Type 2 Diabetes-Associated Phenylacetylglutamine Induces Deleterious Inflammation Cycle in Myeloid Cells through β₂ Adrenergic Receptors and Impedes Wound Healing

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Despite advances in glucose-lowering therapies, many diabetic patients still suffer inflammation-related complications such as chronic non-healing wounds. The microbiota-derived metabolite phenylacetylglutamine (PAGln) is identified as a causal driver of these wounds via a transmissible, β 2 -adrenergic receptor-mediated trained-immunity loop. Metabolomics reveals PAGln is elevated in type 2 diabetes and tightly associated with poor healing in both diabetic and non-diabetic human patients. Pharmacokinetic comparison shows that mouse PAGln exposure closely matches the concentrations and kinetics seen in humans. It is validated that PAGln delays wound closure, impairs collagen restoration, and reduces neovascularization in wild-type, T1DM, and T2DM mice-defects rescued by β-blocker treatment. Mechanistically, PAGln epigenetically trains myeloid cells via β 2 -adrenergic receptors, promoting their hyperresponsiveness, heightening systemic inflammation. This epigenetic reprogramming extends to HSCs, expanding hyper-responsive myeloid cells and sustaining a myeloid-biased inflammatory loop. This PAGln-induced hyper-inflammatory, wound-healing deficit is transmissible via bone marrow transplantation to irradiated naïve recipients, confirming that PAGln-trained hematopoietic cells propagate these deleterious phenotypes. β-blockers co-treatment reverses PAGln-induced cytokine elevation

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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