Indole induces intestinal T helper-17 cell overproduction during inflammatory bowel disease through PKA/SP1-mediated Trim21 transcription
Year: 2026
Type: article
Abstract: Gut microbiota induce intestinal Th17 cells in both physiological and disease states, yet whether there are shared mechanisms remains unclear. We previously identified the Fbxw7-Trim21 axis as critical for Alcaligenes faecalis -driven physiological Th17 differentiation. Here, we reveal its dual role in inflammatory bowel disease (IBD)-associated Th17 cell induction. The IBD model was adopted by DSS-induced acute colitis, TNBS-induced acute colitis, Il10 −/− chronic mice and Rag1 −/− mice transferred with CD4 + T cell chronic colitis. Fbxw7 fl/fl , dLck-Cre , Rag1 −/− , Il10 −/− , Il17a GFP and Trim21 −/− mice were used in this paper. Mechanistic studies used molecular and multiomics approaches. mEVs/αCD4/TΔR were constructed by coincubation at 37 °C for 3 h. Dubosiella newyorkensis ( D. newyorkensis ) were colonized to prevent IBD. Key findings were validated in DSS-induced colitis by orally mEVs/αCD4/TΔR treatment or D. newyorkensis colonized. Indole from IBD-gut microbiota reinforces the interaction between protein kinase PKA and transcription factor SP1, promoting SP1 phosphorylation and activation. Then, SP1 induces more E3 ubiquitin ligase Fbxw7 degradation by promoting E3 ubiquitin ligase Trim21 transcription, causing Th17 cell overproduction. Tryptophan-rich feeding enhances Indole production, aggravating IBD, while D. newyorkensis colonization alleviates IBD by shifting tryptophan catabolism toward Kynurenine. Furthermore, blocking Trim21 function through CD4 + T cell-targeting extracellular vesicles carrying RING domain-deficient Trim21 suppresses Th17 cell generation, mitigating IBD. Our data indicate that Indole-induced Trim21 upregulation is crucial for Th17 cell generation in IBD and propose microbial interventions and Trim21 inhibition as potential therapeutic strategies.
Source: BMC Medicine
Institutions: Wenzhou Medical University, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Sir Run Run Shaw Hospital, Zhejiang University, First Affiliated Hospital of Wenzhou Medical University, Westlake University, Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine, Second Affiliated Hospital of Zhejiang University, First Affiliated Hospital Zhejiang University, Zhejiang A & F University, Children's Hospital of Zhejiang University
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W7223214921