Glucose stimulates intestinal epithelial crypt proliferation by modulating cellular energy metabolism

Abstract

The intestinal epithelium plays an essential role in nutrient absorption, hormone release, and barrier function. Maintenance of the epithelium is driven by continuous cell renewal by stem cells located in the intestinal crypts. The amount and type of diet influence this process and result in changes in the size and cellular make-up of the tissue. The mechanism underlying the nutrient-driven changes in proliferation is not known, but may involve a shift in intracellular metabolism that allows for more nutrients to be used to manufacture new cells. We hypothesized that nutrient availability drives changes in cellular energy metabolism of small intestinal epithelial crypts that could contribute to increases in crypt proliferation. We utilized primary small intestinal epithelial crypts from C57BL/6J mice to study (1) the effect of glucose on crypt proliferation and (2) the effect of glucose on crypt metabolism using an extracellular flux analyzer for real-time metabolic measurements. We found that glucose increased both crypt proliferation and glycolysis, and the glycolytic pathway inhibitor 2-deoxy-d-glucose (2-DG) attenuated glucose-induced crypt proliferation. Glucose did not enhance glucose oxidation, but did increase the maximum mitochondrial respiratory capacity, which may contribute to glucose-induced increases in proliferation. Glucose activated Akt/HIF-1α signaling pathway, which might be at least in part responsible for glucose-induced glycolysis and cell proliferation. These results suggest that high glucose availability induces an increase in crypt proliferation by inducing an increase in glycolysis with no change in glucose oxidation.

Evidence for a direct effect of the autonomic nervous system on intestinal epithelial stem cell proliferation

“…; Zhou et al. ). Animals were single housed in shoebox cages and maintained with ad libitum access to tap water and laboratory chow (Teklad 22/5, Envigo, Madison, WI) on a 12:12 light:dark cycle (lights on 0700) in a climate‐controlled room (temperature = 21 ± 2°C and humidity = 50 ± 10%).…”

“…These transgenic animals were selected for their global and constitutive expression of a green fluorescent protein tag on the intestinal epithelial stem cell marker Lgr5 (Barker et al 2007). A power analysis (G*Power 3.1.9.2) based on previously published and our preliminary data investigating mRNA expression differences between IESCs and other crypt cells show that to achieve a power = 0.8 and a type I error of 0.05, an n = 3 mice per group are needed (Mustata et al 2011;Akcora et al 2013;Tsai et al 2014;Kechele et al 2017;Zhou et al 2018). Animals were single housed in shoebox cages and maintained with ad libitum access to tap water and laboratory chow (Teklad 22/5, Envigo, Madison, WI) on a 12:12 light:dark cycle (lights on 0700) in a climate-controlled room (temperature = 21 AE 2°C and humidity = 50 AE 10%).…”

Ileal Transcriptome Profiles of Japanese Quail Divergent in Phosphorus Utilization

“…These renewal processes and intestinal functions such as absorption processes consume 15%-25% of the total energy required by birds [30]. In the current study, animals with high PU appear to have a higher proliferation rate of intestinal cells, as indicated by the enrichment of the oxidative phosphorylation pathway [31]. In contrast, quail with a low PU might exhibit shifts in energy metabolism utilizing signal transduction mechanisms of the "sirtuin signaling pathway" (Table 1).…”

Autophagy Reprograms Alveolar Progenitor Cell Metabolism in Response to Lung Injury

“…The effects of glucose metabolism on AT2 cells appear to be mediated by both autophagy-dependent and -independent mechanisms. Glucose has recently been shown to stimulate intestinal epithelial crypt proliferation by inducing glycolysis (Zhou et al, 2018). Blockade of pyruvate entry into mitochondria increased proliferation and expanded intestinal stem cell compartments (Schell et al, 2017).…”