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-Ketoglutarate Administration1
,2
*
INSERM U402, Faculté de médecine Saint-Antoine, 75012 Paris, France;
Laboratoire de Biologie de la Nutrition, E.A. 2498, Faculté de Pharmacie, 75270 Paris Cedex 06-France;
**
Laboratoire de bactériologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France;
Laboratoire de physiologie humaine, UFR de Pharmacie, 49000 Angers, France;
INSERM U458, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; and
INSERM U341, Hôtel-Dieu, 75181 Paris Cedex 04-France
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-ketoglutarate (OKG) in preventing
bacterial translocation and dissemination, metabolic disorders and
changes in mucosal enzyme activities was assessed in a model of
bacterial translocation in rats. Antibiotic decontamination was
performed 4 d before intragastric inoculation with an
Escherichia coli strain (1010 bacteria/kg
body). Two days later, the rats were given either a lipopolysaccharide
(LPS) 0127:B8 or a saline injection and were deprived of food for
24 h. Enteral nutrition, [Osmolite, 880 kJ/(kg · d)]
supplemented with either OKG (LPS + OKG) or glycine (Saline + Gly or
LPS + Gly), was then given for 2 d. Urinary total nitrogen losses
and 3-methylhistidine excretion were determined daily. On killing at d
3, bacterial translocation to the mesenteric lymph nodes (MLN) and
dissemination to the spleen and liver were evaluated, jejunal mucosa
enzyme activities were assayed and tissue free amino acids in muscles
were measured. Endotoxin induced translocation from the gut lumen to
the MLN in all groups, whereas dissemination occurred only in
LPS-treated rats. OKG significantly reduced dissemination of the
bacteria in the spleen. 3-Methylhistidine excretion was greater in the
LPS + Gly group (+25%, P < 0.05) than in either
the LPS + OKG or Saline + Gly group. The group fed the OKG-enriched
diet had higher muscular glutamine, ornithine and arginine
concentrations than did the Gly-supplemented groups
(P < 0.05). Intestinal sucrase and aminopeptidase
activities were higher in the LPS + OKG group than in the LPS + Gly
group (-30%, P < 0.05). OKG supplementation
limits bacterial dissemination and metabolic changes after injury in
rats and thus may be useful in the prevention of gut-derived sepsis
in critically ill patients.
KEY WORDS: • ornithine -ketoglutarate • endotoxemia • bacterial translocation • protein catabolism • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Berg 1992
). The gut was first thought to be of major
importance in these situations because it is a large reservoir of
microorganisms usually retained by a powerful mucosal barrier
(Laissue and Gebbers 1992
). Numerous studies in animals
later demonstrated that bacterial translocation is a multifactorial
phenomenon. Disruption of the normal ecological balance of the
indigenous microflora, resulting in bacterial overgrowth, impaired host
immune defenses or physical disruption of the gut mucosal barrier, may
promote bacterial translocation (Berg and Garlington 1979
, Berg 1992
, Deitch and Berg 1987
, Deitch et al. 1987a
and 1987b
,
Gennari et al. 1995
, Gianotti et al. 1993
). Because these different factors may be related to the
nutritional status of the host, subsequent studies have investigated
the metabolic changes occurring during infection, i.e., a severe
catabolic state and an impaired nitrogen metabolism are often
associated with bacterial translocation and dissemination to the
extraintestinal organs (Braga et al. 1994
, Cerra 1992
, Gennari et al. 1995
, Gianotti et al. 1994
and 1995
, Schlegel et al. 1999
).
It has become evident that providing adequate nutritional support can
improve the metabolic status and immune defenses in critically ill
patients (Braga et al. 1994
, Elia 1995
,
Gennari et al. 1995
). In addition, compared with
parenteral nutrition, enteral nutrition may specifically prevent
translocation of bacteria from the gut (Braga et al. 1994
, Daly et al. 1992
, Deitch et al. 1987b
, Gianotti et al. 1994
). Supplementing the
enteral diet with nutrients known to have trophic effects on
enterocytes and to sustain the functionality of immunologic intestinal
cells has opened an exciting new area in postsurgical care
(Cerra 1992
, Cynober 1995
and 1999
,
Daly et al. 1992
). Thus, the use of ornithine
-ketoglutarate
(OKG;3
Cétornan-Laboratoires Chiesi, Courbevoie, France) has attracted
attention in recent years. OKG is a salt formed from one molecule of
-ketoglutarate and two molecules of ornithine. It is quickly
dissociated after both parenteral and enteral administration. However,
interactions between the metabolic pathways of the two components have
been shown, resulting in the formation of glutamine, arginine and
proline (Cynober 1991
, 1995
and 1999
). The beneficial
effects of OKG on the nutritional status and protein metabolism have
been documented in various catabolic states, including burns, surgery
and trauma [for a review, see Cynober (1995)
]. More
recently, studies [reviewed in Cynober (1999)
] have
also indicated the beneficial effect of OKG on intestinal structure and
function, and on cellular immunity.
However, all of the studies described in the literature have focused
solely on the metabolic response, the intestinal functions or immunity,
and it remains unclear whether OKG limits primarily bacterial
translocation, bacterial dissemination or both. The aim of this study
was to investigate the effect of enteral OKG supplementation in
preventing mucosal functional changes in the jejunum (where ornithine
and -ketoglutarate are absorbed) and bacterial dissemination. The
action of OKG on the host hypercatabolic response was assessed
simultaneously by measuring nitrogen balance, urinary 3-methylhistidine
excretion and tissue amino acid pools together. For this purpose, a rat
model of endotoxemia followed by selective bowel decontamination and
bacterial recontamination was used. This model offers the advantages of
eliciting a high catabolic response and of mimicking a clinical
situation encountered in an intensive care unit (Schlegel et al. 1999
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Wistar rats (Center d’élevage René Janvier, St-Denis-les-Laval, France), 4 wk old, weighing 50–75 g on arrival were used (n = 30). They were housed in individual metabolic cages with wire-grid bottoms. Temperature, humidity and light conditions (reversed 12-h light:dark cycle) were controlled automatically. Food (A03, Usine d’Alimentation Rationnelle, Epinay-sur-Orge, France; 13400 kJ/kg, 235 g protein/kg and 37.6 g N/kg) and water were consumed ad libitum during the acclimation period of 4–6 d. The rats were weighed every day to check growth and detect any underlying disease. They were then randomly assigned to three experimental groups as described below.
Two of the investigators (C.C.L. and L.C.) are authorized by the French Ministry for Agriculture to use this model. Animals were housed in a facility approved by the French Ministry for Agriculture.
Experimental design.
At the end of the acclimation period, the rats underwent selective
intestinal decontamination with 1 g/kg amoxicillin (SmithKline Beecham,
Nanterre, France), 0.2 g/kg streptomycin (Laboratoire Diamant, Puteaux,
France), 0.1 g/kg vancomycin (Lilly France SA, Saint-Cloud, France)
and 0.05 g/kg amphotericin B (Bristol-Myers Squibb, Paris-La
Défense, France) given orally, twice a day, for a total of 4 d (i.e., from d -6 to -2). The Escherichia coli STA
strain was prepared as previously described (Schlegel et al. 1999
). On d -2, the rats were inoculated orally with
1010 bacteria/kg body and continued to receive streptomycin
alone until the end of the experiment so as to allow a selective
advantage to E. coli STA vs. other enteric bacteria. Two
days after oral colonization with E. coli (i.e., d 0),
lipopolysaccharide (LPS) from E. coli ATCC 12740
serotype O127:B8 (Sigma-Aldrich, St-Quentin-Fallavier, France) was
prepared in saline. Rats (n = 22) were given an
intraperitoneal LPS injection (3 mg/kg body). Control rats
(n = 8), which were antibiotic-decontaminated
and colonized by the same E. coli strain, received a
saline injection instead of LPS. Food was then withdrawn for 24 h
(d 0 to 1) to amplify the LPS-induced hypercatabolism
(Schlegel et al. 1999
).
The rats were observed for signs of toxicity (inactivity, ruffled fur,
chromodacryorrhea) and mortality for 24 h. On d 1, an enteral
nutrition solution (Osmolite, Laboratoires Abbott, Rungis-France,
Table 1
) was given intragastrically by gavage three times a day for 48 h
as previously described (Le Boucher et al. 1997b
and 1997c
, Roch-Arweiler et al. 1996
). The enteral
nutrition solution was supplemented with either 5.0 g/(kg · d) OKG
(LPS + OKG group) or 3.5 g/(kg · d) glycine (LPS + Gly and Saline +
Gly groups). Hence, the three experimental groups received
isonitrogenous supplemented diets [184 g N/(kg · d)]. The OKG
dose was selected according to the literature (Cynober 1995
). Water was consumed ad libitum throughout this period.
|
Evaluation of the postinjury hypermetabolic response.
The thymus and muscle [extensor digitorum longus (EDL) and anterior
tibialis] were removed at the time of killing and weighed. The muscle
tissue was immediately frozen in liquid nitrogen and stored at -80°C
for amino acid analysis. Homogenates were prepared in 10%
trichloroacetic acid containing 0.5 mmol/L EDTA (1 mL/100 mg tissue).
After centrifugation at 2500 g for 10 min the amino
acids were quantified in the supernatants by ion-exchange
chromatography (Hitachi L8500A-Sciencetec, Les Ulis, France) as
previously described (Le Boucher et al. 1997a
).
Total urinary nitrogen excretion was determined daily by pyrochemiluminescence (Antek 7000N analyzer, Antek, Houston, TX). The nitrogen balance (nitrogen intake - urinary nitrogen losses) was calculated daily and totaled for the 3 d of the experiment. Urinary 3-methylhistidine was measured after hydrolysis (HCl 6 mol/L, 110°C for 24 h) by ion-exchange chromatography (Hitachi L8500A).
Measurement of bacterial translocation.
Mesenteric lymph nodes (MLN), spleen and liver were aseptically removed
according to Berg and Garlington (1979)
, weighed and
homogenized in sterile water. Aliquots of homogenates (100
µL) were plated onto Drigalski gram-negative
bacilli selective agar for bacterial counts. After 18 h of aerobic
incubation at 37°C, each colony was identified according to its
biochemical profile (API 20E, bioMérieux, La Balme-les-Grottes,
France) and its antibiotic resistance profile established using a disk
diffusion method (Comité de l’Antibiogramme 1998
). The bacterial count was expressed as colony-forming
units (cfu) per gram of tissue. The detection limit of the assay was 20
cfu/g.
Jejunal mucosa enzyme activity.
The jejunum was quickly removed and the first 10 cm, starting at the ligament of Treitz, was measured with no traction. This segment was washed with cold NaCl (90 g/L) and gently dried. It was then weighed and everted. The mucosa were removed by scraping with a glass slide onto a chilled plate and frozen in liquid nitrogen before storage at -80°C.
Before analysis, the mucosa were homogenized in phosphate buffer.
Enzyme activities for sucrase isomaltase and lactase were measured
using a modified method of Dahlqvist as previously described
(Cézard et al. 1979) and for neutral brush border
aminopeptidase as described by Cézard et al. (1994)
. Protein concentrations were assayed by the method of
Lowry et al. (1951)
. Results are expressed per 10 cm
intestine (total activity) and per mg of protein (specific activity).
Statistics.
Qualitative data such as mortality or bacterial translocation incidence
among groups were analyzed using the 
2 or Fischer’s
exact test where appropriate (see Results). Other results are presented
as means ± SEM. One-way ANOVA followed by a
Newman-Keuls test was used for statistical analysis (PCSM,
DeltaSoft, Grenoble, France). Differences were considered significant
at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), indicating that the manipulation of the flora had no deleterious
effect per se. The 2nd day after E. coli administration was
chosen for the LPS injury because the bacterial population had reached
a high and stable level by this day (Fig. 1)
. Throughout the
experimental period, we did not find any differences among groups in
body weight or fecal bacterial population, which supports the
presentation of a single statistical mean for all rats in Figure 1
. On
the day after the endotoxin injection, the rats were lethargic, their
eyes were closed and their fur ruffled. Three deaths occurred, all in
the LPS + Gly group. Surviving LPS-treated rats promptly recovered
and, at the time of killing, displayed no signs of intestinal
distension.
|
) in the first 24 h compared with the Saline controls. On d 2, the
LPS + Gly rats had a significantly lower nitrogen balance than did
either the Saline + Gly or LPS + OKG groups (P = 0.03).
In the Saline + Gly, LPS + Gly and LPS + OKG groups, cumulative
3-methylhistidine excretion was 5402 ± 145, 6791 ± 305 and
5790 ± 447 µmol/3 d (P < 0.05, LPS
+ Gly vs. Saline + Gly and LPS + OKG), respectively. Relative thymus
weights were lower, and spleen and liver relative weights were higher
in the LPS + Gly group than in the LPS + OKG–supplemented rats
(Table 2
). The anterior tibialis, EDL and jejunal mucosa tissue weights did not
differ among groups (Table 2)
. The concentrations of glutamine and
other OKG-related amino acids (arginine, glutamate, proline,
citrulline and ornithine) were significantly greater in the anterior
tibialis of rats after OKG administration than after Gly (Table 3
). A similar pattern was found in EDL (data not shown). Free amino acid
levels in the jejunal mucosa did not differ among groups (data not
shown).
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).
|
).
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The experimental model we designed (Schlegel et al. 1999
), using endotoxemia as the injury after decontamination
and recontamination of the gut, associates a severe catabolic response
with an increased susceptibility to gut-derived infection in rats.
This model mimics a situation encountered in intensive care units [see
Schelgel (1999)
]).Weanling rats were selected because they are more
sensitive to injury than adult rats (Cynober 1989
,
Vaubourdolle et al. 1991
). Our experimental protocol led
to a bacterial overpopulation on the day of injury (i.e., LPS
administration) sufficient to enhance bacterial translocation
(Berg and Garlington 1979
, Berg 1992
,
Schlegel et al. 1999
). Increased 3-methylhistidine
excretion and a reduction in the intramuscular free glutamine pool were
observed in our model for as long as 72 h postinjury. These
changes are similar to alterations usually observed in injured rats and
indicate that a long-lasting hypercatabolic state was achieved
(Austgen et al. 1991
, Vaubourdolle et al. 1991
).
Previous studies have demonstrated the efficacy of OKG supplementation
on postinjury metabolic response (Dumas et al. 1998
,
Le Boucher et al. 1997b
, Vaubourdolle et al. 1991
). The optimal regimen for OKG administration remains
undefined, but the dose of 5 g/(kg · d) was used by most
investigators (Cynober 1995
) as a pharmacologic dose in
rats. Additional results have recently shown an OKG dose-response
effect on free glutamine and nitrogen metabolism in tissues
(Pernet et al. 1999
). Reduction of nitrogen losses and
impairment of myofibrillar catabolism, together with an increase in
glutamine concentration in tissues, are consistent with the changes
previously observed in similar models of endotoxemia in rats (Le Boucher et al. 1997b
, Pernet et al. 1999
,
Vaubourdolle et al. 1991
). However, none of these
studies have simultaneously explored the metabolic, trophic and
immunologic effects of OKG in a unique and well-defined animal
model of experimental injury.
Effect of OKG on bacterial translocation and dissemination.
The occurrence of bacterial translocation to the MLN in noninjured
animals was previously observed in similar models in rats or mice
(Deitch and Berg 1987
, Deitch et al. 1987a
, Kalfarentzos et al. 1996
). It was assumed
to be a part of the normal antigenic stimulation of the
gut-associated lymphoid tissue in the absence of injury
(Berg and Garlington 1979
, Berg 1992
,
Laissue et al. 1992
). In our model (Schlegel et al. 1999
), the LPS injection did not actually induce bacterial
translocation because it occurred at the same level in the saline
controls; more specifically, it led to the dissemination of bacteria to
the extraintestinal organs such as the spleen and liver. We
(Schelgel et al. 1999
) and others (Deitch et al. 1987b
, Gianotti et al. 1993
, 1994
and 1995
) have
postulated that bacterial translocation, dissemination and infection
occurring after injury involve both impairment of the gut barrier and a
failure and suppression of the local specific immune response. The
simultaneous reduction of thymic weight and increase in spleen and
liver weights in our model suggest a redistribution of the lymphoid
cells from the lymphoid central compartment to splanchnic areas. Our
observations are consistent with the results of other studies
(Lasnier et al. 1996
, Torre et al. 1993
).
We hypothesized that the adaptive response to injury was not efficient
in LPS + Gly-treated rats because the bacterial dissemination occurred
to a large extent in that group. Dissemination may be considered to be
a direct consequence of a functional defect in the immune cells
(Gianotti et al. 1994
, Kalfarentzos et al. 1996
, Xu et al. 1998
). Oral supplementation with
OKG counteracts a reduction of thymic weight, an increase of spleen or
liver weight, and simultaneously reduces bacterial dissemination after
an endotoxin injection in rats. These protective effects were observed
previously in experimental models of endotoxemia (Lasnier et al. 1996
), radiation-induced enterocolitis (Kalfarentzos et al. 1996
), small bowel resection (Czernichow et al. 1997
, Dumas et al. 1998
) or transplantation (de Oca et al. 1997
). OKG has been demonstrated to display
immunostimulating properties, improving the oxidative burst of
neutrophil polymorphonuclear cells (Moinard et al. 1999
,
Roch-Arveiller et al. 1996
) and immune cell responses
(Albina 1993
, Moinard et al. 2000
,
Robinson et al. 1999
) in rat models of burn, cancer or
dexamethasone treatment. Thus, we speculate that OKG is responsible for
a better host response against infection originating from the gut
through its action on the immune cells involved in the defense of the
organism. In addition, OKG supplementation may preserve the
functionality and integrity of the intestinal mucosal barrier because
it was effective in improving the restitution of a normal mucosal
architecture (Dumas et al. 1998
, Raul et al. 1995
) and in reducing degenerative changes after injury
(Czernichow et al. 1997
, Kalfarentzos et al. 1996
).
OKG action of intestine functionality.
Although changes in the intestinal architecture after endotoxemia and
refeeding have been studied extensively (Deitch and Berg 1987
, Deitch et al. 1987a
and 1987b
,
Dumas et al. 1998
, Raul et al. 1995
), the
effects of injury and OKG supplementation on enzymatic activities of
the enterocytes are less well known. This study shows that endotoxemia
is associated with reduced specific activities of sucrase and
N-aminopeptidase, an effect that is counteracted in part by
OKG administration. Previous studies have implicated either a reduction
in both number and height of the villi, or a delayed enzymatic
differentiation during epithelial cell migration from the crypt to the
villus, through a reduction of disaccharidase activities (Holt et al. 1985
, Lee et al. 1997
, Raul et al. 1995
). Interestingly, OKG had a stimulating effect on villous
height in both the jejunum and ileum (Czernichow et al. 1997
, Dumas et al. 1999
, Kalfarentzos et al. 1996
, Raul et al. 1995
). Because our study
was limited to the jejunal segment of the intestine, and also because
we studied total mucosal homogenates instead of the purified brush
border membrane, we may have observed a limited effect of injury and
treatment on the enzymatic activities. In addition, some studies using
the resection model (Czernichow et al. 1997
,
Zaouch et al. 2000
) indicate that the extent of both the
morphological and functional adaptive response of the gut to injury may
be limited after 4 d and may have occurred between 4 and 7 d
after injury. These preliminary results warrant further cellular and
molecular studies to explore the regulation of the intestinal
disaccharidase activity in trauma and the mechanism of action of OKG.
In conclusion, we demonstrate here for the first time in a single study that OKG administration in injured rats significantly reduces both the hypercatabolic response, and immunologic and functional defects of the intestinal cells. OKG contributes to a better adaptive response to injury as shown by a limitation of bacterial dissemination and subsequent reduction of hypercatabolism and muscular protein wasting. These results suggest that critically ill patients, admitted shortly after injury, might benefit from the addition of OKG to their enteral diet with the goal of reducing gut-derived sepsis and the occurrence of infected multiple-system organ failures.
|
FOOTNOTES |
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3 Abbreviations used: cfu, colony forming units; EDL, extensor digitorum longus; Gly, glycine; LPS, lipopolysaccharide, MLN, mesenteric lymph nodes; OKG, ornithine -ketoglutarate.
Manuscript received March 27, 2000. Initial review completed May 23, 2000. Revision accepted August 28, 2000.
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