Microbial metabolites and MAMPs: orchestrators of intestinal stem cell function

Intestinal stem cells (ISCs) are essential for maintaining and regenerating the intestinal epithelium. Recent studies have highlighted the critical role of the gut microbiota in regulating ISC function through diverse molecular signals, particularly microbial metabolites and microbe-associated molecular patterns (MAMPs). Microbial metabolites, such as short-chain fatty acids (SCFAs) and indoles, modulate ISC activities by influencing proliferation, differentiation, and overall epithelial renewal. MAMPs, such as lipopolysaccharide (LPS) and peptidoglycan-derived muramyl dipeptide (MDP), interact with pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), affecting ISC proliferation and epithelial regeneration. In this review, we discuss emerging evidence on how these microbial signals regulate ISC function and elucidate the mechanisms underlying epithelial renewal and tissue repair. A comprehensive understanding of these host-microbe interactions holds therapeutic potential for enhancing epithelial regeneration and restoring gut homeostasis, paving the way for novel regenerative medicine strategies.