Chronic inflammatory and degenerative disorders are driven by interconnected immune dysregulation, metabolic instability, epithelial barrier disruption, and impaired tissue repair, limiting the durability of conventional single-target therapies. The global rise in chronic inflammatory, metabolic, and age-related degenerative diseases underscores an urgent need for multi-dimensional therapeutic strategies that move beyond isolated molecular targets. Despite rapid advances in microbiome science and regenerative medicine, these fields have largely evolved in parallel, with limited integration at the translational level. Emerging evidence identifies the gut microbiome as a central regulator of systemic immunometabolic homeostasis through microbial metabolites, barrier integrity modulation, and immune-cell education. In parallel, mesenchymal stem cell (MSC)–derived peptides, key components of the MSC secretome, function as potent cell-free mediators of immunomodulation, angiogenesis, cytoprotection, and extracellular matrix remodeling. This review advances the concept of a microbiome–peptidome therapeutic axis in which microbiome conditioning enhances the permissiveness of tissues to regenerative peptide signaling. Lactobacillus reuteri DSMZ 17648 is highlighted as a strain-specific probiotic capable of pathogen co-aggregation, ecological modulation, and anti-inflammatory microenvironment stabilization, while MSC-derived peptides act as downstream paracrine effectors driving tissue repair. Integrating mechanistic insights with disease-oriented evidence across gastrointestinal, metabolic, neuroinflammatory, and fibrotic conditions, we propose that upstream microbiome stabilization may potentiate peptide-mediated regeneration. However, translational challenges including microbiome heterogeneity, peptide standardization, regulatory complexity, and limited combination trials must be addressed. Coordinated, biomarker-guided clinical studies are required to validate this multi-tier therapeutic paradigm.
Agha et al. (Thu,) studied this question.