A shift toward proteolytic gut fermentation links systemic inflammation to clinical phenotypes in major depressive disorder.

BACKGROUND: The "Neuro-Immune-Metabolic-Oxidative Stress" (NIMETOX) theory identified systemic dysregulation in Major Depressive Disorder (MDD), yet the precise gut-derived metabolic triggers initiating this cascade remain elusive. This study investigated the interplay between fecal short-chain fatty acids (SCFAs), systemic immune activation, and clinical phenotypes to identify a potential "gut-immune biotype" for MDD. METHODS: Fecal SCFA profiles and serum immune-inflammatory markers were quantified in 102 patients with MDD and 38 matched healthy controls. A multistage statistical approach was employed: binary logistic regression and linear discriminant analysis were utilized to evaluate the joint discriminative performance of the biomarkers, while multivariable regression models were applied to examine associations with clinical phenotypes, including the overall severity of depression (OSOD), physiosomatic symptoms, and recurrence of illness (ROI). RESULTS: MDD patients exhibited a significant depletion of protective straight-chain SCFAs (acetate, propionate, butyrate) and an elevation in branched-chain SCFAs (BSCFAs), indicating a pathological shift from saccharolytic to proteolytic fermentation. This metabolic shift correlated with elevated acute phase inflammatory index (API) and epidermal growth factor (EGF). A multidimensional model combining BSCFAs, acetate, API, and EGF discriminated MDD from controls with adequate accuracy (AUC = 0.871). Furthermore, elevated BSCFAs and decreased protective SCFAs were strongly associated with higher OSOD, more severe physiosomatic symptoms, and increased ROI. Notably, 5-HT1A agent use remained associated with higher BSCFA levels after adjustment for MDD status. CONCLUSION: MDD is characterized by a distinct "gut-immune biotype" tightly linked to toxic proteolytic gut fermentation. This metabolic-immune fingerprint provides a systems biology explanation for MDD and highlights the need for microbiome-targeted interventions in precision psychiatry.