Abstract
Destruction of clonogenic cells in the crypt following irradiation are thought to cause altered gastrointestinal function. Previously, we found that an amino acid-based oral rehydration solution (AA-ORS) improved gastrointestinal function in irradiated mice. However, the exact mechanisms were unknown. Electrophysiology, immunohistochemistry, qPCR, and Western blot analysis were used to determine that AA-ORS increased proliferation, maturation, and differentiation and improved electrolyte and nutrient absorption in irradiated mice. A single-hit, multi-target crypt survival curve showed a significant increase in crypt progenitors in irradiated mice treated with AA-ORS for six days (8.8 ± 0.4) compared to the saline-treated group (6.1 ± 0.3; P < 0.001) without a change in D0 (4.8 ± 0.1 Gy). The Dq values increased from 8.8 ± 0.4 Gy to 10.5 ± 0.5 Gy with AA-ORS treatment (P < 0.01), indicating an increased radiation tolerance of 1.7 Gy. We also found that AA-ORS treatment (1) increased Lgr5+, without altering Bmi1 positive cells; (2) increased levels of proliferation markers (Ki-67, p-Erk, p-Akt and PCNA); (3) decreased apoptosis markers, such as cleaved caspase-3 and Bcl-2; and (4) increased expression and protein levels of NHE3 and SGLT1 in the brush border membrane. This study shows that AA-ORS increased villus height and improved electrolyte and nutrient absorption.
Highlights
Gastrointestinal (GI) toxicity manifests itself in the first week following accidental and therapeutic radiation exposure and is the most significant dose-limiting factor in the clinical course of radiotherapy[1,2,3,4,5,6]
Differentiated villus cells are involved in fluid absorption secondary to sodium (Na+), chloride (Cl−), and nutrient absorption, whereas the less differentiated, immature epithelial cells located in the crypt are predominantly involved in Cl− secretion and fluid loss
This study shows that in situ stem cells and the intestinal epithelial cell proliferation induced by acid-based oral rehydration solution (AA-ORS) increased electrolyte and nutrient absorption by increasing villus height that comprised of mature, differentiated epithelial cells
Summary
Gastrointestinal (GI) toxicity manifests itself in the first week following accidental and therapeutic radiation exposure and is the most significant dose-limiting factor in the clinical course of radiotherapy[1,2,3,4,5,6]. Human intestinal epithelial cells are generated from a fixed population of stem cells functionally situated in the lower portion of the intestinal crypts, including fast cycling crypt base columnar cells (CBCs) and more quiescent “+4” cells above Paneth cells in mice[15,16,17] These stem cells give rise to absorptive enterocytes, mucus cells, Paneth cells, and enteroendocrine cells[18]. Treatment with AA-ORS for a period of 14 days improved electrolyte absorption, decreased paracellular permeability as well as plasma endotoxin and proinflammatory cytokine levels, better preserved body weight, and improved survival in mice exposed to an otherwise lethal dose of total-body irradiation (8.5 Gy TBI)[20].
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