Serotonin Variants & Gut Microbiota in Mental Health

Background: The gut-brain-microbiota axis (GBA) represents a complex, bidirectional communication system. Microbial tryptophan metabolism is a key mechanism within this axis - approximately 95% of the body's serotonin is synthesized peripherally in the gut. Host genetic variants can influence both serotonin biology and gut microbiome composition.

Objective: To explore correlations between multi-system genetic variants (TPH2, SLC6A4, MTHFR, FUT2, MUC1, IL-6, and others) and gut microbiome compositional and functional profiles (particularly tryptophan metabolism pathways) in adults with self-reported mental health conditions.

Design: Decentralized observational pilot study. Participants complete digital questionnaires and provide at-home biospecimen collections (saliva and stool) using prepaid medical-grade kits.

Genomic Methodology: Saliva samples undergo DNA extraction and array-based genotyping (Illumina GSA-24 v3.0) at Gene By Gene (CLIA No. 45D1102202, CAP-accredited). Data processed via OmicsEdge bioinformatics platform.

Metagenomic Methodology: Stool samples analyzed by Tiny Health using whole-genome shotgun metagenomics. Human reads are depleted against GRCh38. Taxonomic profiling via GTDB/GenBank database (111,000+ genomes). Functional annotation via KEGG Orthology and CAZy.

Statistical Analysis: Descriptive statistics; alpha diversity (Shannon index); beta diversity (Bray-Curtis dissimilarity); PERMANOVA; exploratory non-parametric comparisons between genotype-defined groups. Effect sizes calculated for future study design.

IRB: Approved by Sterling Institutional Review Board (Atlanta, GA), IRB ID 16153.

Inclusion criteria

• Age: Adults aged 18 to 44 years.
• Residency: Current legal residents of the United States.
• Clinical Phenotype: Self-report of Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), Post-Traumatic Stress Disorder (PTSD), or Panic Disorder.
• Medication Stability: If currently prescribed psychotropic medications (e.g., SSRIs, SNRIs, benzodiazepines), the dosage must remain stable with no changes in molecule or quantity for at least 3 months prior to enrollment.
• Language and Technology: Proficiency in English and access to a smartphone or computer for digital data entry.
• Financial Commitment: Explicit agreement to the "Citizen Science" model, including payment for discounted testing kits. Kit shipping (both directions) is prepaid by the study.

Exclusion criteria

• Use of systemic antibiotics, antifungals, or antivirals within the 8 weeks prior to specimen collection.
• Regular use of commercial probiotics or concentrated prebiotic supplements within 4 weeks of collection.
• Frequent use of osmotic or stimulant laxatives, or motility agents, within 4 weeks of collection.
• Chronic use (>3 times/week) of NSAIDs, systemic corticosteroids, or high-dose Omega-3 supplementation (>2g/day) within 4 weeks of enrollment.
• Use of weight-loss medications or GLP-1 receptor agonists (e.g., semaglutide, liraglutide, tirzepatide) within the 3 months prior to enrollment.
• Confirmed diagnosis of Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (Crohn's or Ulcerative Colitis), Celiac Disease, or history of major gastric/intestinal resection.
• Current pregnancy or lactation.
• Presence of cognitive impairments that preclude the ability to provide informed consent.
• Individuals undergoing active cancer treatment.