Probing the oral-brain connection: oral microbiome patterns in a large community cohort with anxiety, depression, and trauma symptoms, and periodontal outcomes

Abstract

The role of the oral microbiome in mental health has recently been appreciated within the proposed oral-brain axis. This study examined the structure and composition of the salivary microbiome in a large-scale population-based cohort of individuals reporting mental health symptoms (n = 306) compared to mentally healthy controls (n = 164) using 16S rRNA sequencing. Mental health symptoms were evaluated using validated questionnaires and included depression, anxiety, and posttraumatic stress disorder (PTSD), with accompanying periodontal outcomes. Participants also indicated current or previous diagnoses of anxiety, depression, periodontitis, and gingivitis. Mental and periodontal health variables influenced the overall composition of the oral microbiome. PTSD symptoms correlated with a lower clr-transformed relative abundance of Haemophilus sputorum and a higher clr-transformed relative abundance of Prevotella histicola. The clr-transformed relative abundance of P. histicola was also positively associated with depressive scores and negatively associated with psychological quality of life. Anxiety disorder diagnosis was associated with a lower clr-transformed relative abundance of Neisseria elongate and a higher clr-transformed relative abundance of Oribacterium asaccharolyticum. A higher clr-transformed relative abundance of Shuttleworthia and lower clr-transformed relative abundance of Capnocytophaga were evident in those who reported a clinical periodontitis diagnosis. Higher Eggerthia and lower Haemophilus parainfluenzae clr-transformed relative abundances were associated with reported clinical periodontitis diagnoses and psychotherapeutic efficacy. Functional prediction analysis revealed a potential role for tryptophan metabolism/degradation in the oral-brain axis, which was confirmed by lower plasma serotonin levels across symptomatic groups. This study sheds light on the intricate interplay between oral microbiota, periodontal and mental health outcomes, and a potential role for tryptophan metabolism in the proposed oral-brain axis, emphasizing the need for further exploration to pave the way for novel therapeutic interventions and predicting therapeutic response.

Fig. 1. Effect sizes of variables that had a statistically significant effect on the oral microbiome community variation (distance-based redundancy analysis (dbRDA) on genus-level Aitchison distance) in our cohort (n = 470).

Color intensity is proportional to the q-values (False Discovery Rate (FDR) corrected p-values); adjusted R² effect sizes are indicated on the y-axis. Certain variables were not available for the entire cohort: gingivitis diagnosis (ever), oral bleeding or inflammation, loose teeth, consumption of dietary whole grains (n = 284); alveolar bone loss (n = 184), psychoactive medication use (n = 265), and having arthritis or gout (n = 282). BMI - body mass index, CESD - Center for Epidemiologic Studies Depression, Whole grains – weekly whole grain consumption, TeetchCAL5 criteria - probable severe periodontitis based on the “≥50% of teeth with clinical attachment level (CAL) ≥ 5 mm” criteria.

Fig. 2. The relative abundance of oral taxa associated with mental health outcomes, trauma, and well-being.

a Higher relative abundance of S. mutans in individuals who experienced childhood emotional neglect. b Lower relative abundance of H. sputorum and higher relative abundance of P. histicola in individuals with symptoms of PTSD compared to controls. c Individuals with a current anxiety disorder diagnosis had lower levels of N. elongata and higher levels of O. asaccharolyticum. d The relative abundance of P. histicola was positively associated with CESD depressive scores and (e) negatively associated with World Health Organization Quality Of Life (WHOQOL) scores for domain 2. f Summary graphic highlighting common taxa associated with mental health outcomes, trauma, and well-being (positive associations are indicated in yellow tones, negative associations in blue tones, color intensity is proportional to standardized GLM β coefficients, and point size is proportional to the q-values (FDR corrected p-values)). Horizontal lines on the violin plots indicate the median and the thicker part of the violin around the median represents the interquartile range (IQR). Significance q ≤ 0.1 (only statistically significant taxa are illustrated). Relative abundance is the clr-transformed and filtered relative abundance values. H. sputorum - Haemophilus sputorum, P. histicola - Prevotella histicola, N. elongata - Neisseria elongate, O. asaccharolyticum - Oribacterium asaccharolyticum, CESD - Center for Epidemiologic Studies Depression, PTSD - posttraumatic stress disorder, GLM - generalized linear model.

Fig. 3. Summary graphic highlighting common taxa associated with periodontal outcomes (self-reported clinical diagnosis of current periodontitis/gingivitis available for all participants, n = 470; questionnaire data to predict severe periodontitis available for n = 196 [48%] of the participants).

Positive associations are in shades of yellow, negative associations in shades of blue, and color intensity is proportional to standardized GLM β coefficients, and point size is proportional to the q-values (FDR corrected p-values). Periodontitis diagnosis (n = 34, 7%) – participants reported having a current clinical diagnosis of periodontitis; Gingivitis diagnosis (n = 30, 11%) – participants reported having a current clinical diagnosis of gingivitis; TeetchCAL5 - probable severe periodontitis based on the “≥50% of teeth with clinical attachment level (CAL) ≥ 5 mm” criteria (n = 93, 47%); TeethPPD6 - probable severe periodontitis based on the “≥25% of teeth with probing pocket depth (PPD) ≥ 6 mm” criteria (n = 81, 41.3%).

Fig. 4. Shared (solid line boxes) and unique (dotted line boxes) gut-brain modules (GBMs) associated with predicted severe periodontitis (stages III-IV) as well as mental health, childhood trauma, and quality of life variables.

Positive correlations are displayed in yellow tones and negative correlations in blue tones (white tones indicate values close to zero). Color intensity is proportional to standardized GLM β coefficients, and point size is proportional to the q-values (FDR corrected p-values).

Fig. 5. Log transformed plasma levels (nmol/ml) of serotonin (5-HT) and the ratio of serotonin/tryptophan (5-HT/TRP) in participants with self-reported mental health symptoms.

Lower plasma levels of 5-HT and 5-HT/TRP in participants with (a) depressive, (b) trait anxiety, (c) state anxiety, and (d) PTSD symptoms had lower plasma levels of 5-HT and 5-HT/TRP compared to healthy controls. Horizontal lines on the violin plots indicate the median, and the thicker part of the violin around the median represents the interquartile range (IQR). Significance p < 0.01. PTSD posttraumatic stress disorder.