Obsessive-Compulsive Disorder (OCD) and Major Depressive Disorder (MDD) frequently co-occur, with depressive symptoms affecting OCD progression and vice versa. Identifying biomarkers is crucial for improving diagnosis and treatment. While the gut microbiota's role in psychiatric disorders is well-studied, this research focuses on alterations in the oral microbiota and their relationship with BDNF (Brain-Derived Neurotrophic Factor) DNA methylation in OCD and MDD patients compared to healthy controls. Our findings reveal significant changes in microbiota composition with OCD patients showing increased Actinobacteriota and Firmicutes abundances (p<0.05; CTRL=n.24, OCD=n.21), while MDD patients exhibiting increased Actinobacteriota and Firmicutes, with reduced Bacteroidota and Proteobacteria abundances (p<0.05; CTRL=n.24, MDD=n.16). These alterations, including potential post-streptococcal autoimmunity, highlight the microbiota's role in OCD and MDD pathophysiology. Selective changes in BDNF DNA methylation were observed in both disorders at CpG sites in exon I and IV, significantly reduced in OCD and MDD (p<0.05; CTRL=n.24, OCD=n.23, MDD=n.16) and, following miRNome analysis showed altered expression of BDNF-targeting microRNAs, with miR-16-5p and miR-29a-3p upregulated in OCD (p<0.05; CTRL=n.24, OCD=n.17), and miR-29a-3p upregulated and miR-191-5p downregulated in MDD (p<0.05; CTRL=n.24, MDD=n.16). These findings suggest disorder-specific microbiota and epigenetic profiles, positioning saliva as a non-invasive tool for biomarker identification. This research advances understanding of microbial-epigenetic interactions in OCD and MDD, potentially guiding early diagnosis and targeted therapies.

The authors have declared no competing interest.

This research was partially funded by European Union-Next Generation EU. Project Code: ECS00000041; Project CUP: C43C22000380007; Project Title: Innovation, digitalization and sustainability for the diffused economy in Central Italy-VITALITY; by Italian Minister of the University and Research, PRIN 2022 Project code: 2022K7YKTY to C.D. This work was supported, in part, by research grants from Science Foundation lreland (SFI) to APC Microbiome lreland through the Irish Government's National Development Plan SFI/12/RC/2273_P2.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All participants had given their written informed consent to participate in the study, which included the use of personal and clinical data as well as saliva drawing for the analysis. The local Ethics Committee "Milano Area 1" had previously approved the study protocol (protocol number 0045196/2022), dated 02/11/2022.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors.