Host-microbiota interaction in intestinal stem cell homeostasis

Abstract

Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

Keywords: Intestinal stem cells; dietary nutrients; gut homeostasis; immune homeostasis; intestinal organoid; metabolic interaction; microbiome; micronutrients.

Figure 1.

ISCs and differentiated progeny in the small intestine. (a) Active ISCs feed daughter cells into the transit-amplifying compartment, and TA cells differentiate into mature intestinal epithelial cells, including absorptive and secretory cells. Quiescent ISCs can be converted to active ISCs to promote intestinal epithelial repair. (b) Villus-crypt axis structure of the small intestine. Intensity gradient of the four crucial signaling pathways for ISC maintenance along the villus-crypt axis. This figure was drawn using online Figdraw software (https://www.figdraw.com/#/).

Figure 2.

Essential signaling pathway regulating ISC fate. The principal Wnt, Notch, BMP, and EGF signaling cascades collectively regulate ISC behavior and homeostasis. Further details are provided in the main text. This figure was drawn using online Figdraw software (https://www.figdraw.com/#/).

Figure 3.

The effects of key microbiota-derived metabolites on ISCs and the pathways that control gut homeostasis. Microbiota-derived metabolites, such as SCFAs, lactate, succinate, indoles and their derivatives, and bile acids, play a crucial role in regulating ISC homeostasis and associated signaling pathways. Further details are provided in the main text. This figure was drawn using online Figdraw software (https://www.figdraw.com/#/).

Figure 4.

The establishment and engineering improvement of the intestinal organoid model. (a) Flowchart of the establishment of the mammalian intestinal organoid model. Intestinal crypts were isolated from intestinal tissue, and further embedded in Matrigel® with culture medium to form intestinal organoids. (b) Engineering improvement of the intestinal organoid model. (a) 2D organoids; (b) intestinal organoid polarization; (c) co-culture of intestinal organoids with intestinal mesenchymal and immune cells. (d) High-throughput automated organoid culture. Phenotypic analysis, RT-PCR, imaging, single-cell RNA sequencing, and other indicators can be used to evaluate organoid function. This figure was drawn using online Figdraw software (https://www.figdraw.com/#/).