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The Journal of Nutrition Vol. 129 No. 1 January 1999,
pp. 32-38
,
* Nutritional Immunology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, Department of Food Science, Lipid Chemistry and Metabolism Laboratory, Purdue University, West Lafayette, IN 47907 and ** Department of Nutrition, Food & Movement Science, The Florida State University, Tallahassee, FL 32306-2033
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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Aging is associated with a decline in the immune response in mammals. Conjugated linoleic acid (CLA) has been suggested to have immunoenhancing properties. We examined the influence of dietary CLA on the immune response of young and old mice. Forty young (4 mo) and 40 old (22 mo) mice consumed ad libitum diets containing 0 or 1 g CLA /100 g for 8 wk. Splenocytes from half of the mice were isolated to evaluate proliferation to concanavalin A (Con A) (0.5, 1.5, 5.0 mg/L) and phytohemagglutinin A (PHA) (5, 20, 40 mg/L) and lipopolysaccharide (LPS) (5, 15, 30 mg/L), natural killer cell (NK) activity and prostaglandin (PG)E2 and interleukin (IL)-2 production. The remaining mice were used to evaluate in vivo delayed-type hypersensitivity (DTH) skin response. There was a significant decline due to age in response to all three mitogens tested (P < 0.05). CLA supplementation significantly increased all CLA isomers measured in hepatic neutral lipids and phospholipids (P < 0.05). Young mice fed 1% CLA had greater splenocyte proliferation in response to Con A (0.5 and 5.0 mg/L) and PHA (40 mg/L) (P < 0.05) than young mice fed control diet. Old mice fed 1 g CLA/100 g had significantly higher proliferative response to optimal concentrations of Con A (1.5 mg/L) (P < 0.001) than the mice fed the control diet. Old mice fed the control diet had significantly lower splenocyte IL-2 production than the young mice (P < 0.005). CLA-supplemented young mice had significantly higher splenocyte IL-2 production than those fed the control diet (P < 0.05). CLA had no effect on NK cell activity, PGE2 production or DTH in young or old mice. Further studies are needed to determine the mechanism of CLA-induced enhancement of IL-2 production and T cell proliferation.
KEY WORDS: conjugated linoleic acid · mice · immune response · age
Considerable evidence indicates that aging is associated with altered regulation of the immune system (Miller 1994 Intervention with antioxidant nutrients (vitamin E, One potential dietary component that may have an impact on the aging immune response is conjugated linoleic acid (CLA), a naturally occurring substance originally described as an anti-carcinogenic agent in grilled ground beef. Ha et al. (1987) The effect of CLA on the immune system has not been well investigated. When CLA was added to porcine lymphocyte cultures in vitro, it increased mitogen induced lymphocyte blastogenesis, lymphocyte cytotoxic activity and murine macrophage killing ability (Michal et al. 1992 The mechanism by which CLA exerts its immunological or anticarcinogenic effects has not been well studied. Several investigators have suggested that it may be due to the antioxidant properties of CLA, which were demonstrated in cell free systems (Ha et al. 1990 Animals.
Forty specific pathogen-free young (4 mo) and old (22 mo) C57BL/6NCrlBR mice were obtained from NIA colonies at Charles River Laboratories (Kingston, NY). Mice were housed singly in micro-isolator cages at a constant temperature (23°C) with a 12 h light-dark cycle and consumed ad libitum a semi-purified diet supplemented with either 0 or 1 g /100 g CLA (Nu-Check-Prep, Elysian, MN; Table 1). The levels of CLA were chosen based on reports in the literature that noted optimal anti-tumor activity at 1 g/100 g CLA of a similar diet as well as on our own preliminary data. The reported isomeric composition of CLA (96% purity) was 43% cis (c) 9 trans (t) 11- and t9, c11 - CLA, 45% t10 c12-CLA, 6% c9 c11-c10 c12, t10 t12-CLA, 2% linoleate and 4% unidentified compound. CLA was added to the soybean oil prior to its addition to the diet, keeping the total fat at 5 g/100 g. Fat sources were added to the diets on a weekly basis, and diets were stored at 4°C to prevent oxidation. Fresh diets were provided daily, and body weights were monitored weekly. Because previous reports indicated no effect of CLA on the food intake of animals or their weight (Ha et al. 1990
Tissue collection and cell culture.
At the end of the feeding period, mice were killed via CO2 asphyxiation. Spleens were aseptically removed and placed in 5 mL RPMI 1640 media (Gibco, Grand Island, New York) supplemented with 25 mmol Hepes/L, 2 mmol glutamine/L, 10,0000 U penicillin/L and 100 mg streptomycin/L (Gibco, Grand Island, NY). Livers were then excised, wrapped in aluminum foil, and immediately frozen in liquid nitrogen.
Natural killer cell assay.
The natural killer (NK) cell activity against YAC-1 target cells were assessed as previously described (Meydani et al. 1988 Splenocyte blastogenesis.
One hundred µL cell suspension (4 billion cells/L) were added to wells of 96-well plates (Falcon Labware, Lincoln Park, NJ). To these wells 100 µL of media containing either no mitogen, Con A (final concentrations 0.5, 1.5 and 5.0 mg/L), PHA (final concentrations 5, 20 and 40 mg/L) or LPS (final concentrations 5, 15 and 30 mg/L) were added in triplicate. Plates were incubated at 37°C, 5% CO2 and 100% humidity for 72 h. Cells were then pulsed with 18.5 µBq of [3H]-thymidine for the final 4 h of incubation. The cells were harvested onto glass fiber mats (Wallac, Gaithersburg, MD) by Tomtec harvester (Wallac) and cell proliferation was quantified by the amount of [3H] thymidine incorporation into DNA as determined by liquid scintillation counting in a 1205 Betaplate counter (Wallac). The counter had an efficiency of <50% for 3H. Data are expressed as corrected counts per minute (cpm), which is the cpm of mitogen-stimulated cultures minus the cpm of cultures without mitogen.
Interleukin-1 and interleukin-2 production.
For IL-2 production 100 µL of cell suspension at 10 billion cells/L were added to 96-well plates. One hundred µL of media or media containing 20 mg Con A/L or 40 mg PHA/L was added. Cultures were set up in quadruplicate. For IL-1 production, 0.5 mL of cell suspension at 10 billion cells/L and 0.5 mL media containing 200 mg LPS/L was added to 24-well plates (Falcon Labware). Plates for both IL-1 and -2 were incubated at 37°C, 5% CO2 and 100% humidity for 24 h (IL-1, IL-2) at which time they were centrifuged at 400 × g at 4°C for 10 min. Supernatants were collected and stored at Prostaglandin E2 production.
Five hundred µL of cell suspension of 10 billion cell/L was added to 24-well plates (Falcon Labware). Five hundred µL of media or media containing 10 mg Con A/L was added to the culture wells. Plates were incubated for 48 h at 37°C, 5% CO2 and 100% humidity. After the incubation period, plates were centrifuged at 800 × g for 20 min at 4°C. Supernatants were collected and immediately frozen at Delayed-type hypersensitivity.
DTH was measured by a previously described radioisotopic method (Vadas et al. 1975
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
, Siskind 1980 ). Age-related functional changes were reported for both humoral and cell-mediated immune responses (Hausman and Weksler 1985, Makinodan 1981, Siskind 1980; ). Although all four major cell types of the immune system, i.e. stem cells, macrophages, T cells, and B-cells, show age-related changes, the major alterations were demonstrated in the T cells (Makinodan 1981,Miller and Stutman 1981). In vivo T cell-mediated functions, such as delayed-type hypersensitivity (DTH)5, resistance to tumors and parasites, and graft vs. host reactions, are depressed with age. Among in vitro indices of T cell-mediated function, the ability of T cells to proliferate in response to antigen or polyclonal T cell mitogens concanavalin A (Con A) and phytohemagglutinin (PHA) and their production of interleukin (IL)-2 were shown to consistently decrease with age (with some exceptions for IL-2).
-carotene and glutathione) were shown to enhance the immune response in aged rodents and humans (Beharka et al. 1997, Furukawa et al. 1987, Meydani et al. 1986 and 1990, Wu et al. 1994). These nutrients are proposed to exert their immunoenhancing effects through suppression of lipid peroxide and/or prostaglandin (PG) E2 production (Beharka et al. 1997, Furukawa et al. 1987, Meydani et al. 1986 and 1990).
demonstrated that the application of CLA to mouse skin significantly inhibited the initiation of DMBA [7,12-dimethylbenz(a)anthracene]-induced mouse epidermal tumors. Gavage feeding of CLA also significantly inhibited the initiation of mouse stomach tumorigenesis by benzo(a)pyrene (Ha et al. 1990). Ip et al. (1991) have demonstrated that feeding CLA to mice as 0.5, 1 or 1.5 % of the diet will reduce total tumor incidence and tumor weight of DMBA-induced mammary tumors. In vitro addition of CLA was shown to inhibit cancer cell proliferation (Schultz et al. 1992).
). An increase in PHA-stimulated blastogenesis was also noted in CLA fed-chicks challenged with LPS (Cook et al. 1993). In two feeding experiments, CLA added at 0.5% to the diet of chicks or rats decreased the weight loss of these animals in response to Escherichia coli LPS challenge (Cook et al. 1993). The authors reported that while CLA had no effect on the animals' response to being injected with the red blood cells of sheep, it did result in an improvement in phytohemagglutin foot pad swelling as well as macrophage phagocytosis in rats.
), liver microsomes (Pariza et al. 1991) and in mammary glands (Ip et al. 1991). It was suggested that CLA may be a more potent antioxidant than 
-tocopherol and almost as effective as butylated hydroxytoluene (BHT) (Ha et al. 1990). CLA may also exert its effect through alteration of eicosanoid synthesis. PGE2 was demonstrated to be suppressive to the cellular arm of the immune system (Goldyne and Strobo 1982, Goodwin and Webb 1980, Goodwin et al. 1977). CLA may act in part by competing with linoleic acid in the biosynthesis of arachidonic acid (Ha et al. 1987). In a recent study, Cook et al. (1993) showed that feeding chicks a diet containing 0.5% CLA significantly reduced the level of arachidonic acid in foot pad fatty acids. Also, Belury and Kempa-Steczko (1997) demonstrated that feeding rats 0.5, 1.0 and 1.5% CLA resulted in decreased arachidonic acid levels in hepatic neutral lipids. Arachidonic acid is the precursor for PGE2; thus, increased CLA intake may decrease PGE2 production. PGE2 was shown to have a suppressive effect on IL-2 production and T cell proliferation (Goodwin and Webb 1980, Goodwin et al. 1977). The purpose of the current study was to examine if dietary supplementation with CLA would enhance the immune response of aged mice and to determine if the mechanism of immune enhancement is through alteration of PGE2 production.
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
, Ip et al. 1991, Zu and Schut 1992), they were not pair-fed. Ten mice from each group were used for in vitro experiments, and 10 mice from each group were used for in vivo DTH experiments. All conditions and handling of animals were approved by the Animal Care and Use Committee at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and followed NIH Guidelines for the Care and Use of Laboratory animals.
View this table:
Table 1.
Composition of the basal diet1
).
70°C until analyzed. IL-1 and 2 concentrations were measured by ELISA kits (Genzyme, Boston, MA) according to the manufacturer's instructions.
70°C until analyzed. PGE2 concentrations were measured by radioimmunoassay as previously described (Hayek et al. 1994).
). Briefly, mice were sensitized to 2,4-dinitrofluorobenzene (DNFB) by applying 50 µL of a 2% DNFB solution in ethanol on their shaved backs. After 5 d, 10 µL of a 1% DNFB solution in olive oil was painted on both sides of the right ear, and olive oil was applied to the left ear as a control. Ten hours after the second administration of DNFB, mice were injected intraperitoneally with 74 µBq of [125I] iodo-2-deoxyuridine ([125I] Urd) (Amersham, Arlington Heights, IL). Sixteen hours after [125I] Urd injection, the mice were killed and both ears were removed at the hairline and counted in a Cobra II auto-gamma counter (Packard, Meriden, CT). A stimulation index was calculated as:
Statistical analysis. Statistical analysis was conducted using the SAS statistical program (Release 6.03, 1988, SAS Institute, Cary, NC). Data were analyzed by a 2 × 2 factorial two-tailed ANOVA with individual differences analyzed by single degree of freedom comparison using Fisher's least significant difference procedure and are reported as means ± SEM. Significance of difference was set at P < 0.05.
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RESULTS |
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Abstract
Introduction
Methods
Results
Discussion
References
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Old mice had significantly greater body weights than young mice throughout the feeding period (Table 2; P < 0.001). At Weeks 3 and 4,Young mice fed CLA had lower body weights than those fed the control diet (7% lower, P < 0.01). A similar difference was noted in old mice at Week 3 (6% lower; P < 0.05). Similar effects of CLA on murine body weights have been reported (Belury and Kempa-Steczko 1997).
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Conjugated linoleic acid is a mixture of nine isomers with c9, t11-t10, c12-, t9, t11- and t10, t12-octadecadienoic acids being the four major derivatives that account for more than 90% of total CLA, whereas the c9, c11-, t9, c11-,c10, c12-, and c10, t12- octadecadienoic acids represent only minor constituents (Ha et al. 1989
Manuscript received 6 January 1998. Initial reviews completed 25 February 1998. Revision accepted 14 September 1998.
The authors thank Timothy S. McElreavy for the preparation of this manuscript.
View this table:
Table 3.
Effect of conjugated linoleic acid (CLA) supplementation on fatty acid composition of livers of young and old mice.1,2
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[in a new window]
Fig 1.
Effect of conjugated linoleic acid (CLA) supplemenation on mitogenic response of splenocytes to Concanavalin A (Con A) in young and old C57BL/6NCrlBR mice. One hundred µL of 4 billion splenocytes/L were added to 96-well plates in the presence of 100 µL media or Con A at final concentrations of 0.5, 1.5 or 5.0 mg/L. Plates were incubated at 37°C at 5% CO2 and 100% humidity for 68 h, and pulsed with 18.5µBq of [3H]-thymidine for an additional 4 h. The cells were harvested on glass fiber strips and [3H]-thymidine incorporation into DNA was determined by liquid scintillation counting. Mitogen-stimulated counts were corrected for background media stimulation (cpm). Data are presented as the means ± SE, n = 10. Bars within a mitogen concentration without common superscripts are significantly different (P < 0.05).
View larger version (23K):
[in a new window]
Fig 2.
Effect of conjugated linoleic acid (CLA) supplemenation on mitogen response of splenocytes to phytohemagglutinin (PHA) in young and old C57BL/6NCrlBR mice. One hundred µL of 4 billion splenocytes/L were added to 96-well plates in the presence of 100 µL media or PHA at final concentrations of 5, 20 or 40 mg/L. Plates were incubated at 37°C at 5% CO2 and 100 % humidity for 68 h and pulsed with 18.5 µBq of [3H]-thymidine for an additional 4 h. The cells were harvested on glass fiber strips and [3H]-thymidine incorporation into DNA was determined by liquid scintillation counting. Mitogen-stimulated counts were corrected for background media stimulation (cpm). Data are presented as the means ± SE, n = 10. Bars within a mitogen concentration without common superscripts are significantly different (P < 0.05).
View larger version (31K):
[in a new window]
Fig 3.
Effect of conjugated linoleic acid (CLA) supplementation on mitogen response of splenocytes to lipopolysaccharide (LPS) in young and old C57BL/6NCrlBR mice. One hundred µL of 4 billion splenocytes/L were added to 96-well plates in the presence of 100 µL media or LPS at final concentrations of 5, 15, or 30 mg/L. Plates were incubated at 37°C at 5% CO2 and 100 % humidity for 68 h and pulsed with 18.5 µBq of [3H]-thymidine for an additional 4 h. The cells were harvested on glass fiber strips and [3H]-thymidine incorporation into DNA was determined by liquid scintillation counting (cpm). Mitogen-stimulated counts were corrected for background media stimulation. Data are presented as the means ± SE, n = 10. Bars within a mitogen concentration without common superscripts are significantly different (P < 0.05).
View this table:
Table 4.
Effect of conjugated linoleic acid (CLA) supplementation on interleukin (IL)-1, prostaglandin (PG) E2, and IL-2 production from splenocytes of young and old mice1
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). However, only the c9,t11-CLA isomer was incorporated into the forestomach phospholipid fraction of mice fed CLA (Ha et al. 1990) and the phospholipid fraction of livers and mammary tumors of rats fed CLA (Ip et al. 1991), leading these investigators to conclude that this is the biologically active isomer. In this study, all CLA isomers measured were incorporated into the hepatic neutral lipids and phospholipids of mice fed CLA (Table 3)
, Fink et al. 1985, Iversen et al. 1985, Szebeni et al. 1986). The potential for increasing CLA concentration in humans was demonstrated in a study that showed that supplementation of cheddar cheese (~112 g/d providing 178.5 mg CLA) increased plasma CLA:LA molar ratio by approximately 130% (Huang et al. 1994). It was also proposed that nonruminants have the ability to produce CLA via the action of intestinal microflora (Chin et al. 1994).
and Chew (1993) who demonstrated that when CLA was added to porcine lymphocyte cultures in vitro, it increased lymphocyte blastogenesis, lymphocyte cytotoxic activity and murine macrophage killing activity. Also, Cook et al. (1993) noted that CLA-supplemented chicks challenged with LPS had higher T cell blastogenic response to PHA. CLA supplementation, however, did not influence in vivo DTH reaction in this study.
). In the old mice, however, a numerical increase in IL-2 production was observed but there was no statistically significant difference in IL-2 production by splenocytes of old mice supplemented with CLA and those of young mice fed the control diet. Therefore, supplementation with CLA partially restored decreased IL-2 production in old mice. The reason for the difference in CLA immune enhancement in the different age groups is not clear from this data; however, one potential explanation is the observed trend for lower CLA incorporation into the neutral lipids of old mice in this study.
, Ha et al. 1987, Ip et al. 1997, Liu and Belury 1997) or inhibition of lipoxygenase (Cunningham et al. 1997).
, Ip et al. 1991). In recent studies, Cook et al. (1993) showed that feeding chicks with 0.5 g CLA /100 g significantly reduced the level of arachidonic acid in foot pad fatty acids and that feeding rats with 0.5 g CLA/100 g decreased muscle arachidonic acid levels. Belury and Kempa-Steczko (1997) also demonstrated decreased arachidonic acid levels in hepatic neutral lipids of rats fed 1.0 and 1.5 g CLA/100 g . Because arachidonic acid is a precursor for PGE2, increased CLA incorporation into cellular membranes may decrease PGE2 production. We, however, did not observe a significant decrease in arachidonic acid incorporation in hepatic samples or splenocyte production of PGE2 in young or old mice despite an increase in CLA concentration in both the neutral lipids and phospholipids. This agrees with two recent studies reported that rats fed diets supplemented with 1 g CLA/100 g had increased concentrations of CLA isomers in several tissues and decreased ex vivo PGE2 production in bone, but not in liver or macrophages (Li et al. 1997, Turek et al. 1997). Also, we did not observe a significant displacement of linoleic acid in the livers of mice fed CLA. This is in agreement with recent data on fatty acid composition of mammary tissue from mice fed CLA (Ip and Schimeca 1997). Thus, CLA replacement of phospholipid arachidonic acid might not be adequate to cause a significant change in PGE2 production. Further studies are needed to determine whether the effect of CLA on PGE2 production is species-, organ-, or tissue-specific.
, Ip et al. 1991, Zu and Schut 1992) that CLA had no effect on weight, Belury and Kempa-Steczko (Belury 1997) recently reported a weight-reducing effect of CLA. A nutritional intervention that has been demonstrated to enhance immune response is calorie restriction (Umezawa et al. 1990, Weindruch et al. 1982 and 1986). It could be suggested that the immunoenhancing effect of CLA may be through energy restriction. This, however, is not likely as Belury and Kempa-Steczko (1997) reported that CLA resulted in lower body weights in mice without significantly affecting food disappearance, but food wastage was not measured. Also, the beneficial effects of energy restriction on immune response has been observed with an 18% or greater decline in body weight (Umezawa et al. 1990, Weindruch et al. 1986). In our study, only a 7% decline was observed. Lastly, energy restriction needed to be conducted for 6 mo before a beneficial effect on immune response could be observed (Umezawa et al. 1990), whereas the duration of our study was only 1 mo.
. They observed that under these conditions, CLA was a more potent antioxidant than -tocopherol and almost as effective as BHT. In another study, Pariza et al. (1991) found that when liver microsomes were subjected to oxidative stress using a non-enzymatic iron-dependent lipid peroxidation system, the microsomes from CLA-treated mice were far more resistant to oxidation than microsomes from control animals. Also, it was reported that feeding CLA to mice from 1 to 6 mo resulted in a decrease in lipid peroxidation in mammary glands but not in the liver, as measured by thiobarbituric acid reactive substances (Ip et al. 1991). However, others have demonstrated that CLA does not act as an antioxidant when tested for its ability to protect membranes composed of 1-palmitoyl-2-linoleoyl phosphatidylcholine from oxidative modification under conditions of metal ion-dependent or -independent oxidative stress (van den Berg et al. 1995). Our study did not directly examine the antioxidant capability of CLA in these mice. However, in preliminary experiments we noted that CLA had no effect on H2O2 production from peritoneal macrophages (data not shown), which suggests a lack of antioxidant function. This is further supported by observations that CLA was more effective in enhancing immune response in young compared to old mice that have been reported to have higher concentrations of free radicals (Sohal and Weindruch 1996).
) as well as potential regulation of protein kinase C (PKC) (Pariza et al. 1991). The former authors suggested that because PKC controls superoxide generation (Merrill 1989), CLA might serve as an antioxidant directly, but indirectly as well (i.e., prevention of superoxide generation via its effect on PKC). Further research is required to determine if these mechanisms can explain CLA's enhancement of T cell proliferation and IL-2 production.
1
This project has been funded at least in part with Federal funds from the US Department of Agriculture, Agriculture Research service under contract number 53-K06-01 and a grant from the national Diary Council. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
FOOTNOTES
2
The costs of publication of this article were defrayed in part
by the payment of page charges. This article must therefore be hereby marked "advertisement"
in accordance with 18 USC section 1734 solely to indicate this fact.
3
Current address: The Iams Company, P.O. Box 189, Lewisburg, OH 45338.
4
To whom correspondence should be addressed.
5
BHT, butylated hydroxytoluene; c, cis; CLA, conjugated linoleic acid; Con A, concanavalin A; cpm, counts per minute; ccpm, corrected counts per minute; DMBA, 2,4-dinitrofluorobenzene; DNFB, 2,4-dinitrofluorobenzene; DTH, delayed type hypersensitivity; FAME, fatty acid methyl esters; [125I] Urd, [125I] iodo-2-deoxyuridine; IL, interleukin; LPS , lipopolysaccharide; NK, natural killer; PG, prostaglandin; PHA , phytohemagglutinin; PKC, protein kinase C; t, trans.
ACKNOWLEDGMENTS
LITERATURE CITED
Abstract
Introduction
Methods
Results
Discussion
References
-carotene on cellular host defense.
FASEB J.
1992;
6:A1102-carotene on the in vitro growth of human cancer cells.
Cancer Lett.
1992;
63:125-133[Medline]
0022-3166/99 $3.00 ©1999 American Society for Nutritional Sciences
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M. B. Sisk, D. B. Hausman, R. J. Martin, and M. J. Azain Dietary Conjugated Linoleic Acid Reduces Adiposity in Lean but Not Obese Zucker Rats J. Nutr., June 1, 2001; 131(6): 1668 - 1674. [Abstract] [Full Text]
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K. L. Ritzenthaler, M. K. McGuire, R. Falen, T. D. Shultz, N. Dasgupta, and M. A. McGuire Estimation of Conjugated Linoleic Acid Intake by Written Dietary Assessment Methodologies Underestimates Actual Intake Evaluated by Food Duplicate Methodology J. Nutr., May 1, 2001; 131(5): 1548 - 1554. [Abstract] [Full Text]
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M. J. Azain, D. B. Hausman, M. B. Sisk, W. P. Flatt, and D. E. Jewell Dietary Conjugated Linoleic Acid Reduces Rat Adipose Tissue Cell Size Rather than Cell Number J. Nutr., June 1, 2000; 130(6): 1548 - 1554. [Abstract] [Full Text]
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B. Kamlage, L. Hartmann, B. Gruhl, and M. Blaut Intestinal Microorganisms Do Not Supply Associated Gnotobiotic Rats with Conjugated Linoleic Acid J. Nutr., December 1, 1999; 129(12): 2212 - 2217. [Abstract] [Full Text]
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