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 10-fold cross-validated linear discriminant analysis (LDA) were utilized to evaluate diagnostic accuracy, while multivariable regression models were applied to identify robust predictors of 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, EGF, and T helper 2 discriminated MDD from controls with adequate accuracy (AUC = 0.874). Furthermore, elevated BSCFAs and decreased protective SCFAs strongly predicted higher OSOD, more severe physiosomatic symptoms, and increased ROI. Notably, 5-Hydroxytryptamine receptor 1A agonists were independently associated with elevated BSCFAs. Conclusion: MDD is characterized by a distinct gut-immune biotype tightly linked to toxic proteolytic gut fermentation. This metabolic-immune fingerprint offers an objective diagnostic tool and highlights the need for microbiome-targeted interventions in precision psychiatry.