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<p>Major depressive disorder (MDD) is a risk factor for neurodegeneration, yet its heterogeneity makes identifying at-risk subtype challenging. Notably, MDD frequently co-occurs with REM sleep behavior disorder (RBD), a specific prodrome of α-synucleinopathy. It remains unclear whether comorbid MDD + RBD reflects a benign antidepressant effect, or higher neurodegenerative risk. Given growing recognition of gut-brain axis in neuropsychiatry, we aimed to delineate microbial signatures of MDD + RBD. We employed a four-group case-control design (N = 420) comprising 124 healthy controls (HC); 80 MDD without RBD features (MDD-only); 82 MDD + RBD; and 134 iRBD without psychiatric disease. All participants underwent clinical evaluation and provided fecal samples for metagenomic sequencing. Random Forest model was used to distinguish MDD + RBD, and further assessed in a validation dataset of 65 participants with MDD + RBD (n = 31) and MDD-only (n = 34). MDD + RBD exhibited prodromal neurodegenerative features, including elevated total likelihood ratio of prodromal Parkinson’s Disease, olfactory deficits, and subtle motor signs. The microbial composition in MDD + RBD differed from HC and MDD-only, while resembling iRBD. Taxonomically, MDD + RBD exhibited an iRBD-like dysbiosis (e.g., enriched <i>Akkermansia muciniphila</i>, <i>Ruthenibacterium lactatiformans</i>; depleted <i>Faecalibacterium prausnitzii</i>), alongside depression-associated shifts (e.g., <i>Streptococcus parasanguinis</i> and <i>Actinomyces oris</i>). Functionally, MDD + RBD showed attenuated capacity of B‑vitamin biosynthesis and polysaccharides degradation, mirroring iRBD. The Random Forest machine-learning model distinguished MDD + RBD in older adults from MDD-only with an AUC of 0.73 in cross-validation and 0.79 in the validation dataset. MDD + RBD may represent a biologically distinct depression subtype associated with potential neurodegenerative risk. Gut microbiome provides a candidate approach for potential risk stratification in psychiatric populations.</p><p></p>

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Gut Microbiome in Depression with and without REM Sleep Behavior Disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Yuhua Yang,
  • Ningning Li,
  • Li Zhou,
  • Siyi Gong,
  • Zhixuan He,
  • Shi Tang,
  • Jianzhang Ni,
  • Yaping Liu,
  • Joey W. Y. Chan,
  • Brian P. N. Or,
  • Siu Ping Lam,
  • Jihui Zhang,
  • Paul K. S. Chan,
  • Zigui Chen,
  • Sunny H. Wong,
  • Vincent C. T. Mok,
  • Ngan Yin Chan,
  • Steven W. H. Chau,
  • Christopher K. C. Lai,
  • Filip Scheperjans,
  • Jing Wang,
  • Bei Huang,
  • Yun Kwok Wing

摘要

Major depressive disorder (MDD) is a risk factor for neurodegeneration, yet its heterogeneity makes identifying at-risk subtype challenging. Notably, MDD frequently co-occurs with REM sleep behavior disorder (RBD), a specific prodrome of α-synucleinopathy. It remains unclear whether comorbid MDD + RBD reflects a benign antidepressant effect, or higher neurodegenerative risk. Given growing recognition of gut-brain axis in neuropsychiatry, we aimed to delineate microbial signatures of MDD + RBD. We employed a four-group case-control design (N = 420) comprising 124 healthy controls (HC); 80 MDD without RBD features (MDD-only); 82 MDD + RBD; and 134 iRBD without psychiatric disease. All participants underwent clinical evaluation and provided fecal samples for metagenomic sequencing. Random Forest model was used to distinguish MDD + RBD, and further assessed in a validation dataset of 65 participants with MDD + RBD (n = 31) and MDD-only (n = 34). MDD + RBD exhibited prodromal neurodegenerative features, including elevated total likelihood ratio of prodromal Parkinson’s Disease, olfactory deficits, and subtle motor signs. The microbial composition in MDD + RBD differed from HC and MDD-only, while resembling iRBD. Taxonomically, MDD + RBD exhibited an iRBD-like dysbiosis (e.g., enriched Akkermansia muciniphila, Ruthenibacterium lactatiformans; depleted Faecalibacterium prausnitzii), alongside depression-associated shifts (e.g., Streptococcus parasanguinis and Actinomyces oris). Functionally, MDD + RBD showed attenuated capacity of B‑vitamin biosynthesis and polysaccharides degradation, mirroring iRBD. The Random Forest machine-learning model distinguished MDD + RBD in older adults from MDD-only with an AUC of 0.73 in cross-validation and 0.79 in the validation dataset. MDD + RBD may represent a biologically distinct depression subtype associated with potential neurodegenerative risk. Gut microbiome provides a candidate approach for potential risk stratification in psychiatric populations.