May 31, 2023

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Oral host-microbe interactome: a healthy ecological clock?

Oral host-microbe interactome: a healthy ecological clock?

Oral host-microbe interactome: a healthy ecological clock? Most preliminary studies of oral microbes focused on solving Koch’s hypothesis and generating aerobic isolates in pure cultures.


More and more studies have shown that the host-microbe interaction network is coordinated with each other, affecting human health and disease. Recently, some evidence has shown the connection between the acquisition of complex microbiota and adaptive immunity, supporting that the host-microbiota symbiosis relationship has evolved as a means of maintaining homeostasis.

Here, it is assumed that the oral host-microbe interaction relationship can be used as an ecological timer for health and disease, with special attention to dental caries, periodontal disease and cancer. This article reviews the current status of human oral microbiota and its relationship with host innate immunity and host cytokine regulation.

The purpose is to use this information to predict diseases and design new treatments for local and systemic disorders. In addition, the role of new host-microbial signals as potential biomarkers and their relevance to the future of dentistry and medicine are discussed.


Paper ID

  • Original name: The Oral Host-Microbial Interactome: An Ecological Chronometer of Health?
  • Journal: Trends in Microbiology
  • IF: 13.546
  • Posting time: 2020.12
  • Corresponding author:. A Edlund
  • Corresponding author unit: University of California




1 Oral microbiome

Most preliminary studies of oral microbes focused on solving Koch’s hypothesis and generating aerobic isolates in pure cultures. The culture-based method enables people to pay attention to key pathogens that are considered to be related to oral diseases. DNA technology was conducted in 1970 to apply recombinant and genetic methods to elucidate the cellular mechanisms that exist in several oral species. By the 1980s and 1990s, DNA technology was commonly used to characterize many oral pathogens and symbiotic bacteria. 16S rDNA gene (16S) sequence. Porphyromonas gingivalis was the first oral microorganism whose genome was completely sequenced in 2003. As early as 2010, Bik and colleagues used Sanger sequencing to describe the oral microbiota of 10 healthy people, revealing phylogenetic phyla of 247 species and 9 bacterial phyla. Following the advent of 454 and Illumina sequencing, oral metagenomic research has become more common and has been included in the key human microbiome project that began in the early and late 21st century. Metagenomics investigations are essential to reveal the complete genetic characteristics of the oral complex. Other tests used to describe the oral microbiome include Streptomyces mutans to evaluate gene expression, metabolomics to evaluate small molecules produced by community members, proteomics and other “omics” techniques, which are used Have a deeper understanding of the functional mechanisms of the oral microbiota.


2 Bacterial characteristics and anthropology of the oral microbiome

A number of studies have been carried out to obtain the microbial characteristics of the global population and the characteristics of human body parts. In a review by Gupta et al., the biogeographic microbiome pattern of the global population was explored, including data from the gut, skin, oral cavity, and urogenital tract. Multiple patterns related to lifestyle, diet, race, age, gender, parasitic load, and exposure to modern treatments have been identified. A major finding is that, compared with agricultural populations, Haemophilus is more common in dental plaque in contemporary hunter-gatherer populations, and the incidence of dental caries is lower.

Their results also show that both tooth and tooth root morphology may play a role in the composition of the oral microbiome and the innate immune response to infectious agents. By understanding the evolutionary forces that led to the selection of our modern oral microbiota, we can gain a deeper understanding of the role of host genetics, immune selection, and dietary influences. The evolutionary microbiome research revealed the differences in the composition of the microbiota between gorillas, ancient humans, and modern humans.

A significant decrease in microbial diversity has been observed in modern humans. The loss of microbial diversity in modern people is believed to be the result of lifestyle changes, such as a shift in diet to high-energy foods and away from plant-based foods. Unlike other body cavities, the oral cavity can provide evidence of ancient human microbiomes and contemporary eating habits, because DNA is relatively preserved in the formation of calculus on teeth.

By analyzing the composition of bacteria in calculus in different periods, it has recently been proposed that dietary changes brought about by agriculture have greatly changed the human microbiome more than 7,500 years ago, and have been affected by the recent shift to an animal-based and fat-rich Western diet. Change again. This reduction in diversity is believed to be part of the cause of microbial dysbiosis, which is a process that affects the composition of the bacterial community and subsequent microbial metabolism. In the human microbiota of the modern world, microecological disorders are often associated with various metabolic, inflammatory, and autoimmune diseases.

In order to understand the complex interaction network between the human host, microbiota and the environment, new methods have been developed using data-driven informatics and computational models. A groundbreaking genome-wide association study (GWAS) conducted by the author examined oral microbiota-host genome interactions and reported that the genetic signature of oral microbes over time when studying caries-related microbiomes in twins Lost as it goes by. However, before the signal disappears, the health-related Prevotella pallidum is highly inherited in the population representing children aged 5-7 years, suggesting that the interaction between the host and this taxa may affect the younger age in children. Further exploration in the group is of great significance. In addition, preliminary evidence from microbiome studies of GWAS and ancient and modern bacterial communities preserved in dental plaque indicates that host genomics, age, gender, and various environmental factors are important choices that affect these correlations. Like most microbiome fields, the GWAS research field is still in its infancy, begging for further research to determine the forces that shape the interaction between the host and the oral microbiota, which can be used as a target for early disease detection, diagnosis, and treatment in the future.


3 Saliva and oral mucosal immunity

As the first entrance to the gastrointestinal tract, the oral mucosal epithelium is composed of stratified squamous epithelium, divided into chewing epithelium and lining mucosa. The overall permeability of oral tissues is heterogeneous; keratinized areas have low cell permeability (gingival tissue and palatal mucosa, lips), while non-keratinized areas with higher permeability (long junction epithelium, vestibule, buccal mucosa) Presents a more diverse immune system.

The oral mucosa is mainly composed of antigen-presenting cells (APC) and neutrophils to form an innate immune cell network, signal activation of lymphocytes including T cells and B cells. In healthy connective tissue, the associated microbiota stimulates the activity of adaptive immune cells, which are responsible for maintaining homeostasis and preventing tissue loss. However, when pathogenic microbial species are present in the disease, heterogeneous APC subpopulations become activated. Recently, researchers have developed a new protocol for reliable evaluation of saliva immunity.

Contrary to oral mucosal tissue, saliva is a biological fluid that has been shown to be mainly composed of epithelial cells and immune cells, with increased levels of neutrophil heterogeneity, followed by lymphocytes and other bone marrow cells. The machine learning strategy of single-cell RNA sequencing and flow cytometric labeling proved that novel salivary neutrophil populations with different maturity levels are expressed by chemokines. The heterogeneity of cells derived from oral fluids is huge, but functional and mechanism analysis is required to determine the function of this extensive cell bank.

Among all immune cells, neutrophils account for 95% of the total white blood cells in oral tissues. 30,000 neutrophils allow immune cells to enter the oral cavity by connecting the epithelium and the oral mucosa. When multiple microorganisms and symbiotic biofilms turn into periodontal disease, the estimate of these neutrophils increases. Although the number is small, other important immune cells reside in the gum tissue; these cells include resident T cells and B cells, innate lymphocytes, macrophages, and dendritic cells. Compared with the traditional multi-layered lining oral epithelium, the gingival tissue lacks the submucosa, so a closer interaction between the lamina propria and the alveolar epithelium is established.

In addition to mucosal immunity, saliva content also has significant value for oral immunity. Saliva plays an important role in maintaining oral health and regulating the oral microbiome. It is involved in digestion, removal of microorganisms, hard and soft tissue lubrication. First, the salivary membrane is composed of proteins required for early microbial colonization, and some Gram-negative bacilli and filamentous bacteria soon appear. Saliva also provides antimicrobial and antiviral activity through lactoferrin, lactoperoxidase, lysozyme, statins and histostatins produced by the host and microbial cells. Under normal circumstances, the average flow rate of unstimulated whole saliva is 0.3-0.4 mL/min, and the flow rate of stimulated saliva is about 1.5-2.0 mL/min. Loss of saliva flow caused by systemic diseases, drugs, and environmental factors is a known cause of progressive dental caries and infections.


4 Host-microbiota interactions in health and disease

Various systemic diseases are affected by microbial metabolism and host interaction. Examples of the correlation between human diseases and specific microbiota characteristics include: (i) obesity, which is associated with a decrease in the ratio of Firmicutes and Bacteroides; (ii) Inflammatory bowel disease shows an increase in Enterobacteriaceae bacteria; (iii) Cardiovascular diseases promoted by phosphatidylcholine derived from the intestinal flora; (iv) Psoriasis shows an increase in the ratio of Firmicutes and Actinomycetes; (v) The correlation between colon cancer and Fusobacterium. The analysis of the human microbiome is mainly based on observations and is related to disease phenotypes and microbial components.

In order to understand causality and pathogenesis, model organisms provide important methods that can help validate omics findings. However, when conducting host-microbiome interaction studies, such as cage effects, cophagy and mouse strain genetics are all worth considering. However, the humanized model provides more relevant human disease states and direct regulation of the immune system. Studies on the oral interface have shown that the interaction between the microbiota and the host has an important impact on disease susceptibility, microbial metabolic activity, and immunity (Figure 1). Factors affecting the pathological transition from health to oral disease, including caries, gingivitis, periodontal disease and oral cancer, are still important issues that need to be studied. Table 1 gives a general view of the three most common oral diseases and examples of known immune microbial interactions and bacterial pathogens associated with each disease.

Periodontal diseases

Within the ecosystem, there are considerable differences in the composition of specific morphological microbial communities according to their exact location. The highly innervated tissue that supports and surrounds the teeth is called periodontal tissue, which is derived from multiple tissue layers including primitive tissues of the ectoderm, mesoderm, and endoderm. The eruption of teeth corresponds to major changes in the oral microbiome and the formation of periodontal niches (gingival sulcus, gingival fluid, and periodontal pockets). The microbiome is even different in millimeters; the supragingival and subgingival plaque are evolutionarily selected according to different composition, niche anatomy, antigen and immune exposure, and nutritional background. Periodontitis is characterized by microbial-related host-mediated inflammation, leading to loss of periodontal attachment. The pathophysiology of the disease includes host-derived proteases, cell heterogeneity, and periodontal loss of ligament fibers and the edges of the connecting epithelium. The occurrence and development of the disease are regulated by the ecological imbalance of the biofilm attached to the surface of the tooth/tooth root and the ecology of the saliva plankton.

Table 1 Examples of potential taxonomic biomarkers and oral health and disease research

Oral host-microbe interactome: a healthy ecological clock?
Abbreviation:FISH , Fluorescence in situ hybridization

Oral host-microbe interactome: a healthy ecological clock?

Figure 1 The symbiotic and non-symbiotic relationship of host microbial cells at the oral, dental, and craniofacial interfaces. (A) Microbial colonization of human soft and hard tissues leads to the formation of biofilms. (B) The interaction between the mucosal immune system and the microbiota promotes homeostasis mechanisms and health. (C) Due to environmental stress (for example, tissue damage) or stress-induced microecological disorders, the signal between the host and the microbiota changes, leading to a series of effects, including triggering pro-inflammatory factors, which can cause tissues if not treated in time Inflammation, followed by tissue loss. (D) Inflammation in the oral cavity is related to systemic diseases, such as type 2 diabetes, arthritis and joint sclerosis.


(Caries) is one of the most common diseases in the world. Dental caries stems not only from poor oral hygiene habits, sugary diet, immune and genetic factors, but also from the presence of pathogenic bacteria, such as Streptococcus mutans, Lactobacillus acidophilus and Bifidobacterium groups. Studying the known cariogenicity of Streptococcus mutans strains and the ability to secrete hundreds of millimoles of acidic lactic acid within a few minutes, it was found that it caused rapid demineralization of tooth enamel and made the condition worse. Streptococcus mutans also produces an insoluble glucan matrix that makes it adhere to tooth enamel, preventing the diffusion of acid metabolites and further increasing its toxicity. Diseases can be prevented not only by directly inhibiting pathogens related to acid production and acidic caries, but also by interfering with the environmental factors that drive the selection and enrichment of these bacteria. After the introduction of deep sequencing technology, it was discovered that caries is a multi-microbial disease, and different species are related to different stages of the disease.

Oral Cancer

The development of cancer involves specific microorganisms with multiple mechanisms, especially the production of toxins, the loss of hormone homeostasis and immune tolerance, the induction of chronic inflammatory signals, and the induction of carcinogenic metabolites. Some pathogens, especially viruses, are involved in human carcinogenesis. Research has found that there is a positive correlation between certain microorganisms and cancer. Other pathogens are also related to certain types of cancer, such as Streptococcus bovis in colon cancer and Salmonella typhi in liver and gallbladder cancer. In addition, human papillomavirus is related to the pathogenesis of cervical cancer and head and neck cancers (HNCs). Changes in the oral microbiome environment are now considered a risk factor for HNC.

Current evidence suggests that many human diseases are attributable to overall changes in the microbiome. In the study of human intestinal and esophageal abnormalities related inflammation, the production of chemical carcinogens such as acetaldehyde and N-nitroso compounds is one of several mechanisms that affect the transformation of cells into malignant tumors through the microbiota. The possibility of similar microbiota-host relationships in the oral cavity is high, but these have not yet been explored. The composition of the intestinal and oral microbiomes is very different, so the metabolism from the two niches may be different. The intestines are mainly affected by the Bacteroides phylum, but saliva and oropharyngeal swabs show that Firmicutes dominate the oral cavity. In addition to the microbiome, it is well known that environmental and risk factors such as smoking and drinking also regulate bacteria in oral tissues. Neisseria is associated with high alcohol dehydrogenase activity, which converts ethanol to acetaldehyde and is a carcinogen. Similarly, increased acetaldehyde levels were also found in heavy drinkers and smokers. Regardless of whether there are differences in individual microbial content, there is a hypothesis that metabolic microecological disorders may lead to cancer. Future studies on microbial-related carcinogenic mechanisms will provide a clearer understanding of the extent to which these interactions can provide new ways for the development of HNC diagnosis and treatment.

5 Oral-systemic axis (oral-intestinal, oral-brain, oral-systemic inflammation)

2700 years ago, Describes early indications of oral health and systemic effects. Focal infections of oral origin may originate from closed or open areas. Open lesions include caries, periodontal pockets and extraction sockets, while closed lesions include infections around the apex, infected and non-erupted teeth, and infected pulp tissue. The microbiome (bacteria, viruses, and fungi) may spread along the connective tissue, muscle and fascial planes, through bone cavities, along the blood or lymphatic vessels or nerves, or through the mucosal surface of the salivary glands, directly into deep tissues from oral lesions.

This system allows organisms to “transfer” and move from their original location to other places through circulation. Another mechanism called “indirect mechanism” indicates that by-products of microorganisms, including proteins, peptides, lipids, and nucleotides, can reach the system area. This understanding suggests that oral-system signals from the interaction of the immune microbiome provide potential information for homeostasis, pre-disease and disease progression.

Sum up:

The era of separation of dentistry and oral science from medicine has passed, and dental medicine has become an important field of health care. Recent studies have shown that the human body is a complex ecosystem in which microorganisms and host cells continue to interact.

Although recent findings can prove the taxonomic changes of bacteria at the individual and population levels, the complexity of the host-microbiota interaction only reveals the tip of the iceberg. By strengthening the research in these research fields, it will be possible to realize the host-microbiota characteristics as a clinical timer, which can track the early onset of diseases and promote the development of microbiome targeted therapy.




(source:internet, reference only)

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