Stem Cells in the Intestine: Possible Roles in Pathogenesis of Irritable Bowel Syndrome

Abstract

Irritable bowel syndrome is one of the most common functional gastrointestinal (GI) disorders that significantly impair quality of life in patients. Current available treatments are still not effective and the pathophysiology of this condition remains unclearly defined. Recently, research on intestinal stem cells has greatly advanced our understanding of various GI disorders. Alterations in conserved stem cell regulatory pathways such as Notch, Wnt, and bone morphogenic protein/TGF- β have been well documented in diseases such as inflammatory bowel diseases and cancer. Interaction between intestinal stem cells and various signals from their environment is important for the control of stem cell self-renewal, regulation of number and function of specific intestinal cell types, and maintenance of the mucosal barrier. Besides their roles in stem cell regulation, these signals are also known to have potent effects on immune cells, enteric nervous system and secretory cells in the gut, and may be responsible for various aspects of pathogenesis of functional GI disorders, including visceral hypersensitivity, altered gut motility and low grade gut inflammation. In this article, we briefly summarize the components of these signaling pathways, how they can be modified by extrinsic factors and novel treatments, and provide evidenced support of their roles in the inflammation processes. Furthermore, we propose how changes in these signals may contribute to the symptom development and pathogenesis of irritable bowel syndrome.

Keywords: Intestinal stem cells; Irritable bowel syndrome; Notch; Transforming growth factor beta; Wnt.

Figure 1

Intestinal epithelium: cellular components, their anatomical positions and key transcription factors for their fate specification. Two types of stem cells reside in the intestinal crypt—Lgr5-expressing crypt base columnar (CBC) stem cell (purple) and +4 stem cell (green). Cell fate specification of stem/ progenitor cells to either secretory or absorptive lineage relies on appropriate level and proper temporal expression of key transcriptional regulators (written in grey). Stem cell maintenance and fate decision is governed by signaling pathways such as Notch, Wnt and bone morphogenic protein (BMP). Recent reports suggest that differentiated secretory cells and +4 stem cells may dedifferentiate to replenish stem cell/progenitor pool during injury.

Figure 2

Signaling pathways important for stem/progenitor cells regulation. (A) Notch signaling pathway. Cell-cell interaction is required for lateral inhibition. The sending cell produces Delta which binds and activates Notch in the adjacent cell. Matrix metalloproteinases (MMPs) such as Adam10 and Adam17 proteolytically cleave Notch extracellular domain while gamma secretase cleaves intracellular domain, leading to transcriptional activation of Notch target genes which feedback to inhibit Notch in the sending cell. (B) Wnt signaling pathway. In the absence of ligand (left), β-catenin is inhibited by the destruction complex. Binding of Wnt ligand to receptors frees β-catenin which displaces the transcriptional repressor Groucho. Together with the T cell factor (TCF) transcription factor, β-catenin activates Wnt target genes including some of its own receptors. Of note, R-spondin can potentiate Wnt signaling through inhibiting ZNRF3/RNF43 which normally inhibits the Wnt transmembrane receptor Frizzled. DKK, Dickkopf.

Figure 3

Pathogenesis of inflammatory bowel disease (IBD). (A) Interaction between external factors such as diet and microbiota and the cells of the intestine and enteric nervous system is depicted. Panel A shows regulatory circuitry during normal repair process. (B) Panel B shows disrupted system during dys-regulated repair in IBD. Imbalanced microbiota and diet can affect stem cells and niche cells. The resulting increase in inflammatory cytokines and other signaling molecules leads to failure to maintain the stem cell pool, fate choice bias, and persistent inflammation.

Figure 4

Pathogenesis of irritable bowel syndrome (IBS). In IBS context, external factors such as diet and microbiota can affect intestinal stem cells, niche cells, enteric glia and neurons, as well as immune cells. The resulting increased permeability and production of stimulatory signals, both inflammatory cytokines and other signaling molecules, disrupt intestinal homeostasis, leading to sensitization of the enteroendocrine and enteric nervous system. In particular, changes in enteroendocrine number, subtypes, and functions result in altered levels of neuropeptides and hormones, inducing hypersensitivity and dysmotility.