Figure 4.

Indirect mechanisms of interaction between Gut Microbiota and LGR5+ Intestinal Stem Cells. (Figure 4 follows the key attached with Figure 3 for cell type reference) Significant interactions along the gut microbiota – intestinal stem cell axis, and their effects on proliferation and differentiation of ISCs have been depicted in homeostasis (left panel) and IBD (right panel). Paneth cells mediate these interactions through release of ISC proliferative signals like Wnt3A and phospholipase A2 (PLA II) (a). During IBD, these PC-mediated ISC-microbiota interactions are dysregulated (e). Enteroendocrine cells (EECs) forge microbiota-ISC interactions through the release of GLP-2 in response to microbial metabolites like SCFAs, which not only regulates their own differentiation from progenitors, but also drives underlying mesenchyme to release growth factors supporting ISC renewal (b). IBD – characterized dysbiosed microbiota leads to alterations in these interaction (f). Microbial stimulation can similarly lead to different helper T lymphocyte populations (Th1, Th2, Th17 and Treg) and ILC3, mediating either ISC self-renewal or differentiation (c). These mechanisms go haywire during IBD (g). Mesenchymal component of the ISC niche produces factors like IL-33, IL-6 and Wnt, in response to microbial signals, which regulate ISC proliferation and differentiation (d). PLA II (Phospholipase A2), SCFA (Short-chain fatty acids), GLP-2 (Glucagon-like peptide 2), EGF (Epidermal growth factor)/IGF (Insulin-like growth factor)