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Background: The gingival sulcus hosts a diverse microbial community that exists in a state of dynamic equilibrium with the immuno-inflammatory system. When this equilibrium is disrupted, it can result in gingivitis and periodontitis, two diseases affecting the periodontal tissues. Although both diseases are primarily caused by plaque, other factors can increase risk for disease, and the extent and severity can be modified by host systemic factors1. This is also may be the reason that the susceptibility of the disease varies among different individuals. The different individual response to plaque has been documented and has been assigned to just plaque quantity or quality. Finding from previous papers helps us to understand that there are high and low responders to the dental plaque. Since both host and bacterial variables can affect the severity of the immuno-inflammatory response to oral biofilms, it is important to employ a comprehensive methodology to investigate differences in both host and bacterial factors between normal, low and high responders. Therefore, we aimed to investigate clinical differences in host response to bacterial plaque with metabolomic signatures in saliva in a group of orally and systemically healthy individuals. Methods: 60 subjects were recruited following informed consent and divided intogroups based on gingival index (GI), plaque index (PI) and GI/PI ratio. Metabolomic analysis was performed on saliva samples using MALDI_TOF. The data normalized by root mean square transformation and the m/z points were annotated.Results: The study subjects were stratified as Normal responders (NR), Low responders (LR) and High responders (HR). The mean ± standard error (median, range) for PI in NR was 0.463 ± 0.064 (0, 0.48 – 0.74), for LR was 1.059 ± 0.073 (1, 0.48 – 1.74) and for HR was 0.699 ± 0.081 (0.5, 0.48 – 1.36). The mean plaque score was significantly different between NR and LR as well as LR and HR. The mean± standard error (median, range) for GI in NR was 0.286± 0.57 (0, 0.08 – 0.55), for LR was 0.528 ± 0.626 (0, 0.03 – 1.11), and for HR was 0.698± 0.725 (0, 0.25 – 1.48). The GI score between NR and LR, LR and HR was significantly different. Overall, 35422 peaks were detected from 59 samples. In the NR group 20387 peaks were detected, in LR group 17799 peaks and 13378 peaks in HR group were detected. A total of 472 peaks were common to all groups of which 439 were statistically significant between groups. (p |