Immune–Microbiome interactions & new T1D therapies
Pleun de Groen, Lente C.H.M. Blok, Coco M. Fuhri Snethlage, Nordin M.J. Hanssen, Elena Rampanelli, Max Nieuwdorp
Unraveling Type 1 Diabetes: Integrating Microbiome, Metabolomics, and Immunomodulation for Next-Generation Therapies. Int J Mol Sci . 2025 Nov 6;26(21):10788.
Type 1 diabetes (T1D) is an autoimmune disease driven by immune-mediated destruction of pancreatic beta cells, resulting from a complex interaction between genetic susceptibility and environmental triggers. While advances in insulin delivery and glucose monitoring have transformed diabetes management, T1D remains incurable and associated with substantial long-term morbidity and reduced life expectancy.
Recent years have seen major progress in understanding the immunopathology of T1D, including the roles of autoreactive T cells, regulatory immune dysfunction, and inflammatory signaling pathways. In parallel, mounting evidence implicates the gut microbiome and its metabolites as key environmental modulators of immune tolerance and autoimmunity. This review integrates emerging insights from immunology, microbiome research, and metabolomics to evaluate novel therapeutic strategies aimed at preserving beta cell function and modifying disease progression.
This narrative review synthesizes preclinical and clinical evidence on immune-modulatory and microbiome-based interventions in T1D. The authors discuss immune-targeted therapies such as monoclonal antibodies, regulatory T-cell–based approaches, CAR-Treg therapy, and JAK-STAT inhibition, alongside microbiome-focused strategies including fecal microbiota transplantation (FMT), dietary modulation, and microbial metabolite supplementation. The review highlights both the promise and limitations of these approaches and emphasizes the need for integrated, personalized treatment strategies.
Key findings:
- Immune-targeted therapies such as anti-CD3 antibodies, co-stimulation blockade, and JAK-STAT inhibitors can delay disease onset or partially preserve beta cell function, but their effects are variable and often time-limited.
- Regulatory T-cell dysfunction plays a central role in T1D pathogenesis, making Treg-based therapies, including CAR-Treg approaches, a promising but technically challenging avenue.
- Individuals with or at risk of T1D consistently show reduced gut microbiome diversity and altered microbial function, particularly decreased production of short-chain fatty acids.
- Microbiome-derived metabolites influence immune tolerance through effects on gut barrier integrity, regulatory T-cell induction, and inflammatory signaling pathways.
- Early clinical studies suggest that autologous fecal microbiota transplantation may help stabilize residual beta cell function in recent-onset T1D, although evidence remains preliminary.
- Metabolite-driven interventions and dietary fiber supplementation can modulate immune markers and gut permeability, but have shown inconsistent effects on glycaemic outcomes.
The review underscores that neither immune-based nor microbiome-based interventions alone are likely to fully halt T1D progression. Instead, the authors argue for integrated therapeutic strategies that combine immune modulation with targeted manipulation of the gut microbiome and its metabolic outputs. Precision medicine approaches—leveraging multi-omics profiling, patient stratification, and early intervention—are presented as essential for translating these experimental strategies into durable clinical benefit.
Concluding, the authors state
"The combination of microbiome-targeting strategies and immunotherapy may provide long-term preservation of beta cell function by re-establishing intestinal and systemic immune homeostasis" -
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