Introduction
Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by disrupted interactions between the gut microbiota and the host immune system, notably associated with the depletion of spermidine-producing Blautia species. Here, we investigated whether restoring this microbial–metabolite axis could rebalance intestinal immunity via spermidine-driven signaling pathways in regulatory B cells (Bregs).
Aims & Methods
We assessed the therapeutic potential of live Blautia coccoides in a dextran sulfate sodium (DSS)-induced colitis mouse model, comparing it to treatments with heat-killed Blautia, exogenous spermidine, and a spermidine synthesis-deficient Blautia mutant (ΔSPDS). Daily oral treatments were initiated during colitis induction. Disease progression was evaluated using clinical scoring, histopathological analysis, and intestinal permeability assays. Spermidine levels in fecal and tissue samples were quantified, while Breg populations and STAT3 activation were analyzed by flow cytometry and phospho-specific staining. To explore clinical relevance, we performed spatial transcriptomics on UC patient biopsies and ex vivo stimulation of PBMCs from anti-TNF-refractory UC patients with Blautia-derived metabolites.
Results
Live Blautia treatment significantly improved both clinical and histological outcomes, including reduced mucosal ulceration, decreased inflammatory infiltration, and restored expression of tight junction proteins. In contrast, heat-killed bacteria provided no therapeutic benefit. Intestinal permeability assays confirmed the recovery of barrier integrity following Blautia or spermidine administration, an effect absent in ΔSPDS-treated mice. Early in treatment, local spermidine levels were restored, coinciding with a progressive expansion of IL-10-producing Bregs exhibiting robust STAT3 phosphorylation. These immunological responses were absent in both ΔSPDS-treated and STAT3-deficient mice. Cytokine profiling revealed a shift toward an anti-inflammatory environment, with decreased TNF-α and IL-6 and elevated IL-10 levels in colonic tissues. Spatial transcriptomics identified microanatomical niches where Blautia co-localized with STAT3-activated Bregs and increased IL-10 transcripts. Furthermore, ex vivo stimulation of PBMCs from refractory UC patients with Blautia metabolites promoted Breg differentiation and restored their ability to suppress TNF-α release, reinforcing the role of microbial-derived metabolites in regulating immune homeostasis.
Conclusion
Our findings establish Blautia as a critical regulator of intestinal immunity, acting through a spermidine–STAT3–Breg axis to repair immune–epithelial dysfunction in UC. This comprehensive validation—from bacterial genetics and animal models to human tissue analyses—supports the development of targeted probiotic or precision microbiota-based therapies aimed at replenishing spermidine-producing Blautia in patients with refractory UC.
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