Glutamine analogues as adjunctive therapy for infectious diarrhea

Abstract

Glutamine is the major fuel for the gut as well as for many cells in the immune system that becomes conditionally essential during catabolic states. Glutamine supplementation improves intestinal mucosal repair and function. Glutamine, even at high doses, is without side effects and is well tolerated. Though unstable in solution, this is overcome by creating stable dipeptides such as alanyl-glutamine. In HIV-positive patients with wasting, glutamine enhances intestinal absorptive function and weight gain. Glutamine enhances sodium and water absorption in a rabbit model of cholera and Cryptosporidium-infected piglet intestine. Both glutamine and alanyl-glutamine have recently proven effective in a bovine model of Cryptosporidium as well. Finally, a rat model of cholera toxin-induced diarrhea also showed that alanyl-glutamine enhanced water and electrolyte intestinal absorption even better than the traditional glucose solutions. Clearly glutamine and its stabler derivatives hold promise for enhancing repair of mucosal injury by a wide range of infections or toxic agents, and hence have great potential as a new oral rehydration and nutrition therapy for patients with enteric infection, malnutrition, or chemotherapy- or radiation-induced enteritis.

Alanyl-Glutamine and Glutamine Supplementation Improves 5-Fluorouracil-Induced Intestinal Epithelium Damage In Vitro

“…In addition, critical growth factors, such as the insulin-like growth factor-1 (IGF-1), are involved in intestinal mucosal healing following injury, and have now been associated with increased amino acid transporters in the enterocyte membrane [34,35]. Our findings further support the strategy of exogenous glutamine administration in an attempt to supply adequate fuel to the rapidly proliferating immune and intestinal cells, following endogenous glutamine tissue deprivation in the severely ill, as observed in successful clinical trials with glutamine-enriched oral hydration therapy and parenteral supplementation [16,21,36,37]. Furthermore, the observed beneficial effects in 5-FU-injured intestinal cells in this study suggests a possible protective or reparative role of glutamine or alanyl-glutamine supplementation during chemotherapy in clinical situations.…”

“…Rat intestinal jejunal crypt cells (IEC-6, passages [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] were purchased from American Type Culture Collection (Rockville, MD) and were cultured at 37°C in a 5% CO 2 incubator. The maintenance cell media was Dulbecco's modified eagle media (DMEM; Gibco BRL, Grand Island, NY) supplemented with 5% fetal calf serum (FCS), 5 mg bovine insulin, 50 μg/ml penicillin/streptomycin (DMEM; Gibco BRL, Grand Island, NY), and a final concentration of 1 mM sodium pyruvate.…”

“…Glutamine supplementation in rats pretreated with toxic doses of methotrexate enables reduction in the severity of the intestinal mucositis [17] and improves intestinal permeability in patients treated with 5-FU and folinic acid [18]. Although glutamine has been shown to reduce diarrhea duration in children [19][20][21] and is generally recognized to be a conditionally essential amino acid in the critically ill patient [22], there remains a debate regarding the efficacy of glutamine due to its limited solubility, stimulating the pursuit of more stable glutamine compounds for clinical use [23,24].…”

Caspase and Bid Involvement inClostridium difficileToxin A-Induced Apoptosis and Modulation of Toxin A Effects by Glutamine and Alanyl-Glutamine In Vivo and In Vitro

“…These actions support the use of glutamine as a therapeutic adjuvant in infectious diarrhea (9) and catabolic stressful conditions (i.e., cancer chemotherapy, prolonged parenteral nutrition, sepsis, and human immunodeficiency virus-related wasting syndrome) (7,12,41,55). Furthermore, glutamine not only acts as a building block for protein synthesis, it also modulates specific cellular signaling pathways, such as induction of heat shock protein (HSP) expression (52), activation of protein kinases (37), and regulation of redox status (29).…”

Enteric infections, diarrhea, and their impact on function and development

“…The discovery that glutamine and its stable derivative, alanyl glutamine, drive not only epithelial repair but also electrogenic sodium absorption (even in the presence of villus damage) provides an attractive approach to ORNT (158)(159)(160)(161). Glutamine causes improvement that cannot be completely explained by enhanced fluid and Na absorption, and it seems to improve intestinal epithelial cell integrity and enhance tight junction function (162)(163)(164). An additional key amino acid for renewal of the intestinal epithelium is arginine, which is often deficient in malnourished patients.…”