Salivary bacterial signatures in depression-obesity comorbidity are associated with neurotransmitters and neuroactive dipeptides

Depression and obesity, both of which are highly prevalent and inflammation underlies, often co-occur. Microbiome perturbations are implicated in obesity-inflammation-depression interrelationships, but how microbiome alterations contribute to underlying pathologic processes remains unclear. Metabolomic investigations to uncover microbial neuroactive metabolites may offer mechanistic insights into host-microbe interactions. Using 16S sequencing and untargeted mass spectrometry of saliva, and blood monocyte inflammation regulation assays, we determined key microbes, metabolites and host inflammation in association with depressive symptomatology, obesity, and depressive symptomatology-obesity comorbidity. Gram-negative bacteria with inflammation potential were enriched relative to Gram-positive bacteria in comorbid obesity-depression, supporting the inflammation-oral microbiome link in obesity-depression interrelationships. Oral microbiome was highly predictive of depressive symptomatology-obesity co-occurrences than obesity and depressive symptomatology independently, suggesting specific microbial signatures associated with obesity-depression co-occurrences. Mass spectrometry analysis revealed significant changes in levels of signaling molecules of microbiota, microbial or dietary derived signaling peptides and aromatic amino acids among host phenotypes. Furthermore, integration of the microbiome and metabolomics data revealed that key oral microbes, many previously shown to have neuroactive potential, co-occurred with potential neuropeptides and biosynthetic precursors of the neurotransmitters dopamine, epinephrine and serotonin. Together, our findings offer novel insights into oral microbial-brain connection and potential neuroactive metabolites involved.