Host-microbiota interaction in intestinal stem cell homeostasis

Figures & data

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/#/).

Table 1. Effects of intestinal microbiota-derived metabolites on ISCs.

Metabolites	Findings	Reference
Acetate	Acetate supports the formation, growth and budding of intestinal organoids by inhibition of β-oxidation when acetyl-CoA concentration is reduced.	^Citation95
Propionate	Propionate treatment reserves the chemical injury with loss of expression of ISCs makers LGR5 and OLFM4 in the intestinal organoids of mice.	^Citation96
	Fucose accelerates intestinal epithelial proliferation in a Gpr41/Gpr43-dependent manner by promoting Akkermansia-related propionate metabolism in mice.	^Citation97
Butyrate	Butyrate promotes colonic mucosa proliferation in humans.	^Citation98
	Butyrate increases Lgr5^+ ISC number in small intestinal organoids of mice by inhibiting HDAC.	^Citation99
	Butyrate suppresses colonic stem cells proliferation at the physiological concentration in the FOXO3-dependent manner.	^Citation100
Lactate	Lactate improves epithelial proliferative activity and crypts size of rat cecum.	^Citation101
	Microbiota-derived lactate induces enterocyte hyperproliferation in starvation-refed mice.	^Citation102
	LAB-type symbiont-derived lactate stimulates ISC proliferation through Wnt/β-catenin signals of in mice.	^Citation103
Succinate	Succinate exacerbates the development of ulcerative colitis by inducing mucosal blood flow and generation of superoxide.	^Citation104
	Succinate significantly inhibits colonic cell proliferation and reduces crypt size in the colon of rats.	^Citation105
	Succinate attenuates intestinal barrier function in mice and pigs.	^Citation106,Citation107
Indoleacetic acid	Indoleacetic acid suppresses β-catenin signals through AHR to inhibit ISCs proliferation.	^Citation108
Indole 3-carbinol	Indole 3-carbinol promotes ISCs differentiation to secretory lineages by activating Wnt/β-catenin signals and suppressing Notch signals in an AHR-dependent manner in mice.	^Citation109
Indole-3-aldehyde	Lactobacillus derived-indole 3-aldehyde activates ILC3 cells through AHR ligands to produce IL-22, which further maintains ISCs proliferation in a STAT3-dependent manner in mice.	^Citation25
DCA/LCA	DCA and LCA induce cancer stemness in colonic epithelial cells by modulating M3R and Wnt/β-catenin signaling in colon cancer cells.	^Citation110 ^Citation111
BAs	BAs at the physiological level promote ISCs regeneration and repair after damage via activating TGR5 signaling in mice.	^Citation112
T-βMCA and DCA	T-βMCA and DCA induce proliferation and DNA damage in Lgr5+cells through antagonizing intestinal FXR function.	^Citation113

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/#/).

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Data Availability statement

Data sharing is not applicable to this article, as no datasets were generated or analyzed in the current study. Figures 1–4 were created using Figdraw software (www.figdraw.com).