the human oral cavity. The oral microbiome is one of the most important and complex microbial communities in the human body and is also one of the five research priorities (oral cavity, nasal cavity, vagina, intestine, skin) of the Human Microbiome Project (HMP). With the consummation of the human microbiome project, the understanding of oral microbes has become deeper and is not limited to a greater understanding of the role of oral microorganisms in caries, periodontal diseases, and other oral diseases.
The inflammation of periodontitis leads to the loss of connective tissues and bones. An extensive infiltration of inflammatory cells appears in the connective tissue near the epithelium of the periodontal pocket. It is generally believed that this low-grade inflammation will disrupt the health of the entire body or worsen other systemic diseases. Therefore, in the general population, chronic periodontitis may be an important source of invisible peripheral inflammation. Periodontitis is also called "low-grade systemic disease", which affects a variety of systemic diseases.
In particular, a large body of evidence has shown that bacteria are closely related to tumor development over the past two decades. For example, the role of human papillomavirus in oral cancer, Helicobacter pylori in gastric cancer, Chlamydia pneumoniae in lung cancer, Salmonella typhi in gallbladder cancer, Streptococcus bovis , Bacteroides fragilis , and especially the periodontal pathogen Fusobacterium nucleatum in colon cancer. These studies have led to the possible role of bacteria in tumor development, and subsequent research results provide some supporting evidence.
Growing evidence supports the association between the oral microbiome and human systemic diseases. This association may be attributed to the ability of many oral microbes to influence the inflammatory microenvironment. Excluding unfavorable factors such as physical activity, poor oral condition is closely related to unhealthy body index.
Clinical and basic research on oral health and systemic diseases has become a critical frontier point. In this paper, we review advances in the relationship between oral microbes and digestive diseases, cancer, cardiovascular disease, Alzheimer’s disease, diabetes, rheumatoid arthritis, and preterm birth.
Oral microbes and inflammatory bowel disease
Adults produce more than 1000 ml of saliva every day, almost all of which enters the gastrointestinal tract.
Therefore, oral microbes, as an important reservoir of intestinal microbes, play an important role in maintaining the internal stability of the intestinal microecosystem. Virulent strains in the oral cavity migrate to the intestine through the digestive tract or blood, affecting the process of many inflammatory bowel diseases.
Inflammatory bowel disease ( IBD) is a global disease, especially in developed countries, the prevalence in developing countries is also increasing year by year, the prevalence in China is about 3.44 per 100,000 people. Nonspecific chronic inflammatory bowel diseases, whose etiology is not well understood, are believed to be determined by genetic and environmental factors. The gut microbiome also plays an important role during IBD. At the same time, recent studies found a correlation between oral microbes and IBD.
Oral microbes and liver diseases
There is a significant difference between the tongue flora of patients with liver cancer and healthy people. The oral flora of patients with liver cancer is more diverse, and the composition of the flora is significantly different from that of healthy people, and Bacillus, Leptotrichia, Actinomyces and Campylobacter have higher abundance, while Haemophilus, Streptococcus and Pseudomonas have lower abundance .
Many clinical studies have shown that periodontitis is a risk factor for nonalcoholic fatty liver, and P. gingivalis plays an important role in the course of nonalcoholic fatty liver. Invasion of oral microorganisms has been found in the intestine of patients with liver cirrhosis. The invasion of P. gingivalis in the intestine can change the composition of the intestinal microbiome, increase the permeability of the intestinal mucosa and insulin resistance, lead to the spread of intestinal bacteria to the liver, and increase the triglyceride content in the liver tissue. .
Oral bacteria and cancers
A large body of research evidence shows that oral microbes play an important role in tumor proliferation, invasion, and metastasis. Oral microorganisms can act directly on the appearance and development of tumors through some cytokines and pathways or promote the formation, deterioration and metastasis of tumors by regulating the immune response between tumors and the body.
Oral microbes that play a role in this can be used as potential biomarkers for the study of oral cancers and to detect the development of oral cancer. A deep understanding of the interaction mechanism between oral microbes and tumors will facilitate the design of subsequent new targeted drugs. This will play a great role in the diagnosis, treatment and prognosis of oral cancer patients in the future.
Associations have been described between oral microbiota disorders and squamous cell cancer of the oral cavity, esophageal cancer, pancreatic cancer, and colorectal cancer.
Oral microbes and cardiovascular diseases
Cardiovascular disease refers to diseases that occur in the heart and vascular circulatory system, including coronary heart disease, endocarditis, and myocardial infarction. Atherosclerosis (AS) is an important pathological process of coronary heart disease. It is closely related to the proliferation of vascular smooth muscle cells and the functional changes of vascular intimal cells. The main pathological manifestation of AS is the deposition of lipids on the vascular endothelium of large and medium arteries, forming scattered atherosclerotic plaques or scales, resulting in narrowing of the arterial lumen.
Many cross-sectional studies, case analyzes and epidemiological investigations have found that periodontitis is an important risk factor for cardiovascular disease. The gingival epithelium in the periodontal pockets of patients with periodontitis is prone to breakdown, which helps bacteria enter the systemic circulatory system, leading to bacteremia or ectopic colonization in other organs of the body.
Bacteria related to periodontal disease can destroy the body’s immunity, stimulate cells to produce inflammatory factors such as IL-1β, IL-6, TNF-α, and enter the blood circulation from damaged periodontal tissue, causing inflammation and vascular endothelial damage and the formation of atherosclerotic plaques.
After treatment of periodontitis, C-reactive protein , which is an indicator of the improvement of systemic inflammatory status, was significantly reduced in the patient’s serum, and some other serum inflammatory factors were also significantly reduced. Therefore, the state of periodontal inflammation is directly related to the inflammatory factors in the serum.
Oral microbes and Alzheimer’s disease
The relationship between oral microbes and Alzheimer’s disease has attracted people’s long-term attention. Research and clinical studies have provided some evidence of the causal relationship between periodontitis and Alzheimer’s disease. In a longitudinal cohort study, 152 subjects in the age range of 50 to 70 years were followed for 20 years . The results found that the severity of periodontitis and the level of cognition are in an inverse relationship in subjects with less than 10 missing teeth.
Another longitudinal aging cohort study of 144 subjects showed that people with the APOE-ε4 gene and fewer teeth have faster cognitive decline than people without these two risks. Additionally, a longitudinal cohort study conducted a 32-year survey of 597 male individuals. The results showed that tooth loss, the depth of periodontal pockets and the degree of alveolar bone loss are related to cognitive impairment, especially when they are over 45 years of age.
There is a bidirectional relationship between chronic periodontitis and Alzheimer’s disease. Due to limited mobility and poor oral hygiene in patients with Alzheimer’s disease, it promotes the accumulation of periodontal tissue inflammation and eventually leads to tooth loss. Because tooth loss affects the patient’s diet and nutritional status, it can worsen the patient’s memory and other functions of the nervous system. These have been confirmed in animal experiments. Therefore, the relationship and interaction mechanism between periodontitis and Alzheimer’s disease need to be further studied.
Oral microbes and diabetes
Diabetes is a common endocrine and metabolic disease caused by insulin deficiency, impaired pancreatic islet function, or impaired biological action of insulin. Diabetes with poor blood sugar control is a risk factor for periodontal disease, and periodontitis is the sixth leading complication of diabetes.
Compared with non-diabetic patients, the risk of chronic periodontitis in diabetic patients increases 2 to 3 times . The pathological changes of diabetes can aggravate and accelerate the onset and development of periodontal inflammation, and effective control of periodontitis has a fundamental effect on blood sugar control. Oral microbes in the periodontal pockets of patients with periodontitis have complex interactions with the human immune system, resulting in ongoing chronic inflammation.
Compared with non-diabetic periodontitis patients , the community structure of the subgingival microbiome of diabetic and periodontitis patients has undergone significant changes, and a variety of bacteria between the two are differentially enriched. Oral microorganisms can trigger insulin resistance by influencing immune inflammation and oxidative stress in the body, affecting the diabetes process. Oral microbes may affect the onset and development of diabetes by regulating systemic immune homeostasis. Oxidative stress is an important pathway for host immune defense and microbial killing.
In the state of periodontitis, periodontal pathogens enter the blood circulation directly or indirectly, which can cause bacteremia and can colonize the distal end of the body, thereby inducing systemic inflammation. The systemic inflammatory state caused by periodontitis is different from the direct invasion of bacteria. Inflammatory and periodontitis-related oral pathogens are more likely to be the initiators of systemic inflammation .
Patients with periodontitis have elevated levels of systemic inflammatory mediators, such as c-reactive protein, pentaxin-3, and fibrinogen. Under active periodontal treatment intervention, these biomarkers of systemic inflammation can be significantly downregulated. 173Therefore, the altered oral flora of patients with periodontitis may not only mediate the periodontal inflammatory state but may also affect the systemic inflammatory state of the distal body.
Oral microbes and rheumatoid arthritis
Rheumatoid Arthritis is an autoimmune inflammatory disease with chronic, symmetric polysynovial arthritis and extra-articular lesions as the main clinical manifestations. Patients with rheumatoid arthritis have a higher incidence of periodontitis and are often accompanied by more severe periodontal inflammation. Effective treatment of periodontal disease has a positive effect on the control of rheumatoid arthritis. It is worth noting that rheumatoid arthritis and periodontitis have similar risk factors , such as the human leukocyte antigen HLA-DRB1 allele polymorphism and smoking.
Both have similar pathological manifestations, such as chronic inflammation and bone resorption mediated by IL-1, TNF-α, and matrix metalloproteinases. Therefore, we believe that rheumatoid arthritis and periodontitis may have similar immunoinflammatory causes . Since periodontitis is an immunoinflammatory response induced by oral microbial infection, it is speculated that oral microbial infection may be involved in the pathological process of rheumatoid arthritis as an environmental factor. In recent years, with the continuous deepening of research, the related mechanism of the relationship between oral microbes and rheumatoid arthritis has also continuously gained new insights.
Oral microbes and preterm birth
Premature birth is the delivery of a fetus less than 37 completed weeks of pregnancy or 259 days of gestation.
Newborns born during this period with a weight of 1000 to 2499 g and immature body organs are considered premature babies. Approximately 35% of neonatal deaths worldwide are related to preterm birth. Even if premature babies survive, there may be complications such as mental retardation, abnormal vision and hearing, which seriously increases the burden on the family and society. However, the reasons for preterm birth are unknown and there are many incentives, making its prevention and treatment difficult.
Some common oral microorganisms were detected in the placenta, indicating that the mechanism of preterm delivery can be explored from the oral conditions of pregnant women.
Results from metagenomic sequencing of placental microbial samples showed that the composition of the placental microbiome is more similar to the oral microbiome compared to the vagina, intestine, and respiratory tract. Based on this, it is speculated that bacteria in the oral microecology can colonize the placenta and their virulence factors can produce pathological effects on the local placenta and induce premature birth. The difference in oral microbiota composition at the placental site between preterm birth and term birth may lead to adverse pregnancy outcomes such as preterm birth.
Conclusions and perspectives
The relationship between the structure and function of oral microbes and the balance of human health and disease is becoming clearer. The rapid development of high-throughput sequencing technology and bioinformatics technology has made it possible to comprehensively study the composition of oral microbes. Since the human body is a “super complex” composed of human cells and microorganisms, microorganisms, as the second genome that affects human health, can settle in and on the human body.
As an important part of the human microbiome, the oral microbiome is systemic and community-specific.
However, compared to the gut microbiome, the study of the oral microbiome is still in its infancy. Many studies have focused on the discovery of microbial diversity, and few have addressed the impact of community function, host genetic background, lifestyle, and biological function events on the oral microbiota. The lack of this data has greatly affected people’s comprehensive understanding of the oral microbial community.
How to effectively transform biological big data into clinical diagnosis and treatment methods with practical application value, and then provide patients with effective individualized medical services, there are still many problems that need to be urgently solved. The continued development of metagenomics technology and high-throughput sequencing technology has greatly expanded human understanding of the relationship between the oral microbiome and systemic diseases.
Oral microbiology has moved from studying the pathogenicity of individual bacteria to the relationship between oral microecological balance and systemic diseases . Understanding the specific mechanisms that maintain and regulate oral microecological balance is of great importance for the prevention and treatment of oral diseases and even human systemic diseases.
