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Metabolic Regulation of Intestinal Stem Cell Homeostasis

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The balance between self-renewal and differentiation of intestinal stem cells is essential for intestinal epithelial homeostasis, which can be regulated by dietary cues. Recent evidences indicate that metabolic pathways sense changes in nutritional status to control stem cell fate, which may provide new clues for the prevention of intestinal diseases.

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Metabolic Regulation of Intestinal Stem Cell (ISC) Fate

Intestinal epithelium, a dynamic single-layered crypt-villi structure, is responsible for food digestion and absorption and endocrine and immune regulation. ISCs are a group of cell populations located at the crypt base that are involved in the renewal of small intestinal epithelium every 3–5 days. ISCs are characterized by their unique capacity for both self-renewal and differentiation into various functional cells, including enterocytes, enteroendocrine cells, goblet cells, tuft cells, and

Oxidative Phosphorylation (OXPHOS)

It is generally known that most stem cells are quiescent and display a metabolic disposition for cytosolic glycolysis. However, ISCs are active and contain abundant mitochondria, which provide sufficient energy for the rapid renewal of intestinal epithelium. OXPHOS is a critical process that generates ATP and is indispensable for ISC fate decisions (Figure 1). Evidence has shown that Lgr5+ ISCs present a higher pyruvate/lactate ratio and mitochondrial membrane potentials than neighboring Paneth

Pyruvate Metabolism

ISC and differentiated cell fates can also be affected by cell-intrinsic changes in pyruvate metabolism (Figure 1). The mitochondrial pyruvate carrier (Mpc), a complex for importing pyruvate to mitochondria, has been identified as a key regulator of ISC proliferation [5,6]. Mpc displays low expression in ISCs, but is upregulated during differentiation [5]. ISC-specific Mpc1 knockout significantly skews cell metabolism towards glycolysis and increases ISC proliferation in mice and Drosophila (

Fatty Acid Oxidation (FAO)

Recently, three research teams have confirmed that FAO is required for the survival of ISCs and the renewal of intestinal epithelium (Table 1) [7,9,10]. FAO genes are abundantly expressed in the duodenum and proximal jejunum and expression gradually decreases distally [10]. Intestinal epithelium deficiency of the FAO enzyme Cpt-1α reduces the development of intestinal epithelial cells, increases crypt apoptosis, and inhibits ISC function [9]. Interestingly, ISC-specific Cpt-1α knockout in mice

Ketone Body Metabolism

Ketone bodies, derived from acetyl-CoA produced by FAO, have also been reported to maintain ISC homeostasis (Figure 1) [11,12]. Recent study reports that mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme for ketogenesis, acts as a regulator of ISC fate in response to dietary changes. Hmgcs2 is selectively expressed in Lgr5+ ISCs and ISC-specific deficiency of Hmgcs2 diminishes ISC function and drives their differentiation toward Paneth and goblet cells by

Concluding Remarks

In recent years, significant advances have been made in our understanding of the metabolic requirements of ISCs and the important role of metabolic pathways in regulating ISC function and fate. The distinct metabolic features of ISCs that have high mitochondrial activity drive the rapid renewal of intestinal epithelium. Metabolic pathways, including FAO and ketone body metabolism, are involved in regulation of the role of dietary patterns and nutrients in ISC fate. However, current literatures

Acknowledgments

This research was financially supported by the Project of Innovative Research Groups of the Natural Science Foundation of Hubei Province (No. 2019CFA015), the Project of National Natural Science Foundation of China (No. 31772615), the Project of the Natural Science Foundation of Hubei Province (2020CFB431).

Declaration of Interests

The authors declare no competing interests.

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