**5.** *Pg* **links to PD-related diseases**

Common and frequent activities like mastication and oral care, have been found to release oral pathogens and their components into the lymphatic and cardiovascular systems of PD patients. Therefore, periodontal *Pg* infections likely act as pathogenic reservoirs, possibly promoting certain systemic diseases [52, 54].

#### **5.1 Neurodegenerative disease**

A 2021 study by Franciotii et al. hypothesised that there is a "bidirectional oralbrain" highway through which neurodegenerative processes are stimulated by proinflammatory oral processes and *vice versa* [55].

Most importantly, initiatives towards the innovation of preventative measures for PD have been recommended, especially since the global population is ageing [55].

#### **5.2 Head and neck cancer**

The reports regarding *Pg* infection as a risk factor for oral squamous cell and oesophageal carcinoma, align with the emerging perspective in the clinical arena linking chronic systemic inflammation to serious disease states [23, 56–59].

#### **5.3 Cardiovascular disease**

Regarding PD as it relates to cardiovascular disease, decades of literature reflect a close association [15, 19, 60]. DNA (i.e., 16S rDNA) from *Pg* has been identified in atheroma isolated from patients with coronary heart disease through PCR analysis [61]. Interestingly, *Pg* may also encourage atherosclerosis by switching HDL properties from antiatherogenic to proatherogenic via the manipulation of monocytes [62].

Further to this, *Pg* has been shown to invade and multiply within coronary endothelia *in vitro*, whilst damaging the smooth muscle cells and possibly distorting the vasodilatory mechanism of the central arterial system [63, 64].

Overall, the literature encourages appreciation of the clinical significance of the assault on the coronary endothelia demonstrated by *Pg*, especially since the vasculature acts as a vital line of defence for the cardiovascular system [63, 65].

#### **5.4 Respiratory disease**

Mortality risks from aspiration pneumonia are high in geriatric populations [66]. Of note, *in vitro* studies have identified *Pg* as a potent pro-inflammatory agent in

isolated respiratory epithelia cells [67]. Additional *in vitro* studies identified *Pg*derived OMVs as significant bacterial virulence factors which connect PD to respiratory disease [68].
