Under steady-state circumstances, the oral microbiota is in equilibrium with host tissues, thus contributing to local and systemic health. Any interruption of such equilibrium leads to a condition of dysbiosis with the proliferation of oral pathogens able to cause gingivitis and periodontal disease. The mechanisms of periodontitis will be described, mostly emphasizing the noxious effects exerted by oral pathogens on the periodontium either directly or indirectly via the release of an array of mediators, even including pro-inflammatory cytokines, chemokines, and enzymes. The persistence of local inflammation ultimately leads to systemic inflammation; therefore, the link between periodontitis and obesity, diabetes and cardiovascular disease will be elucidated. Some natural compounds, such as polyphenols, prebiotics, and probiotics, will be discussed for their ability to exert anti-inflammatory and anti-oxidant activities in the context of the inflamed buccal cavity and systemically, as well as for their modulation of the altered gum-gut microbiota.