Electrolyte and nutrient absorption occur in villous epithelial cells. Radiation often results in reduced electrolyte and nutrient absorption, which leads to gastrointestinal toxicity. Therefore, the authors studied: (1) radiation-induced changes in glucose and amino acid absorption across ileal tissues and (2) the effect of amino acid mixtures on absorptive capacity. NIH Swiss mice were irradiated (0, 1, 3, 5, or 7 Gy) using a ¹³⁷Cs source at 0.9 Gy min⁻¹. Transepithelial short circuit current (I(sc)), dilution potential, and isotope flux determinations were made in Ussing chamber studies and correlated to plasma endotoxin and IL-1β levels. Amino acids that increased electrolyte absorption and improved mucosal barrier functions were used to create a mitigating amino acid mixture (MAAM). The MAAM was given to mice via gastric gavage; thereafter, body weight and survival were recorded. A significant decrease in basal and glucose-stimulated sodium absorption occurred after 0, 1, 3, 5, and 7 Gy irradiation. Ussing chamber studies showed that paracellular permeability increased following irradiation and that the addition of glucose resulted in a further increase in permeability. Following irradiation, certain amino acids manifested decreased absorption, whereas others were associated with increased absorption. Lysine, aspartic acid, glycine, isoleucine, threonine, tyrosine, valine, tryptophan, and serine decreased plasma endotoxins were selected for the MAAM. Mice treated with the MAAM showed increased electrolyte absorption and decreased paracellular permeability, IL-1β levels, and plasma endotoxin levels. Mice treated with MAAM also had increased weight gain and better survival following irradiation. The MAAM has immediate potential for use in mitigating radiation-induced acute gastrointestinal syndrome.

The sodium-coupled glucose transporter-1 (SGLT1)-based oral rehydration solution (ORS) used in the management of acute diarrhea does not substantially reduce stool output, despite the fact that glucose stimulates the absorption of sodium and water. To explain this phenomenon, we investigated the possibility that glucose might also stimulate anion secretion. Transepithelial electrical measurements and isotope flux measurements in Ussing chambers were used to study the effect of glucose on active chloride and fluid secretion in mouse small intestinal cells and human Caco-2 cells. Confocal fluorescence laser microscopy and immunohistochemistry measured intracellular changes in calcium, sodium-glucose linked transporter, and calcium-activated chloride channel (anoctamin 1) expression. In addition to enhancing active sodium absorption, glucose increased intracellular calcium and stimulated electrogenic chloride secretion. Calcium imaging studies showed increased intracellular calcium when intestinal cells were exposed to glucose. Niflumic acid, but not glibenclamide, inhibited glucose-stimulated chloride secretion in mouse small intestines and in Caco-2 cells. Glucose-stimulated chloride secretion was not seen in ileal tissues incubated with the intracellular calcium chelater BAPTA-AM and the sodium-potassium-2 chloride cotransporter 1 (NKCC1) blocker bumetanide. These observations establish that glucose not only stimulates active Na absorption, a well-established phenomenon, but also induces a Ca-activated chloride secretion. This may explain the failure of glucose-based ORS to markedly reduce stool output in acute diarrhea. These results have immediate potential to improve the treatment outcomes for acute and/or chronic diarrheal diseases by replacing glucose with compounds that do not stimulate chloride secretion.

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Our objective was to determine the optimal amino acid (aa) formula to mitigate the effect of radiation on the electrolyte and nutrient absorption and mucosal barrier functions of the gastrointestinal (GI) tract.Studies were conducted on small intestinal mucosa of irradiated NIH Swiss mice (0, 1, 3, 5 or 7 Gy). The mucosal barrier mechanism was studied for dilution potential, conductance, and plasma endotoxin and IL‐1β; electrolyte, glucose, and aa absorption were studied with Ussing chamber flux studies and transepithelial electrical measurements. Amino acids that improved GI functions were used to formulate a drink that was tested in survival studies.Radiation (0 vs 7 Gy) decreased anion selectivity (0.48±0.05 vs 0.91±0.07) and increased paracellular conductance (30.5±4.1 vs 54.0±10.1). Plasma endotoxin levels were elevated at 7 Gy (20 vs 120). Radiation (0 vs 7 Gy) decreased Na absorption (9.8±0.8 vs − 0.6±0.3) and increased electrogenic Cl secretion (10.1±1.5 vs 0.1±0.01). Glucose absorption exhibited a dose‐dependent decrease and was abolished in 7‐Gy mice (140.7±32.2 vs 3.2±0.8). Lysine, aspartic acid, glycine, isoleucine, threonine, tyrosine, valine, serine, and tryptophan improved GI functions. Survival studies using the aa mixture showed increased survival for lethally irradiated mice.The aa mixture improved GI mucosal function and mitigated radiotoxicity.Support provided by Enterade, LLC.

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