No abstract

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.

Rotavirus causes severe diarrhea in small children and is typically treated using glucose-containing oral rehydration solutions; however, glucose may have a detrimental impact on these patients, because it increases chloride secretion and presumably water loss. The rotavirus enterotoxin nonstructural protein 4 (NSP4) directly inhibits glucose-mediated sodium absorption. We examined the effects of NSP4 and glucose on sodium and chloride transport in mouse small intestines and Caco-2 cells. Mouse small intestines and Caco-2 cells were incubated with NSP4 in the presence/absence of glucose. Absorption and secretion of sodium and chloride, fluid movement, peak amplitude of intracellular calcium fluorescence, and expression of Ano1 and sodium-glucose cotransporter 1 were assessed. NHE3 activity increased, and chloride secretory activity decreased with age. Net chloride secretion increased, and net sodium absorption decreased in the intestines of 3-week-old mice compared to 8-week-old mice with NSP4. Glucose increased NSP4-stimulated chloride secretion. Glucose increased NSP4-stimulated increase in short-circuit current measurements (I ) and net chloride secretion. Ano1 cells with siRNA knockdown showed a significant difference in I in the presence of NSP4 and glucose without a significant difference in peak calcium fluorescence intracellular when compared to non-silencing (N.S.) cells. The failure of glucose to stimulate significant sodium absorption was likely due to the inhibition of sodium-hydrogen exchange and sodium-glucose cotransport by NSP4. Since glucose enhances intestinal chloride secretion and fails to increase sodium absorption in the presence of NSP4, glucose-based oral rehydration solutions may not be ideal for the management of rotaviral diarrhea.

Chemotherapy-Induced Leukopenia (CIL) is associated with increased mortality and economic burden on patients. This study was conducted to evaluate whether inclusion of green jackfruit flour in regular diet of those patients receiving chemotherapy, could prevent CIL. This was a retrospective study conducted among a group of patients undergoing chemotherapy for solid tumors at Renai Medicity Hospital, Palarivattom, Cochin, Kerala, India, since June 2018. The study group comprised of 50 consecutive subjects, who were supplemented with green jackfruit flour diet in their regular diet and further followed up prospectively. The control group was retrospective with 50 subjects prior to June 2018, with no diet supplements. Those who received less than three cycles were excluded from either arm. The mean age of the participants in study group and control group were 53.16 ± 11.06 and 56.96 ± 12.16 years respectively. In the study group, six patients out of 37, and 20 patients out of 50 in the control group, developed CIL. They received 38 and 105 vials of filgrastim respectively. After excluding those cycles in study group patients, where green jackfruit flour was not taken, the mean number of cycles in which CIL developed (p = 0.00) and number of vials of filgrastim taken per cycle (p = 0.00) were significantly different from control group and no patient in the study group developed CIL. Inclusion of green jackfruit flour as a dietary intervention prevents chemotherapy-induced leukopenia in patients undergoing chemotherapy along with pegfilgrastim.