The Role of the Oral Microbiota Related to Periodontal Diseases in Anxiety, Mood and Trauma- and Stress-Related Disorders

Abstract

The prevalence of anxiety, mood and trauma- and stress-related disorders are on the rise; however, efforts to develop new and effective treatment strategies have had limited success. To identify novel therapeutic targets, a comprehensive understanding of the disease etiology is needed, especially in the context of the holobiont, i.e., the superorganism consisting of a human and its microbiotas. Much emphasis has been placed on the role of the gut microbiota in the development, exacerbation, and persistence of psychiatric disorders; however, data for the oral microbiota are limited. The oral cavity houses the second most diverse microbial community in the body, with over 700 bacterial species that colonize the soft and hard tissues. Periodontal diseases encompass a group of infectious and inflammatory diseases that affect the periodontium. Among them, periodontitis is defined as a chronic, multi-bacterial infection that elicits low-grade systemic inflammation via the release of pro-inflammatory cytokines, as well as local invasion and long-distance translocation of periodontal pathogens. Periodontitis can also induce or exacerbate other chronic systemic inflammatory diseases such as atherosclerosis and diabetes and can lead to adverse pregnancy outcomes. Recently, periodontal pathogens have been implicated in the etiology and pathophysiology of neuropsychiatric disorders (such as depression and schizophrenia), especially as dysregulation of the immune system also plays an integral role in the etiology and pathophysiology of these disorders. This review will discuss the role of the oral microbiota associated with periodontal diseases in anxiety, mood and trauma- and stress-related disorders. Epidemiological data of periodontal diseases in individuals with these disorders will be presented, followed by a discussion of the microbiological and immunological links between the oral microbiota and the central nervous system. Pre-clinical and clinical findings on the oral microbiota related to periodontal diseases in anxiety, mood and trauma- and stress-related phenotypes will be reviewed, followed by a discussion on the bi-directionality of the oral-brain axis. Lastly, we will focus on the oral microbiota associated with periodontal diseases as a target for future therapeutic interventions to alleviate symptoms of these debilitating psychiatric disorders.

Keywords: Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis; anxiety disorders; mood disorders; oral microbiota; periodontitis; trauma-related disorders.

Figure 1

Schematic representation of the oral-gut-brain axis. (1) Periodontal bacteria can directly reach the brain via the bloodstream or areas that lack an intact BBB or with a compromised BBB. (2) Periodontitis can indirectly affect the CNS via pro-inflammatory cytokines that activate endothelial cells that express TNF-α and IL-1 receptors, which, in turn, signal to the perivascular macrophages that communicate and activate microglia, resulting in (3) neuroinflammation. (4) Periodontitis can also result in leaky periodontium and LPS in systemic circulation, which can (5) activate the HPA axis and result in increased stress hormones or neurotransmitters, which subsequently (6) influence gut physiology, microbiota habitat, microbiota community composition, and bacterial gene expression. (7) An altered gut microbiota can result in systemic inflammation, which not only affects the CNS but also (8) exacerbates other inflammatory pathologies, such as periodontitis. Periodontal bacteria can directly influence gut microbial community composition and functioning via (9) enteral transmission or indirectly via (10) hematogenous transmission (which is facilitated by conditions such as gastritis, gastric surgery, or gastric dysfunction). CNS, central nervous system; TNF, tumor necrosis factor; IL-1, interleukin-1; LPS, lipopolysaccharide; BBB, blood–brain barrier; HPA, hypothalamic–pituitary–adrenal. Solid arrows indicate direct pathways and dotted arrows indicate indirect pathways.