Association between brain-gut peptides and depression: A systematic review and meta-analysis

Depression is a chronic mental disorder that has emerged as one of the most prevalent global public health concerns, with its incidence increasing annually. Brain-gut peptides, various gastrointestinal (GI) hormones secreted by the central nervous system, enteric nervous system, and GI tract, have been demonstrated by numerous studies to play a pivotal role in the pathophysiology of depression. This systematic review and meta-analysis was undertaken to examine the association between brain-gut peptide concentrations and depressive disorders.

A comprehensive search was conducted across the CNKI, WanFang Database, VIP, PubMed, Embase, Cochrane Library, and Web of Science databases for observational studies investigating the relationship between brain-gut peptide levels and depression. Included studies comprised cross-sectional investigations with clearly defined data collection time points, case-control studies with comparable demographic characteristics across groups, and cohort studies in which participants were initially free of depression and followed longitudinally. Studies were excluded if they were duplicates, non-Chinese/English publications, lacked outcome data or accessible full texts, involved secondary depression (e.g., postpartum, post-stroke), included comorbid depression with other conditions, or did not report extractable corrected effect sizes. The search was limited to articles published up to November 2024. Odds ratios and corresponding 95 % confidence intervals were used to assess risk relationships. Heterogeneity was evaluated using the Q test. When using the fixed effects model, there was statistical homogeneity between studies (P > 0.10, I² < 50 %). Conversely, a random-effects model was utilized in the presence of significant heterogeneity (P < 0.10, I² > 50 %), with further exploration of potential sources of heterogeneity. Sensitivity analysis was conducted by sequential exclusion of individual studies to evaluate the robustness of the results and to determine whether any single study disproportionately influenced the overall effect size.

A total of 4870 studies were identified, of which 44 met inclusion criteria and were incorporated into the final analysis (inter-rater agreement for the study selection, κ = 0.82; inter-rater agreement for data extraction, ICC=0.91, κ=0.89) involving 4557 participants were included. The meta-analysis revealed that serum levels of substance P (SP), cholecystokinin (CCK), and ghrelin were elevated in the depression group compared to controls. Both the bipolar and unipolar depression subgroups exhibited significantly higher serum SP levels relative to controls. Moreover, no significant differences in serum leptin (LEP) levels were observed between the depression and control groups, nor between male and female subgroups among depressed and non-depressed individuals.

The findings suggest that increased serum concentrations of SP, CCK, and ghrelin are associated with depressive disorders, highlighting their potential as important biomarkers for the detection of depression. In contrast, the role of LEP in depression remains inconclusive and warrants further investigation.