Human umbilical cord mesenchymal stem cells in irritable bowel syndrome: Mechanistic and translational insights

Table 1 Therapeutic effects of human umbilical cord mesenchymal stem cells in diarrhea-predominant irritable bowel syndrome, showcasing mechanisms, translational capabilities, and challenges to human-based treatment

Therapeutic effect of hUC-MSCs	Mechanism of action	Translational considerations
Reduction of mucosal inflammation	Secretion of anti-inflammatory factors (i.e., TSG-6, PGE2, IDO, and TGF-β) and cytokines (IL-10); induction of regulatory T cells and M2 macrophages; suppression of TNF-α, IL-6, and pro-inflammatory immune cells	Benefits: Addresses low-grade inflammation underlying IBS-D; may provide durable relief by resolving immune triggers. Challenge: IBS immune activation is subtle, therefore selecting specific patients with inflammatory phenotypes may be necessary. Regulatory approval will require clear clinical benefit given safety risks of systemic cell therapy. Although, it should be noted that MSCs have a substantiated record of safety
Restoration of intestinal barrier	Paracrine release of growth factors (i.e., EGF and KGF) and PGE2 that promote epithelial repair; upregulation of tight junction proteins and mucins; differentiation into epithelial-like cells or stimulation of resident stem cells	Benefits: Reduces gut permeability, which can alleviate diarrhea and pain by preventing luminal irritants from triggering enteric nerves and immune responses. Challenge: Delivering MSCs to mucosal sites in patients is difficult; intravenous cells may consolidate in the lungs or spleen. Optimizing delivery (i.e., via endoscopy or multiple doses) and demonstrating barrier function in humans, without a list of straightforward biomarkers, are concerns
Rebalancing of gut microbiota	Indirect modulation via improved intestinal environment (i.e., less inflammation, better barrier, and more nutrients for commensals); possible secretion of antimicrobial peptides or metabolites that favor growth of beneficial bacteria (i.e., SCFA producers)	Benefit: A eubiotic microbiome can have systemic benefit, increasing SCFAs that enforce immune tolerance and fortify the gut barrier. Restoring microbial diversity may yield sustained symptom improvement beyond the treatment period. Challenge: Human microbiome responses may vary, since personalized factors influence outcomes. Regulatory agencies will expect mechanistic clarity, and attributing clinical improvement to microbiota changes is complex. Combining MSC therapy with microbiome-based interventions (pre/postbiotics or diet) might be explored to enhance synergistic effects
Alleviation of IBS symptoms (i.e., diarrhea and pain)	Multi-modal actions above converge to reduce core IBS-D symptoms: Less inflammatory signaling and conservative epithelium mitigate urgency/diarrhea; normalized microbiota and immune profile may reduce gas and bloating; MSC secretions (i.e., NGF and opioid-like peptides) could modulate enteric neurons to dull pain perception.	Benefits: Direct improvement in patient-reported outcomes (i.e., stool frequency/consistency and abdominal pain) would fulfill the primary goal of therapy and improve quality of life. MSC therapy could reduce reliance on multiple symptom-directed drugs by addressing upstream causes. Challenge: Pain in IBS has a central nervous system component; MSCs might not fully address brain-gut dysregulation. Placebo response rates in IBS trials are high, necessitating rigorous trial designs to prove efficacy. Long-term safety must be confirmed, especially if repeat infusions are required for chronic management

hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; TSG-6: Tumor necrosis factor-α-stimulated gene 6; PGE2: Prostaglandin E2; IDO: Indoleamine 2,3-dioxygenase; TGF-β: Transforming growth factor β; IL: Interleukin; TNF-α: Tumor necrosis factor-α; IBS-D: Diarrhea-predominant irritable bowel syndrome; IBS: Irritable bowel syndrome; MSCs: Mesenchymal stem cells; EGF: Epidermal growth factor; KGF: Keratinocyte growth factor; SCFA: Short chain fatty acid.