## 1 Introduction  
Periodontitis is a chronic multifactorial inflammatory disease with bacterial etiology affecting tooth-supporting structures (periodontal ligament, gums, cementum, and alveolar bone), that if left untreated, may lead to tooth loss [1]. It is highly spread worldwide, especially in its severe form, which represents the sixth most prevalent condition globally, affecting 10% of adult individuals [2, 3]. Poor oral hygiene and dysbiosis of oral microbiota, in genetically predisposed individuals, may lead to aberrant inflammation mediated by the host's immune system, which damages the periodontal tissues, leading to periodontitis [4]. During recent decades, increasing evidence has demonstrated that periodontitis is not just a local inflammatory condition, but it may also have systemic implications [5]. In fact, it is related to inflammatory systemic diseases, such as diabetes and cardiovascular diseases [6]. Periodontitis is evaluated by measuring clinical periodontal indices, among which are clinical attachment loss (CAL), probing depth (PD), and gingival recession (REC). In particular, a patient is affected by periodontitis when interdental CAL is present in more than one non-adjacent tooth and periodontal charting shows the presence of PPD of 4 mm or more [1]. If left untreated, periodontitis leads to teeth loss, compromising the normal occlusion and the masticatory function. For this reason, the progression of the disease should be arrested as soon as possible, and early diagnosis is the main tool to control it. Traditional diagnostic procedures have some limitations: they require skilled dentists and assistants to assess and document periodontal clinical parameters properly; there may be differences in the clinical evaluation among operators; the probing process may cause patient discomfort; and the procedure is both time consuming and expensive [7]. Beyond the traditional diagnostic methods, research has been focusing on other methods, involving saliva and gingival crevicular fluid (GCF), in order to find out the effectiveness and the possibility of early diagnosis, overcoming the limitations of the traditional diagnostic method. In particular, saliva is a biofluid that contains a wide variety of biomarkers, which reflect both physiological and pathological conditions [8]. Its collection is non-invasive and particularly suitable for tests requiring repeated sampling (Figure 1). Moreover, advancements in test accuracy, sensitivity, and reliability have enhanced salivary diagnostic capabilities and have facilitated the identification of novel biomarkers, especially those involved in oral disease processes, including caries and periodontitis [9]. Metabolomics and proteomics are emerging as viable methods for assessing the salivary metabolites and proteins that are involved in biochemical processes, and their analysis helps elucidate the pathways underlying different oral and syste  
Figure 1: Saliva composition. (**a**) Saliva is composed of lots of components derived from different sources. (**b**) Salivary samples that contain water, electrolytes, proteins, mucus, and antibodies. From [10], under the terms of the Creative Commons CC BY license. tein and metabolite profiles can be regarded as valid tools for diagnosing and monitoring periodontitis [11; 12]. In fact, the omics approach has already been used in some studies for periodontitis patients, giving promising results [13; 14]. By metabolomic and proteomic analysis, it is possible to systematically screen metabolite profiles and protein expression by both quantitative and qualitative means [12; 15]. There are two approaches to omics analysis: targeted and untargeted. The first one, that is the conventional analysis method, focuses on selected subtypes of metabolites; instead, untargeted analysis enables the comprehensive investigation of a broad spectrum of metabolites and proteins without prior assumptions.