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The Journal of Nutrition Vol. 128 No. 5 May 1998,
pp. 789-796
University of Hohenheim, Institute for Biological Chemistry and Nutrition, D-70593 Stuttgart, Germany
It is a great honor for me to present the McCollum lecture at the 16th International Congress of Nutrition in Montreal. Lavoisier, one of the founders of the science of nutrition and chemistry, concluded his last paper before the French Revolution by writing that the nutritional chemist could by his labors aspire to "the glorious title of benefactor of humanity." Indeed, the chemist and nutritionist McCollum certainly earned such a title; McCollum was to nutritional science what Lavoisier was to chemistry (Day 1987 According to the classical definitions acquired from the "Encyclopedia Britannica": the substrate or causa invisibilis may be the substratum, the philosophical characterless substance that supports attributes of reality. This is certainly not the subject of this review; instead the emphasis is on substrates as they pertain to enzymes and nutrition. These With the discovery of common and specific mechanisms for alterations in substrate metabolism, unique opportunities arise to intervene in the disease process. Undoubtedly, the efficacy of providing substrates to the injured, immunocompromised and/or malnourished host has caused a new birth and awakening in the clinical application of dietary intervention in the treatment and prevention of disease (Abbott et al. 1983 Many investigators proceeded on the assumption that "tailor-made" preparations increase the benefits of nutritional efforts for specific patient groups. Thus specific preparations have been developed for treatment of renal and liver disease or to optimize the growth of young infants. Other investigators still hope for benefits from products enriched in branched-chain amino acids (Fürst 1994 Besides having direct nutritional effects, administration of lipids influence phospholipid composition of cell membranes, thereby affecting essential functions such as enzyme activities, transport-receptor and regulatory functions. These essential functions also relate to the formation of prostaglandins and leukotrienes. Without doubt the nutritional and numerous structural and regulatory roles of lipids have an important impact on major physiologic functions, including hemodynamics and oxygenation as well as immune status and hypermetabolism (Alexander and Peck 1990 Medium chain triglycerides (MCT).
MCT were introduced >30 years ago as a constituent of the first "medical food," and were valued because of their rapid hydrolysis and absorption in the gastrointestinal tract as well as their direct transport to the blood and liver (Sailer and Müller 1981 n-3 (
Structured lipids
The general approach to the nutritional care of critically ill, malnourished or stressed patients involves delivery of a balanced diet, including an adequate amount of protein or a suitable amino acid preparation that reflects a high biological value like egg protein (Wilmore 1989 Cyst(e)ine.
In healthy adults, the sulfur-containing amino acid cysteine can be synthesized from methionine via the liver-specific transsulfuration pathway. In liver tissue of fetuses and of preterm and term infants, the activity of cystathionase, a key enzyme in the transsulfuration pathway, was found to be low or undetectable (Gaull et al. 1972
Taurine.
Taurine (2-aminoethane sulfonic acid) is the most abundant free amine in the intracellular compartment (Bergström et al. 1974 Tyrosine.
The aromatic amino acid tyrosine traditionally has been considered a nonessential amino acid for adult humans. Tyrosine is synthesized exclusively from phenylalanine by hydroxylation; inclusion of tyrosine in the diet exerts a sparing effect on the dietary phenylalanine requirement. In premature infants, tyrosine is considered an essential amino acid; reduced endogenous tyrosine synthesis also may occur in full-term infants (Räihä 1973 Glutamine.
Glutamine is the most prevalent free proteic amino acid in the human body. In skeletal muscle, glutamine constitutes >60% of the total free amino acid pool (Bergström et al. 1974 The obvious limitations to use glutamine, tyrosine and cystine as free L-amino acids have initiated an intensive search for alternate substrates. Obviously intravenously administered short chain peptides are efficiently utilized (Fürst 1994
Clinical studies.
In patients undergoing major elective surgery, infusions of TPN solutions supplemented with Ala-Gln and Gly-Tyr over 5 d resulted in a maintenance of the intracellular glutamine pool and an improvement of nitrogen balance on each postoperative day compared with the control group receiving isonitrogenous and isoenergetic TPN without the peptides (Stehle et al. 1989
The reduction of hospital stay by ~5-7 d in the two post-BMT studies (Schloerb and Amare 1993 This review may well illustrate how far we have advanced in our knowledge of the importance of substrates, old and new ones, in modern clinical nutrition. An attempt also was made to highlight directions that hold promise for advancing new and old substrates in future patient care.
All help and cooperation of friends, colleagues, students and my secretary plus the support of my family is gratefully acknowledged.
E. V. MCCOLLUM: CHEMIST AND BENEFACTOR OF HUMANITY
). The insight and revolutionary approach of this unique scientist influenced a whole generation of researchers and launched a new era in nutritional science.
). In addition to McCollum's discoveries and his influence on experimental nutrition research, he contributed much to transfering newer knowledge of nutrition to the public. He always showed a sense of moral obligation to improve the health of mankind. Very early on he emphasized the importance of paying attention to the selection of food and diet: "Eat what you want after you have eaten what you should." In his famous textbook The Newer Knowledge of Nutrition: The Use of Food for Preservation of Vitality and Health he used the phrase "protective foods," a catchword that popularized the principle of "wise eating" and indeed presaged the ongoing debate about chemoprotection, designer and functional foods for >70 years (McCollum 1953).
). To this I would like to add a small quote from Adalbert Stifter, a famous Austrian narrator, who lived in the 19th century "The great deeds of mankind are not the ones which are done with a lot of noise. The great deeds happen as simply as the trickling of water, the moving of the air and the growing of corn...". Scientist and benefactor McCollum embodies this beautiful allegory.
SUBSTRATE, REQUIREMENTS, ESSENTIALITY
SOME DEFINITIONSlike alcohol, certain amino acids, fatty acids, nucleotides etc.are all referred to as old substrates. What has changed is their nutritional significance and their newly recognized functional and physiological properties under various pathological states (Grimble 1994). "Old substrates with new specifications" have been variously described as conditionally essential nutrients, functional nutrients, acquired indispensible nutrients.
proposes that, regardless of the definition used, a final judgement of the usefulness of an essential new substrate will be on the grounds of clinical and nutritional efficacy. According to a more general position, "a possible and useful direction might put more emphasis on metabolic control and its regulation of tissue and organ function and nutritional status" (Young and El-Khoury 1995). This definition offers suggestions as to how certain metabolic characteristics shared by some substances might be used to differentiate the various nutritionally significant substrates. This also would mean that the dietary essentiality of a given substrate is dependent on the ratio of supply to demand; the distinction between "essential" and "nonessential" largely disappears because it is dependent on conditions (Young and El-Khoury 1995).
USE OF OLD AND NEW SUBSTRATES
A RENAISSANCE IN CLINICAL NUTRITION).
NOTION OF OLD SUBSTRATES WITH NOVEL SENSE AND TRUE NEW SUBSTRATES
, Grimble 1994). Although many of these nutrition formulae are now available, they are designed to improve tolerance of the nitrogen load in the presence of illness, malnutrition or organ dysfunction rather than to provide specific nutrients for individual organs or tissues (O'Dwyer et al. 1990). Current research directions consider individual substrates as tissue- or organ-specific single nutrients an alternative approach. Certain diseases accompanied by deficiencies, antagonisms or imbalances in a particular compartment or in various organ tissues might selectively require one or more nutrients that are appropriate for use to support the attenuated organ and/or tissue (Fürst 1994): administration of required substrates might thus greatly facilitate an anabolic response to a life-threatening disease (Wilmore 1991).
). Short-chain fatty acids may function as true essential substrates because organ function is impaired by their absence (Grimble 1994). A novel approach is the possible therapeutic implication of (n-3) fatty acids (Kinsella et al. 1990). The development of so-called structured lipidstruly new substratesis a further alternative to lipid nutrition in clinical practice (Carpentier et al. 1996). The technique of synthesizing structured triglycerides has ushered in a new era of "nutritional pharmacology." The role of nucleic acids is being discussed because expression of the synthesizing enzymes in the de novo pathway apparently is impaired during catabolic stress (Grimble 1994). Arginine is claimed to be a potent immunomodulator during episodes of stress and in particular in cancer patients (Barbul 1995). None of the commercially available amino acid preparations contain glutamine and cystine and inadequate amounts of tyrosine. These nutrients are either unstable or poorly soluble in aqueous solutions (Fürst 1994, Fürst and Stehle 1994b). Recent knowledge concerning the efficient use of intravenously supplied di- and tripeptides opens up the possibility of substituting available amino acid preparations with glutamine, cystine and tyrosine containing stable and highly soluble short-chain peptides (Fürst et al. 1997a and 1997b). These synthetic substances are to be classified as real new substrates. Taurine is postulated as an indispensible substance during catabolic stress and uremia. Additionally, this amine is a potent antioxidant. Its intracellular transport and use might be improved by employing synthetic taurine conjugates representing true new substrates (Fürst et al. 1997b). This review discusses selected old substrates that now are considered conditionally indispensible substances and those that are functionally and operatively related to novel substrates with improved clinical efficacy.
LIPID NUTRITION SUBSTRATES
EXPERIMENTAL PREPARATIONS, Miles 1991).
). Intravenous MCT emulsions have been used in Europe for 10 years and may soon be available in the U.S: In clinical studies, administration of a MCT/LCT mixture in many cases revealed distinct advantages over a LCT emulsion. In surgical patients, the mixed emulsion produced fewer circulating triglycerides and nonesterified fatty acids than LCT alone, suggesting favorable utilization (Crowe et al. 1985). The rapid plasma clearance (Bach and Babayan 1982, Crowe et al. 1985, Sailer and Müller 1981) is associated with improved reticuloendothelial system function (Sorbrado et al. 1985) and thus results in less pulmonary sequestration of bacteria.
3) fatty acids.
The current interest in the use of fish and fish oils has its origin in the epidemiologic observation of a lower prevalence of atherosclerosis and age-adjusted mortality in Greenland Inuits compared with the non-Inuit Danish population (Bang and Dyberg 1976). This early study led to an exponential increase in the number of publications on the subject of the metabolic and clinical effects of fish oil. There is the claim that (n-3) fatty acids (FA) exert a protective effect on the development of cardiovascular (Kromhout et al. 1985) and inflammatory diseases (Hawthorne et al. 1992, Lorenz et al. 1989). Some observations suggest a potential role for fish oils in the treatment of atopic dermatitis and psoriasis (Bittiner et al. 1988), and dietary (n-3) FA treatment offers exciting novel possibilities in malignant diseases (Anti et al. 1992). Furthermore there are indications that premature infants have limited dietary supplies of the (n-3) FA that are required for the normal composition of brain and retinal lipids (Neuringer et al. 1988).
). Indeed, inflammatory symptoms of rheumatoid arthritis, psoriasis, Crohn's disease and ulcerative colitis are all ameliorated by fish oil preparations whether or not directly related to cytokine production. Consumption of eicosapentaenoic acid (EPA) reduces the production of interleukin (IL)-1-
and -
as well as tumor necrosis factor (TNF)- and - in response to an endotoxin stimulus. The anti-inflammatory effects of fish oil also may include decreased production of inflammatory substances like leukotriene B4 and platelet activating factors (PAF) released by the action of cytokines, as well as a large reduction of cytokine-induced synthesis of prostaglandin E2 and thromboxane B2 in the colonic mucosa (Endres et al. 1989, Pomposelli et al. 1988). These findings are in line with a decrease in the arachidonic acid/EPA ratio in blood-mononuclear cell membranes as well as a decrease in neutrophil chemotaxis to leukotriene B4 (Lowry and Thompson 1994). The combined observations may be explained partly by the finding that leukotriene B4 enhances blood monocyte IL-1 production after lipopolysaccharide exposure (Rola-Plezczynski 1985).
). However, total parenteral nutrition (TPN) with fish oil resulted in a decrease of plasma free FA and liver triglycerides. This is in agreement with reports that fish oil promotes FA oxidation and impaires liver triglyceride synthesis. In our study (Nau et al. 1993), fish oil feeding revealed a dose-dependent incorporation of (n-3) FA into tissue total lipids and phospholipids at the expense of (n-6) FA as early as 3-4 d after starting infusion.
). In postoperative patients, treatment with fish-oil-containing TPN was associated with considerable increases of EPA and docosahexaenoic acid (DHA) in leukocyte membrane phospholipids; the maximum incorporation being observed after 5 d of fish oil nutrition (Morlion et al. 1996). The leukotriene B5 and leukotriene C5 syntheizing capacity was also highly increased, indicating high metabolic activity of the infused EPA at the site of the 5-lipoxygenase (Fig. 1). These results suggest immunomodulatory effects on lipid mediator generation during stress. They are also in good agreement with those in active Crohn's disease (Ikehata et al. 1992), showing a marked increase in leukotriene B5 without a decrease in leukotriene B4, possibly due to the excessive linoleic acid content in the emulsion.
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Fig 1.
In vitro leukotriene (LT)-synthesizing capacity of human peripheral blood leukocytes after stimulation with the Ca2+-ionophore A23187 (5 µmol/L). Patients received TPN solutions without fish oil ( 
; n = 10) or with fish oil (
, n = 10). Results are means ± SEM. *P < 0.05, between groups; **P < 0.01, day 6 vs. day 10 (reproduced with permission from Morlion et al. 1996).
true new substrates.
"Structured lipids" are man-made lipids. They were synthesized originally from varying combinations of LCT and coconut oils, resulting in a random assortment of triglycerides containing different MC-LC fatty acids (Mascioli et al. 1987, Mok et al. 1984).
). These effects are assumed to be due to a lower production of inflammatory and immunosuppressive eicosanoids.
). The whole body lipid oxidation rate was increased compared with conventional LCT-based lipid emulsions, and it was associated with minor thermogenic effects (Sandström et al. 1995) (Fig. 2). Overall nitrogen economy was not affected by the type of lipid emulsion. The positive effects with structured lipids are presumably due to their rapid plasma clearance, indicating that these energy-rich new substrates are rapidly available for oxidative processes with minimal thermic effects (energy expenditure) and thus with minor metabolic burden on the organism (Hyltander et al. 1995, Sandström et al. 1995).
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Fig 2.
Whole-body long chain triglyceride and structured triglyceride oxidation in surgical patients. Results are means ± SEM; n = 60; *P < 0.01. Modified with permission from Sandström et al. (1995) .
NEW SUBSTRATES IN PROTEIN NUTRITION
, Wretlind 1981). This approach, however, is not feasible in clinical practice today because poor solubility and/or instability prevent inclusion of glutamine, tyrosine and cystine into the presently available amino acid preparations. Another relevant new protein substrate is taurine (Fürst et al. 1997b).
). In liver disease, cysteine requirements of the body cannot be met due to diminished transsulfuration capacity. In these particular conditions, cysteine is to be considered an essential and conditionally essential amino acid, respectively, and should be exogenously administered (Chawla et al. 1984).
View this table:
Table 1.
The solubility of selected and glutamine-, tyrosine- and cystine-containing dipeptides as compared with the corresponding free amino acids1
). The major pathway for the biosynthesis of taurine is via cysteine sulphinic acid (CSA). Taurine seems to have a functional role in stabilizing the membrane potential, in promoting calcium transport and calcium-binding to membranes and in exerting positive ionotropic effect on the heart as well as showing antiarrhytmic and antihypertensive effects. It is involved in many metabolic responses in the central nervous system (CNS), has an anti-convulsant action, may have an insulinogenic action and is required for eye function (Huxtable 1992).
). Low taurine concentrations in plasma, platelets and urine have been described in infants and children and also in adult trauma patients undergoing taurine-free long-term parenteral nutrition (Geggel et al. 1985, Heird et al. 1988, Kopple et al. 1990, Vinton et al. 1987). Plasma taurine deficiency after intensive chemotherapy and/or radiation is more severe in those patients receiving taurine-free parenteral nutrition than in orally fed patients (Desai et al. 1992). Low intracellular taurine concentrations in muscle are a typical feature in patients with chronic renal failure, probably due to impaired metabolic conversion of CSA to taurine (Bergström et al. 1989, Suliman et al. 1996). Intracellular taurine depletion might be associated with the well-known muscle fatigue and arrhythmic episodes in uremia.
).
).
, Young and Parsons 1973). These results have been repeatedly attributed to reduced oxidation of tyrosine from phenylalanine due to a partial inhibition, (perhaps by uremic toxins) of the enzyme, phenylalanine hydroxylase. Due to the low solubility of tyrosine in aqueous solutions (Table 1), its concentration in amino acid solutions does not exceed 0.4-0.5 g/L, an amount that might be insufficient to met tyrosine requirements in clinical situations. Highly soluble tyrosine containing synthetic dipeptides are now available, enabling adequate tyrosine nutrition in clinical practice.
). It is a precursor that donates nitrogen for the synthesis of purines, pyrimidines, nucleotides, amino sugars and glutathione and is the most important substrate for renal ammoniagenesis (regulation of the acid-base balance). Glutamine serves as a nitrogen transporter between various tissues. Finally, glutamine represents the major metabolic fuel for the cells of the gastrointestinal tract (enterocytes, colonocytes) (Souba 1991, Windmueller 1982) and many rapidly proliferating cells, including those of the immune system (Calder 1994).
).
, MacLennan et al. 1988). Thus glutamine supplements might be beneficial in the treatment of stressed and malnourished patients. Numerous experimental studies support this hypothesis. Glutamine-supplemented enteral or parenteral nutrition solutions are associated with increased intestinal mucosal thickness, DNA and protein content, reduced bacterial translocation after radiation (Souba 1991), weakened adverse effects of experimentally induced enterocolitis (Rombeau 1990), preserved intestinal mucosa during parenteral nutrition (Babst et al. 1993) and enhanced rat mucosal hyperplasia after small bowel resection (Klimberg et al. 1990a). In addition, glutamine supply prevents pancreatic atrophy and the development of fatty liver during elemental feeding (Helton et al. 1990) and supports muscle glutamine metabolism without stimulating tumor growth (Klimberg et al. 1990b).
) and the limited solubility in water (Table 1). Glutamine-containing TPN solutions must be prepared freshly under strict aseptic conditions and stored for a maximum of 2 d at 4°C (Khan et al. 1991). To diminish the risk of precipitation, the glutamine concentrations in such solutions should not exceed 1-1.5%. This means that provision of adequate amounts of glutamine to injured or critically ill patients with such a low concentrated solution represents a severe burden, especially in volume-restricted situations. Consequently, the parenteral use of free glutamine is reserved for controlled clinical trials only; such studies showed improved nitrogen balance compared with control groups (Hammarqvist et al. 1989, Ziegler et al. 1992). Post bone marrow transplantation (BMT) morbidity was diminished with glutamine supplementation: the incidence of clinical infection, total and site-specific microbial colonization and the length of hospital stay were reduced compared with the control groups (Schloerb and Amare 1993, Ziegler et al. 1992).
DIPEPTIDE CONCEPT
TRUE NEW SUBSTRATES IN PROTEIN NUTRITION). Thus a research program was initiated to combine synthesis and characterization of glutamine, tyrosine and cysteine containing short chain peptides or taurine conjugates with investigations designed to examine their in vivo uptake and subsequent tissue utilization in animal models, in healthy subjects and in patients with various disorders. Synthetic dipeptides are highly soluble in water (Table 1) and thermo stable during sterilization procedures and thus meet all necessary chemical/physical criteria.
, Adibi 1987, Herzog et al. 1996, Stehle and Fürst 1990) ensures a quantitative peptide hydrolysis.
View this table:
Table 2.
The effects of free glutamine-supplemented
enteral/parenteral nutrition1
, Albers et al. 1988, 1989, Lochs et al. 1988, Neuhäuser 1985, Stehle et al. 1988, 1991, 1996). The clearance rates of Ala-Gln and Gly-Gln by the kidney are greater than those measured for the viscera or skeletal muscle (Lochs et al. 1988). Infusion of the dipeptides is associated with increased plasma concentrations and enhanced visceral uptake of glutamine and alanine or glycine, respectively (Druml et al. 1991).
). Infusion of the solutions was not associated with any side effects, and postoperative recovery remained within the regular time frame for each patient. These results were confirmed in cholecystectomy patients (Hammarqvist et al. 1990), and muscle protein synthesis improved in postsurgical patients receiving short-term infusion of Ala-Gln (Barua et al. 1992). Glutamine dipeptide-supplemented TPN had beneficial effects on nitrogen economy and lymphocyte recovery in catabolic patients and shortened hospital stay (Morlion et al. 1998). A novel finding is the striking influence of supplemental glutamine dipeptide on cysteine-leukotriene metabolism (Fig. 3). After operations, the low cysteine-leukotriene concentration in isolated polymorphonuclear leukocytes is restored completely with supplemental dipeptides, but remains low with conventional TPN. Cysteine-leukotrienes are potent lipid mediators and their diminished release usually is accompanied by an attenuated endogenous host defense (Morlion et al. 1997).
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Fig 3.
Generation of Cys-leukotrienes (sum of LTC4, LTD4, LTE4) from human polymorphonuclear neutrophil granulocytes after stimulation with Ca-ionophore A23187 (5 µmol/L). Patients receiving Ala-Gln supplemented (n = 5; ) or conventional (n = 5; ) TPN solutions. Values are means ± SEM; *P < 0.05, significantly different from the preoperative (preop.) day, ***P < 0.001, significant difference between groups (reproduced with permission from Morlion et al. 1997).
, Schloerb and Amare 1993, Scheltinga et al. 1991). This interesting finding suggests that provision of glutamine (dipeptide) may affect stress-induced accumulation of extracellular fluid by affecting membrane function (membrane potential) or changing the cellular hydration state (Häussinger et al. 1993).
). Supplemental Ala-Gln maintained absorptive capacity (assessed by D-xylose absorption test) of the small intestine in critically ill patients compared with patients receiving conventional glutamine-free TPN (Tremel et al. 1994). As the large intestine harbors far more bacteria than the duodenum, jejunum or ileum, the maintenance of an intact colonic barrier may be crucial. In this context, the trophism of glutamine and the stable dipeptide Ala-Gln on the colonic mucosa could gain clinical relevance (Scheppach et al. 1994).
). VLBW infants receiving formula alone had a threefold higher incidence of sepsis than those receiving glutamine supplementation (0.3 g/kg) for 
30 d. The decrease in HLA-DR T-cell subsets in glutamine-supplemented infants suggests reduced exposure to bacterial stimulation (Roig et al. 1996). Glutamine-supplemented premature infants at high risk of necrotizing enterocolitis required fewer days of TPN, had a shorter length of time to full feeds and needed less time on the ventilator and also tended to have shorter stays in the intensive care unit (Lacey et al. 1996).
COST EFFECTIVENESS OF GLUTAMINE (DIPEPTIDE) NUTRITION
, Ziegler et al. 1992) and in the surgical investigation markedly diminished hospital costs (Morlion et al. 1998), primarily as a function of reduced charges for room and board (McBurney et al. 1994). A decreased length of hospital stay of the magnitude seen in these studies has important patient care and economic implications. In a standard university hospital, a conservative estimate of $1000 per patient day and 30 (BMT) patients per year would amount to a saving of $180,000 with observed 5.8-d average decrease of hospitalization. Considering the large number of surgical patients, the savings with supplemental glutamine dipeptides are considerable, amounting to about $3000 per patient. In a current prospective block-randomized double-blind study, use of glutamine-supplemented TPN solutions dramatically improved survival (Griffiths et al. 1997). Despite the greater survival in the glutamine group, this did not increase total hospital costs as might be expected, since the excess control deaths occurred late and had a longer post intervention stay in an intensive care unit (Griffiths et al. 1997).
). Critically ill patients exhibit severe intracellular glutamine depletion and suffer from compromised immune competence and low antioxidative capacity. The underlying mechanisms of supplemental glutamine (peptide) in causing reversal of illness might be thus hypothetically due to support of the mucosa, the immune system and the hepatic biosynthesis of glutathione. According to the current proposal, glutamine plays a more global regulatory role by modifying the endogenous inflammatory response, possibly by attenuating the elaboration of proinflammatory mediators and/or by upregulating anti-inflammatory factors (Wilmore 1997).
; Griffiths et al. 1997). The availability of stable dipeptide-containing preparations will certainly facilitate amino acid nutrition in the routine clinical setting and represent a new dimension in clinical nutrition.
FINAL THOUGHTS
ACKNOWLEDGMENTS
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FOOTNOTES |
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Manuscript received 26 August 1997. Initial reviews completed 23 October 1997. Revision accepted 7 January 1998.
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LITERATURE CITED |
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a randomized, placebo-controlled, double-blind cross-over trial. J. Intern. Med. 225 (suppl. 1): 225-232. in rats fed a low protein diet.
J. Nutr.
1992;
122:1369-1375
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