Periodic Reporting for period 3 - BRuSH (Oral bacteria as determinants for respiratory health)
Periodo di rendicontazione: 2022-01-01 al 2023-06-30
The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPSproducing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. The hypothesis will be tested in two longitudinally designed population-based lung health studies. BRuSH aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool we will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency.
The 2010 Global Burden of Disease has estimated that 3.9 billon people worldwide have poor dental health. According to the WHO, 300 million people have asthma. The prevalence of COPD and asthma is expected to increase because of increasing life expectancy and an aging population. Both periodontal diseases and chronic lung diseases will increase in the coming years due to increasing life expectancy and an aging population. Both disease conditions occur more often in groups with low socio-economic status, and lead to poorer quality of life for those affected. Periodontitis are the most common cause of lost teeth during the lifetime. Symptoms of periodontitis could be bleeding when brushing teeth and during dental flossing, redness, and edema of the gums. Periodontitis are heritable but are also affected by age and lifestyle. Early diagnostics and treatment are important to prevent the disease from developing into more severe forms. The decline in use of dental care is most pronounced among individuals of low social status, and social inequalities in dental health and use of dental care services are evident among elderly in Norway as well as in other European countries. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.
The objective of BRuSH is first to explore whether the relative abundance of hexa-, penta-, and tetra-acylated LPS-producing bacteria in gingival and dust samples are associated with asthma severity, changes in lung function and respiratory diseases status over time. Secondly, to investigate whether the levels of LPS in oral and dust samples are associated with those outcomes; and whether the contribution of hexa-, penta-, and tetra-acylated LPS-producing bacteria influences these LPS levels. Third, to apply synthetized lipid As in mice models of experimental asthma and in vitro models of human bronchial epithelial cells. To reach these goals, BRuSH will use data and biobank material from two large population-based studies; the RHINESSA generation study (Respiratory Health In Northern Europe, Spain and Australia; www.RHINESSA.net) and the ECRHS study (European Community Respiratory Health Survey; www.ecrhs.org) and in addition in vitro and in vivo models to test how different lipid As influence lung health.
The 2010 Global Burden of Disease has estimated that 3.9 billon people worldwide have poor dental health. According to the WHO, 300 million people have asthma. The prevalence of COPD and asthma is expected to increase because of increasing life expectancy and an aging population. Both periodontal diseases and chronic lung diseases will increase in the coming years due to increasing life expectancy and an aging population. Both disease conditions occur more often in groups with low socio-economic status, and lead to poorer quality of life for those affected. Periodontitis are the most common cause of lost teeth during the lifetime. Symptoms of periodontitis could be bleeding when brushing teeth and during dental flossing, redness, and edema of the gums. Periodontitis are heritable but are also affected by age and lifestyle. Early diagnostics and treatment are important to prevent the disease from developing into more severe forms. The decline in use of dental care is most pronounced among individuals of low social status, and social inequalities in dental health and use of dental care services are evident among elderly in Norway as well as in other European countries. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.
The objective of BRuSH is first to explore whether the relative abundance of hexa-, penta-, and tetra-acylated LPS-producing bacteria in gingival and dust samples are associated with asthma severity, changes in lung function and respiratory diseases status over time. Secondly, to investigate whether the levels of LPS in oral and dust samples are associated with those outcomes; and whether the contribution of hexa-, penta-, and tetra-acylated LPS-producing bacteria influences these LPS levels. Third, to apply synthetized lipid As in mice models of experimental asthma and in vitro models of human bronchial epithelial cells. To reach these goals, BRuSH will use data and biobank material from two large population-based studies; the RHINESSA generation study (Respiratory Health In Northern Europe, Spain and Australia; www.RHINESSA.net) and the ECRHS study (European Community Respiratory Health Survey; www.ecrhs.org) and in addition in vitro and in vivo models to test how different lipid As influence lung health.
We have analyzed oral microbiome data in relation to self-reported gum bleeding and clinical measures of periodontal health status in the RHINESSA study in Bergen. Self-reported gum bleeding was associated with higher abundance of bacteria associated with periodontal disease, and lower diversity in those applying frequent dental hygiene measures. The microbiome data was further grouped by which type of lipid A the gram-negative bacteria can produce, which tells us about how potent the bacteria are in inducing inflammation in the host.
From 1200 study participants in the European Community Respiratory Health Survey (ECRHS) from five cites in Northern Europe we have samples from the participants homes. The samples have been analyzed for bacteria and endotoxin.Proteobacteria were more abundant in Aarhus and Tartu, while Actinobacteria were more abundant in Bergen and Reykjavik than in other Nordic cities. In terms of bacterial richness, Tartu showed the highest bacterial richness, followed by Aarhus and Uppsala. Bergen, on the other hand, had the lowest bacterial diversity. The same pattern was evident for endotoxin. We find that 54%of the bacteria were penta-acylated lipid A producing bacteria and only 3% were the potent hexa-acylated lipid A producing bacteria, and 30% gram-positive bacteria.
In the ECRHS-study III (Tartu, Bergen and Melbourne centres) we have data on shotgun sequencing (metagenomics) of gingival samples from 350 participants, showing that the highest microbial diversity is present in participants from Tartu, intermediate from Bergen participants and the lowest bacterial community diversity in participants from Melbourne. We are now exploring whether study center per se or if characteristics of the study participants within each of these centers can explain the large difference in oral bacteria diversity.
From 1200 study participants in the European Community Respiratory Health Survey (ECRHS) from five cites in Northern Europe we have samples from the participants homes. The samples have been analyzed for bacteria and endotoxin.Proteobacteria were more abundant in Aarhus and Tartu, while Actinobacteria were more abundant in Bergen and Reykjavik than in other Nordic cities. In terms of bacterial richness, Tartu showed the highest bacterial richness, followed by Aarhus and Uppsala. Bergen, on the other hand, had the lowest bacterial diversity. The same pattern was evident for endotoxin. We find that 54%of the bacteria were penta-acylated lipid A producing bacteria and only 3% were the potent hexa-acylated lipid A producing bacteria, and 30% gram-positive bacteria.
In the ECRHS-study III (Tartu, Bergen and Melbourne centres) we have data on shotgun sequencing (metagenomics) of gingival samples from 350 participants, showing that the highest microbial diversity is present in participants from Tartu, intermediate from Bergen participants and the lowest bacterial community diversity in participants from Melbourne. We are now exploring whether study center per se or if characteristics of the study participants within each of these centers can explain the large difference in oral bacteria diversity.
With the unplanned event such as the Covid-19 pandemic, we have taken the opportunity to move beyond the state of the art and study how the dramatic increase in use of hand-sanitizers, social distancing, increased cleaning, and other preventive measures affect the human microbiome community - both in the short and long run. We are analyzing skin microbiome samples from the same persons collected before and during the pandemic to describe which bacteria are present at both time-points, and to explore whether some bacteria are ‘lost’. With these data we can explore how the exposure have changed during the pandemic. This is important with regard to our findings on associations between exposure to antibacterial chemicals and how this affects oral microbiome composition. Thus, we expect to be able to provide highly important findings on how resilient the human microbiome is over time.
To establish the link between oral inflammatory bacteria and lung inflammation, we are investigating if treatment of periodontitis (gum disease) in a relatively young and healthy population can improve lung function, with lung function measured at several time points before and after treatment of periodontitis. With such a study we can test whether removal of the dental biofilm reduce the source of inflammatory bacteria that can reach the lungs, and thereby reduce lung inflammation and lead to improved lung function.
To establish the link between oral inflammatory bacteria and lung inflammation, we are investigating if treatment of periodontitis (gum disease) in a relatively young and healthy population can improve lung function, with lung function measured at several time points before and after treatment of periodontitis. With such a study we can test whether removal of the dental biofilm reduce the source of inflammatory bacteria that can reach the lungs, and thereby reduce lung inflammation and lead to improved lung function.