The present interventional study showed that even in healthy young individuals, experimentally induced gingivitis as low-level extravascular oral bacterial infection lead to an acute systemic inflammation with enhanced systemic levels of CRP, IL-6, MCP-1 and activated monocytes known as markers and mediators of vascular atherosclerotic disease. This inflammatory process seems to be almost completely reversible by appropriate dental hygiene.
Gingivitis is a chronic local infection affecting the tooth surrounding tissues, caused by bacteria of the dental plaque (e.g. Streptococcus oralis, Veilonella ssp.
etc.) and is accompanied by a local inflammatory response of the host. The oral inflammatory response is, in contrast to periodontitis, limited to the soft gingival tissues not affecting the bone. Moreover, gingivitis differs from periodontitis with respect to its microbial composition and inflammatory responses 
. In consequence, it was not expected at the beginning of the study to observe systemic effects from gingivitis, although they have already been shown for periodontitis 
. Recently, Wahaidi et al. 
was not able to show an association of experimental gingivitis and systemic CRP and IL-6 levels in a population of healthy adults aged 18 to 30 years. These experiments were in accordance with a study of natural gingivitis by Wohlfeil et al. 
. This group also showed no correlation between serum CRP levels and the degree of gingivitis. In contrast, elevated levels of serum IL-6 were found in patients suffering from type 2 diabetes and natural gingivitis compared to patients with diabetes and healthy gingival conditions 
. The different observations between these studies and the present study may be explained at least in part by the young healthy participants of the present study, which do not have any traditional risk factors for cardiovascular diseases. In addition, a very sensitive method for the detection of CRP in serum was used.
Most likely, the observed gingival inflammatory processes, which was induced in the present study affect approximately 75% of Western populations 
. In contrast to periodontitis, gingivitis affects children, adults and elderly in nearly equal ratios 
. Clinically, this inflammatory process becomes obvious by bleeding during brushing the teeth, normally on a limited number of teeth. For the present study this clinical appearance was tried to mimick by inducing the inflammatory processes also just on a limited number of teeth, here seven, during a 21-days plaque accumulation phase. The inflammatory reactions of the gingival tissues are only mild and clinically nearly inconspicuous to the untrained eye. We studied well-characterized young healthy volunteers that yet did not show any traditional risk factor for cardiovascular diseases. Thus, we are assured that the observed systemic changes are a consequence of the local gingival inflammatory processes. However, the participants did not respond equally and showed inter-individual differences regarding the amount of dental plaque load, clinical signs of inflammation and serum markers of inflammation.
To further address the oral inflammatory status, we analyzed the presence of ten different species belonging to variable complexes according to Haffajee et al. 
, in which potential pathogens spread across different clusters. Bacterial species predominantly associated with subgingival lesions of destructive periodontitis were if at all in very low numbers present in the developing supragingival plaques of the present study 
. Only Fusobacterium nucleatum,
a so called ‘bridge-bacterium’ between health and disease, could be detected in high frequency in all plaque samples. Generally periopathogens, namely Porphyromonas gingivalis
, are in the focus of research aimed to identify pathological mechanisms between periodontitis and systemic diseases 
. The present study demonstrated that systemic effects could also be induced by low-level gingival inflammation and by bacterial plaques that do not harbour traditional periopathogens like Porphyromonas gingivalis
. Hence, the present study is the first report that demonstrates adverse effects of local experimentally induced gingival inflammation on circulating serum levels of CRP, IL-6 and MCP-1 and activation of monocytes. These results demonstrated an enhanced systemic inflammatory status of the subjects during the course of the study. Future experiments are warranted to evaluate if natural gingivitis also enhances systemic inflammatory markers and the risk for atherosclerotic diseases. Elevated CRP, IL-6 and MCP-1 serum levels could serve as a direct marker of the inflammatory activity in the subjects’ gingiva. The serum concentrations of hsCRP and IL-6 during the state of gingivitis reached levels, which were previously shown to be associated with high cardiovascular event rate i.e. myocardial infarction 
. The broad concordance between clinical markers of gingival inflammation and systemic inflammatory markers and monocyte activation suggests a relationship between the local and systemic recations. Only one epidemiological study has been published aimed to identify associations between gingival inflammation and angina pectoris, however, the reported results are critical due to various confounding factors and unpredictable outcomes of self-reported data sampling 
. For the present study the clinical parameters of experimental gingivitis were not followed after day 21 of the experimental gingivitis phase, because multiple studies have shown that the clinical signs of gingivitis decline within seven days after the re-initiation of oral hygiene procedures in a group of subjects highly familiar with oral hygiene 
A potential limitation of this study is the sample size of 37 volunteers. However, the single-subject design with the subject as its own control is highly sensitive to detect individual differences. The here presented findings with young healthy individuals could not be generalized since elder subjects have an overall higher risk burden. Nevertheless, we especially have chosen young healthy subjects with no cardiovascular risk factors, to study systemic effects of experimental gingivitis. Thus, this approach offers the best prospect to uncover a potential relationship between local oral inflammation in gingivitis and systemic effects on surrogate markers of atherosclerosis. Definitely, larger randomised multicenter trials with elder subjects are necessary to investigate the hypothesis whether oral low-level gingivitis increases the risk for atherosclerosis or even enhances cardiovascular events.
The mechanisms by which local inflammatory processes of the oral cavity affect systemic conditions remain largely unknown and future experimental studies are warranted. Gingivitis involves bacterial infection with a range of Gram-positive and Gram-negative bacteria that invade the superficial gingival tissues 
. During progression of the gingival disease, the epithelium becomes ulcerated to expose the underlying connective tissues and blood capillaries and facilitates entry of biofilm organisms or their products (e.g. bacterial heat-shock proteins) to the circulation during eating or tooth brushing 
. Pathogens which have entered the bloodstream can directly invade blood vessel walls and atherosclerotic plaques 
. Finally both, local oral infection and circulating infection products lead to an increase in the levels of circulating cytokines, chemokines and acute phase proteins, which are known to be associated with an increased cardiovascular event rate. The present study is the first report that demonstrated elevated serum levels of CRP, IL-6 and MCP-1 in the course of experimental gingivitis. Of interest, even gingival tissues were found to synthesize CRP 
. Other inflammatory diseases, such as lupus erythematosus and rheumatoid arthritis are also associated with an increased cardiovascular risk supporting a mechanistic link between local extravascular inflammation and cardiovascular diseases 
It will be a task for future studies to identify the mechanisms that may account for the observed individual levels of local and systemic host responses. The potential confirmation that natural gingival inflammatory processes are an extravascular stimuli for systemic inflammation and atherogenesis will have great public health implications.