Blood metabolites mediate gut microbiota effects on depression: A Mendelian randomization study
Bibliographic record
Abstract
Accumulating evidence indicates that gut microbiota (GM) influence depression via gut-brain axis signaling, yet the causal relationships and underlying mechanisms are not fully understood. We conducted bidirectional Mendelian randomization (MR) to assess GM-Depression causal effects, with additional analyses examining blood metabolite mediation. We conducted a two-sample Mendelian randomization (MR) analysis using genetic instruments for gut microbiota (GM) from the FINRISK 2002 cohort ( n = 5959). Depression data were obtained from the FinnGen R11 database ( n = 448,069, European ancestry), along with three additional independent datasets: Pan-UK Biobank ( n = 370,457), Jamapsy_Giannakopoulou ( n = 194,548), and PGC-noUKBB ( n = 688,808). A Mendelian randomization meta-analysis was performed combining these datasets. Mediation analysis was conducted using multivariable MR (MVMR) with blood metabolite data from the Canadian Longitudinal Study on Aging (CLSA, n = 8299). Pathway analysis was performed using MetaboAnalyst 5.0. Our bidirectional MR identified Bifidobacteriaceae as a protective factor against depression (IVW OR = 0.93, 95 % CI: 0.89–0.97, P < 0.001), confirmed by meta-analysis (β = −0.05, P = 0.002). The protection was mediated by metabolites (e.g., glycolithocholate sulfate; OR = 0.80, 95 % CI: 0.71–0.90) enriched in BCAA pathways (FDR = 0.013). Conversely, N egativibacillus sp000435195 showed nominal risk effects in IVW (OR = 1.09, 95 % CI: 1.04–1.15, P < 0.001), though meta-analysis did not support this ( P > 0.05; I 2 = 68.5 %). Its potential risk involved metabolites (e.g., sulfated piperine; OR = 1.27, 95 %CI:1.13–1.42) enriched in glycine/serine/threonine pathways (FDR = 0.002). Reverse MR excluded reverse causation (all P > 0.05). Our findings provide genetic evidence for the causal involvement of specific GM in Depression, mediated by distinct metabolic pathways, suggesting potential microbiota-based interventions for Depression treatment. • Bifidobacteriaceae reduce the risk of depression via branched-chain amino acid (BCAA) metabolism. • Negativibacillus raises depression risk by disrupting glycine, serine, and threonine metabolism. • Mendelian randomization minimizes confounding in microbiota-depression research. • Probiotic-dietary interventions may present a new therapeutic intervention for depression
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.023 | 0.043 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.007 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".