J. Marc Rhoads

Arginine metabolism and nutrition in growth, health and disease

Abstractl-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or l-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals.

Glutamine, arginine, and leucine signaling in the intestine

Glutamine and leucine are abundant constituents of plant and animal proteins, whereas the content of arginine in foods and physiological fluids varies greatly. Besides their role in protein synthesis, these three amino acids individually activate signaling pathway to promote protein synthesis and possibly inhibit autophagy-mediated protein degradation in intestinal epithelial cells. In addition, glutamine and arginine stimulate the mitogen-activated protein kinase and mammalian target of rapamycin (mTOR)/p70 (s6) kinase pathways, respectively, to enhance mucosal cell migration and restitution. Moreover, through the nitric oxide-dependent cGMP signaling cascade, arginine regulates multiple physiological events in the intestine that are beneficial for cell homeostasis and survival. Available evidence from both in vitro and in vivo animal studies shows that glutamine and arginine promote cell proliferation and exert differential cytoprotective effects in response to nutrient deprivation, oxidative injury, stress, and immunological challenge. Additionally, when nitric oxide is available, leucine increases the migration of intestinal cells. Therefore, through cellular signaling mechanisms, arginine, glutamine, and leucine play crucial roles in intestinal growth, integrity, and function.

Arginine nutrition in development, health and disease.

Abstract As a precursor of nitric oxide, polyamines and other molecules with enormous biologic importance, L‐arginine plays versatile key roles in nutrition and metabolism. Arginine is an essential amino acid in the fetus and neonate, and is conditionally an essential nutrient for adults, particularly in certain disease conditions. L‐Arginine administration is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, and in facilitating wound healing. The effect of L‐arginine in treating many common health problems is unique among amino acids, and offers great promise for improved health and well‐being in the future.

Altered fecal microflora and increased fecal calprotectin in infants with colic.

OBJECTIVE We explored whether gut inflammation, colonic fermentation, and/or an altered colonic flora could provide a pathophysiological mechanism for colic. STUDY DESIGN The study population consisted of 36 term infants ranging in age from 14 to 81 days. We measured fecal calprotectin (a marker of neutrophil infiltration) by ELISA; stool microorganisms by denaturing gradient gel electrophoresis, cloning, and sequencing; and breath hydrogen levels using gas chromatography. RESULTS During 24 hours, infants with colic (n = 19) cried and fussed for a mean of 314 +/- 36 (SEM) minutes, compared with control infants (n = 17, 103 +/- 17 minutes). Fecal calprotectin levels were 2-fold higher in infants with colic than in control infants (413 +/- 71 vs 197 +/- 46 microg/g, P = .042). Stools of infants with colic had fewer identifiable bands on denaturing gradient gel electrophoresis. Klebsiella species were detected in more colic patients than in control patients (8 vs 1, P = .02), whereas Enterobacter/Pantoea species were detected only in the control patients. These differences could not be attributed to differences in formula versus breast milk feeding, consumption of elemental formula, or exposure to antibiotics. CONCLUSIONS Infants with colic, a condition previously believed to be nonorganic in nature, have evidence of intestinal neutrophilic infiltration and a less diverse fecal microflora.

L-glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis.

Rotavirus enteritis is the leading cause of diarrhea in infants worldwide. A research priority of the World Health Organization is to develop oral rehydration solutions containing amino acids or other additives that will stimulate intestinal absorption more efficiently than the current glucose-based oral rehydration solutions. Glutamine is the principal metabolic fuel of the small bowel and a putative stimulator of mucosal repair. This report describes the transport response to mucosal l-glutamine following intestinal injury caused by porcine rotavirus. Peak symptoms and mucosal damage were observed 2–7 days after oral rotavirus inoculation. In vitro transport studies of the maximally injured region, the midjejunum (80% reduction in lactase), surprisingly, showed transport responses to l-glutamine (30 mmol/L) Sand l-alanine (30 mmol/L) that were similar qualitatively and quantitatively to those observed in control tissue. Subsequent application of mucosal d-glucose (30 mmol/L) caused additional stimulation of electrogenic Na+ transport, but the response to glucose was blunted (P < 0.05) in the infected tissues. Glutamine and alanine enhanced Na+ absorption to a similar degree (2–2.5 μEq · cm−2 · h−1), but glutamine stimulated equal amounts of electrogenic and electroneutral NaC1 absorption, whereas alanine had no significant effect on net Cl− flux. Glutamine is a potentially useful substrate for investigation in oral rehydration solutions for infant diarrhea.

Abdominal migraine: Prophylactic treatment and follow-up

BACKGROUND Abdominal migraine is a syndrome characterized by recurrent stereotypic episodes of paroxysmal abdominal pain and nausea and/or vomiting with wellness between episodes. It is often associated with a positive family history of migraine and no other apparent underlying disease. The purpose of this study was to report in patients diagnosed with abdominal migraine the outcome, the effect of prophylactic treatment, and the duration of treatment. METHODS The records of 53 patients who underwent treatment after a diagnosis of abdominal migraine were retrospectively reviewed. Responses to treatment were graded as excellent (cessation of recurrent abdominal pain), fair (persistence of symptoms but milder and less frequent), or poor (no response). Follow-up data were available in 38 patients. Twenty-four patients were treated with propranolol and 12 with cyproheptadine. Four were not treated because of mild and infrequent symptoms. RESULTS Among the children treated with propranolol, 18 (75%) had an excellent response, 2 (8%) had a fair response, and 4 (17%) had no response. In those treated with cyproheptadine, 4 (33%) had an excellent response, 6 (50%) had a fair response, and 2 (17%) had no response. Patients were instructed to continue medication for 6 months or until cycles had stopped. However, 11 of 24 patients (46%) in the propranolol group took medication for less than 6 months and the remaining patients from 6 months to 3 years. Six patients in the cyproheptadine group (50%) took medication less than 10 months and the remaining patients for 10 months to 3 years. CONCLUSION Patients with abdominal migraine may benefit from prophylactic treatment with propranolol or cyproheptadine.

Glutamine stimulates prostaglandin-sensitive Na+-H+ exchange in experimental porcine cryptosporidiosis

BACKGROUND/AIMS Recent studies of piglet cryptosporidiosis showed an injury-induced impairment of sodium-glucose cotransport and a prostaglandin-mediated inhibition of neutral NaCl absorption. Because glutamine has been shown to stimulate both neutral and electrogenic Na+ absorption, this study examined the mechanism of prostaglandin-mediated inhibition of NaCl absorption and the effect of glutamine on these processes. METHODS Ileal mucosa from control and infected pigs was mounted in Ussing chambers for flux studies or incubated with [14C]glutamine or [14C]-glucose for metabolism studies. RESULTS Glucose and glutamine induced equivalent increases, 2-2.5 microEq.cm-2.h-1, in Na+ absorption and short-circuit current in control ileum. Despite a reduction in villous surface area to one third of the control, glutamine enhanced both neutral and electrogenic Na+ absorption in the infected ileum by 3.5 +/- 0.5 microEq.cm-2.h-1, whereas glucose was only half as effective (P < 0.05). In addition, glutamine was oxidized to CO2 at rates three times those of glucose. Indomethacin enhanced, whereas amiloride, prostaglandin E2, and Cl-free solutions inhibited the glutamine-induced neutral Na+ transport. CONCLUSIONS Glutamine-stimulated neutral Na+ absorption is mediated by a prostaglandin-sensitive apical Na(+)-H+ exchange mechanism. The heightened Na(+)-H+ exchange and tissue oxidation of glutamine suggest that glutamine is superior to glucose for use in oral rehydration solutions.

Persistent and chronic diarrhea and malabsorption: Working group report of the second world congress of pediatric gastroenterology, hepatology, and nutrition

ResearchAssessment of mucosal immunopathology and molecular and cellular biology of persistent diarrhea in representative populations in developing countries.Studies of small bowel microbiology in PD, especially in at-risk populations e.g., malnourished children and HIV endemic areas.Evaluation of the link of micronutrient deficiencies with PD and their relationship with intestinal repair mechanisms. InterventionImproved facility-based approaches and algorithms for the nutritional management of PD and malnutrition.Diagnosis and management of PD in public health system and primary care (including domiciliary) settings.Scaling-up environmental control measures and safe water and hygiene strategies. EducationContinuing medical education strategies to educate medical students and physicians in the recognition, management and prevention of PD.Education of nursing and paramedical personnel in the recognition and management of PD in ambulatory and health system settings.Community and public health education strategies for increased awareness of the prevention of PD and optimal management of acute and prolonged diarrheal episodes.

Oral Bovine Serum Concentrate Improves Cryptosporidial Enteritis in Calves

Cryptosporidium parvum produces a prolonged watery diarrhea unresponsive to conventional antimicrobials. Because of reported efficacy of antibody-based immunotherapy, we studied the effect of inexpensive, commercially available oral bovine serum concentrate (BSC) in experimental cryptosporidiosis. Twenty-four calves were treated with 57 g/d BSC (n = 12) or soy protein (n = 12) added to their standard whey protein-based milk replacer (227 g/2 L twice daily). Of the 24, 9 were also treated with l-glutamine (GLN), 8 g/L (50 mM) in the milk (5 calves in the BSC group and 4 in the soy group). Animals were inoculated with 108 cryptosporidium oocysts per os on d 8 of life and received oral rehydration on d 12–14. Eight uninfected controls were treated with BSC or soy protein. Fecal and urine volume and urinary Cr-EDTA excretion were measured. Animals were killed on d 18 of life. Cryptosporidiosis induced severe watery diarrhea lasting >9 d and produced a 25% increase in intestinal permeability, a 33% decrease in villous surface area, and a 40% reduction in mucosal lactase specific activity. Glutamine treatment had no effect on the diarrhea or any of the intestinal tests; and therefore pooled data were used to compare the 12 calves treated with BSC with the 12 treated with soy. In animals receiving BSC, peak diarrheal volume and intestinal permeability were reduced 33%, fewer oocysts were shed, intestinal crypts were significantly deeper, and villous surface area returned to normal by 9 d after infection (all p ≤ 0.05). BSC should be studied as a treatment for human cryptosporidiosis.

Glutamine and transforming growth factor-α stimulate extracellular regulated kinases and enhance recovery of villous surface area in porcine ischemic-injured intestine ☆ ☆☆

BACKGROUND Epidermal growth factor (EGF) signals enterocyte proliferation via extracellular regulated kinases (ERKs). Because glutamine is required for EGF-stimulated proliferation and stimulates ERKs in intestinal cell culture, we hypothesized that glutamine and the EGF-related peptide transforming growth factor-alpha (TGF-alpha) would synergistically enhance repair associated with stimulation of ERKs. METHODS Thiry-Vella loops were created in juvenile pigs. One half of the loop was subjected to 2 hours of ischemia, and the other half served as control. Loops were infused daily with Ringers solution containing 140 mmol/L glucose, 140 mmol/L glutamine, 140 mmol/L glucose plus 60 micrograms/L TGF-alpha, or 140 mmol/L glutamine plus 60 micrograms/L TGF-alpha. RESULTS After 2 hours of ischemia, complete villous epithelial sloughing was present. By 18 hours, villous epithelium had fully restituted, but villi remained stunted until 144 hours after injury. Glutamine + TGF-alpha triggered sustained increases in ERK activity compared with glucose-treated tissues (maximal at 18 hours), whereas glutamine alone or glucose + TGF-alpha caused only transient elevations in ERK activity. By 72 hours, villous surface area had increased to normal values with glutamine plus TGF-alpha treatment, whereas villi remained stunted with glucose alone, glutamine alone, or glucose plus TGF-alpha. CONCLUSIONS Glutamine plus TGF-alpha treatment restored mucosal architecture within 72 hours of severe ischemic injury associated with sustained elevations in ERK activity.