From Macromolecule to Microbe: Identification ofD3-8 as a Key Degrader of Ejiao and a Novel Therapeutic Probiotic for Ulcerative Colitis.

Abstract

: Ejiao, a macromolecular protein complex derived from donkey hide, is a traditional Chinese medicine with clinically demonstrated efficacy against ulcerative colitis (UC). Due to its large molecular size and poor absorbability, its therapeutic effects are presumed to depend on gut microbiota. We hypothesized that specific gut bacteria capable of degrading Ejiao might also mediate its biological functions.: To test this hypothesis, a systematic investigation was conducted by integrating culturomics, proteomics, metabolomics, 16S rRNA gene amplicon high-throughput sequencing, and animal disease models.: A total of 134 human gut bacterial strains capable of utilizing Ejiao as a nutrient source were isolated. Among them,D3-8 exhibited the strongest growth in Ejiao-based medium. Genomic analysis identified 63 protease/peptidase genes, and peptidomic profiling confirmed its degradation activity, which released 50 novel peptides. Notably, administration ofD3-8 alone significantly alleviated dextran sodium sulfate (DSS)-induced colitis, concurrently increasing the abundance of beneficial bacteriumand elevating the anti-inflammatory metabolite indole-3-carbinol via upregulated tryptophan metabolism.: Our findings identifyD3-8 as both a dedicated Ejiao-degrader and a protective probiotic against colitis. This work provides direct evidence that gut bacteria can utilize Ejiao and proposes a potential novel mechanistic framework in which the biological effects of Ejiao may be mediated through its interaction with specific, functionally potent degraders such asD3-8.