Purpose of Review <p>Mesenchymal stem/stromal cells (MSCs) and probiotics represent two powerful yet independently pursued therapeutic modalities in regenerative medicine. MSCs provide potent immunomodulation and tissue repair through paracrine signaling, while probiotics restore microbial homeostasis and modulate host immunity. This review aims to asses biological and translational rationale for combining these modalities, what preclinical evidence supports their synergy across disease contexts, and what mechanistic, manufacturing, and regulatory barriers currently impede clinical translation. A particular emphasis was placed on neurological indications, the gut-brain-immune axis, and the largely unexplored interface of MSC apoptosis, efferocytosis, and probiotic conditioning.</p> Recent Findings <p>Preclinical evidence demonstrates robust synergy, particularly in inflammatory bowel disease models, where probiotic-primed MSCs exhibit enhanced immunomodulatory capacity through three key mechanisms: (1) metabolite-driven immune licensing favoring regulatory T-cell expansion and efferocytosis modulation (2) bidirectional paracrine and extracellular vesicle-mediated crosstalk, and (3) microenvironment conditioning that optimizes MSC engraftment and function. Promising preclinical data further extend to autoimmune disorders, wound healing, and neurological conditioning, where combined probiotic and MSCs administration demonstrated synergistic neuroprotection in animal models. Metabolic diseases. However, comprehensive review of clinical trial registries reveals a striking translational gap, no registered human trials combining these modalities exist despite extensive preclinical evidence and regulatory approval of MSC monotherapy for perianal Crohn’s disease.</p> Summary <p>The probiotic-MSC alliance represents a scientifically compelling frontier with strong mechanistic rationale and robust preclinical validation, yet remains entirely untested in human clinical trials. The major takeaways are: (1) the gut microbiome functions as a critical upstream modulator of MSC therapeutic efficacy, acting systemically through SCFA licensing, efferocytic amplification, and extracellular vesicle cargo modulation, even where MSCs do not physically reach the intestinal mucosa due to pulmonary first-pass entrapment; (2) the neurological domain, particularly Parkinson’s disease and ischemic stroke, represents a high-priority but empirically unexplored frontier for combination approaches targeting the gut-brain-immune axis; and (3) successful clinical translation will require factorial trial designs in IBD and metabolic disorders, sophisticated GMP-compliant manufacturing infrastructure for combination Live Biotherapeutic Product–Advanced Therapy Medicinal Products, tiered multi-assay potency matrices, and biomarker-driven patient stratification leveraging multi-omics and machine learning. The next five years represent a critical inflection point for translating this powerful biological synergy into meaningful clinical benefit for patients with complex inflammatory and metabolic diseases. The field is advancing toward precision medicine through engineered probiotics, multi-omics patient stratification, and personalized delivery platforms. Machine learning-guided microbiome profiling may enable identification of patient “theratypes” predicting therapeutic response, while novel delivery systems including enteric-coated formulations and programmable ingestible capsules promise optimized spatiotemporal release.</p> Graphical Abstract <p></p>