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1 Gut Health Division, Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, UK
2 MTT Agrifood Research Finland, FI-31600 Jokioinen, Finland
Correspondence
R. John Wallace
john.wallace{at}rowett.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Present address: ADISSEO France S.A.S., Route de Chamblet, 03600 Commentry, France.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Pariza, 2004) first identified the anticarcinogenic component of beef as rumenic acid (cis-9,trans-11 conjugated linoleic acid, RA), a conjugated isomer of linoleic acid (cis-9,cis-12-18 : 2, LA), considerable research has been directed towards understanding the formation, physiological effects and potential health benefits of conjugated linoleic acid (CLA; of which RA is one stereoisomer) in a range of biological models (Kritchevsky, 2000; Wahle et al., 2004; Bauman et al., 2005). Isomers of CLA were first discovered as intermediates during the metabolism of LA to stearic acid (18 : 0, SA) by ruminal bacteria (Polan et al., 1964; Harfoot & Hazlewood, 1997). Subsequently it was found that LA was also converted to RA by human intestinal bacteria (Kamlage et al., 1999; Coakley et al., 2003; Devillard et al., 2007). Thus, in addition to systemic health benefits from CLA in the diet, CLA formation in the human intestine could promote health. It is therefore important to understand how CLA is formed and metabolized by intestinal bacteria.
CLA formed in the intestine might be absorbed and contribute to systemic CLA. However, experiments with germ-free rats inoculated with a human faecal microbiota and fed a diet enriched with sunflower-seed oil indicated that no benefit accrued in terms of tissue concentrations of CLA (Kamlage et al., 1999). Even if CLA absorption from the intestine is minimal, there may be in situ benefits from intestinal CLA production, however. In mouse models of inflammatory bowel disease, CLA was shown to exhibit anti-inflammatory properties via endoplasmic and nuclear mechanisms (Bassaganya-Riera et al., 2002, 2004). Further studies have demonstrated that CLA exerts anti-carcinogenic activity in the rat colon (Nichenametla et al., 2004) and exhibits anti-proliferative properties on the growth of human colon cancer cells in vitro (Kemp et al., 2003). Therefore, mechanisms by which CLA might be delivered to and formed in the intestine have important implications for long-term human health.
The precise isomer(s) that is formed has importance too, given the very different biological effects of RA and other isomers, particularly trans-10,cis-12-CLA (Pariza, 2004; Bauman et al., 2005). Such information could have particular relevance to patients using the slimming drug tetrahydrolipstatin (orlistat; Hauptman et al., 2000) or similar agents that prevent lipid absorption in the human small intestine. Large amounts of lipid reach the large intestine in patients using orlistat, sometimes with deleterious consequences (Chanoine et al., 2005). Conversion of LA to RA under such circumstances might be beneficial, but the formation of 10,12 isomers detrimental (Pariza, 2004; Bauman et al., 2005).
Given these concerns, we have re-examined the mechanism of CLA formation by intestinal bacteria, using methods employed recently to establish the mechanisms involved in CLA isomer formation by ruminal bacteria (Wallace et al., 2007). The rumen seems to possess a single group of bacteria, closely related to Butyrivibrio fibrisolvens, that play a predominant role in biohydrogenation of dietary fatty acids (Polan et al., 1964; Harfoot & Hazlewood, 1997; Wallace et al., 2006). In contrast, several colonic species, of which Roseburia would usually be most numerous, form RA and/or vaccenic acid (VA) in the human intestine (Devillard et al., 2007). Furthermore, some Roseburia spp. form 10-OH-18 : 1 rather than RA from LA (Devillard et al., 2007). This hydroxy fatty acid then serves as a substrate for RA synthesis by other species in the mixed microbiota. Thus, there appeared to be two potential routes of RA formation in the human intestine (Fig. 1). This investigation was undertaken to establish the relative importance of the different mechanisms of formation of different CLA isomers by mixed faecal microbiota and also pure cultures of intestinal bacteria, and to elucidate the molecular mechanism of formation of different CLA isomers.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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To establish the possible role of hydroxy fatty acids (HFA) as a precursor to RA formation and establish the ability of human microbiota to metabolize HFA, similar incubations were carried out with ricinoleic acid (cis-9,12-hydroxy-18 : 1).
Bacteria and growth conditions.
The bacteria selected in this study are known to metabolize LA (Devillard et al., 2007). Bifidobacterium breve NCFB 2258 was isolated originally from the human infant intestine (Coakley et al. 2003). Butyrivibrio fibrisolvens 16/4 was isolated from human faeces (Rumney et al., 1995). Roseburia hominis A2-183T and Roseburia inulinovorans A2-194T were isolated in a study of butyrate producers from human faeces (Barcenilla et al., 2000) and subsequently reclassified (Duncan et al., 2006). Strain A2-162 was isolated in the same study; based on 16S RNA phylogenetic analysis it is closely related to Ruminococcus obeum (Duncan et al., 2007). Propionibacterium freudenreichii subsp. shermanii DSM 4902T is the type strain of this species (obtained from DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany), originally isolated from cheese (Van Niel, 1928) and considered to be a potential probiotic organism.
The growth media were based on the liquid form of M2 medium (Hobson, 1969). All transfers and incubations were carried out under O2-free CO2 at 37 °C in Bellco tubes as described previously (Devillard et al., 2007). Inoculum volumes were 5 % (v/v) of a fresh culture into 5 ml of medium. One batch of medium was made up using unlabelled water, the other prepared with 50 % (v/v) deuterium oxide. LA was added to a final concentration of 50 mg l–1. In other cultures, ricinoleic acid (cis-9-12-OH-18 : 1) was added to the same concentration. Fatty acids were prepared as a separate solution, sonicated for 4 min in a small volume of medium and added to the medium before dispensing and autoclaving. Triplicate 5 ml cultures were grown for 24 h. Subsamples (1 ml) were removed for protein analysis (Herbert et al., 1971) and analysis of the deuterium enrichment in water. Thereafter, 100 µl of nonadecanoic acid (200 mg l–1 in methanol) was added and the tubes were stored at –70 °C and subsequently freeze-dried.
Fatty acid extraction and analysis.
Extraction of total fatty acids, preparation of fatty acid methyl esters (FAME) and 4,4-dimethyloxazoline (DMOX) derivatives and analysis by GC-MS were performed using standard procedures (Wallace et al., 2007). Enrichment in the m/z (m+1), (m+2) and (m+3) isotopomers (molecular ion+1 +2 and +3, respectively) was determined by GC-MS of FAME (Wallace et al., 2007). Analysis of DMOX derivatives by GC-MS was used to identify the position of deuterium labelling in the fatty acid moiety. Enrichment in water was determined by gas isotope ratio mass spectrometry (GIRMS) (Wallace et al., 2007).
Data analysis.
Three replicate measurements were made in incubations with faecal suspension samples from each of four human donors. Experimental data were analysed by ANOVA for repeated measures with a model that included the fixed effect of incubation time and random effects of volunteer assuming a compound symmetry covariance structure using the mixed linear model procedure of Statistical Analysis Systems software package version 8.2 (SAS Institute). This experimental design accounts for potential autocorrelation between sequential measurements. Measurements of fatty acid concentrations over time during incubation of LA with pure cultures of intestinal bacterial were analysed by ANOVA for repeated measures with a model that included the fixed effect of incubation time and random effects of replicate assuming a compound symmetry covariance structure. Least-square means±SE are reported and effects were considered significant at P<0.05. Enrichment of (m+1) isotopomers was calculated from the m/z ratios at m, m+1, m+2 and m+3 by deconvolution according to Campbell (1974). Natural abundance was calculated from the isotopomer distribution of LA in zero-time samples.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). However, the background concentration of SA varied between samples (Fig. 2). Concentrations of SA increased with time in the sample from volunteer B, the vegetarian, which also exhibited the highest zero-time SA concentrations.
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). Trace amounts of trans-10,cis-12-CLA were also present, but at concentrations below 3 % of total CLA.
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) whilst labelling at m+2 was not detected. In contrast, mean labelling at m+1 for trans-10,cis-12-CLA was 0.310, SE 0.056. There was no evidence of differences in labelling at m+1 in samples collected at 1 or 4 h (data not presented). Enrichment of VA and SA end products could not be determined due to their high concentrations in zero-time samples.
The mass spectrum of the DMOX derivative of RA (Fig. 3) indicated enrichment in ion fragments from the molecular ion above m/z 262. The occurrence of ion fragment isotopomers with m/z lower than 262 was comparable to the natural abundance of about 20 % MPE. These data provide clear evidence that deuterium was labelled on C-13 of the fatty acid moiety (Fig. 3). Mass spectra of other 9,11 geometric CLA isomers revealed a similar pattern of enrichment as indicated by GC-MS analysis of the DMOX derivative of trans-9,trans-11 CLA (Fig. 3). Due to the low concentration of trans-10,cis-12-CLA following the conversion of FAME to DMOX derivatives, it was not possible to identify the position of the small amount of label.
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) were grown in the presence of 50 mg LA l–1 in deuterium oxide-enriched medium and samples were collected for fatty acid determinations in the stationary phase. Bif. breve and P. freudenreichii subsp. shermanii produced RA as the predominant product, with smaller concentrations of trans-9,trans-11-CLA also being formed (Table 2). The latter species also produced a small quantity of trans-10,cis-12-CLA. LA was metabolized to VA in the four other species, with only minor amounts of CLA being detected. No SA was formed by any culture during incubations with LA.
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). Labelling was 0.011, SE 0.004, in the m+2 isotopomer. The other isomer formed, trans-10,cis-12-CLA, was unlabelled. Values in Bif. breve cultures were similar for RA, but a higher enrichment was determined for trans-9,trans-11-CLA (Table 2). The mass spectrum of labelled RA produced by pure cultures was similar to that of mixed microbiota, indicating that labelling was located on C-13 (spectra not shown). However, the spectra of the DMOX derivative of trans-9,trans-11-CLA were less informative. Ion fragments corresponding to C-13 (m/z 262 and 263) appeared to indicate small amounts of label in the product from P. freudenreichii subsp. shermanii, whereas the trans-9,trans-11-CLA peak in Bif. breve samples contained a higher enrichment than RA. It is possible that, because trans-9,trans-11-CLA and trans-10,trans-12-CLA co-elute during GC analysis, the labelling pattern was due to the contributions of both CLA isomers.
Enrichment of VA was comparable for all four VA-producing species, Bu. fibrisolvens, Ros. hominis, Ros. inulinivorans and Rum. obeum (Table 2). The m+1 isotopomers had an MPE ratio of 0.879–0.941 relative to water, while the ratio for m+2 isotopomers varied between 0.214 and 0.303. There was no evidence of labelling at m+3. Mass spectra of DMOX derivatives of VA revealed a clear pattern of labelling in ion fragments of m/z 210 and 211 that was absent at m/z of 196 and 197 (Fig. 4). Low abundances of ions corresponding to C-10 to C-12 of the fatty acid moiety did not permit discrimination between singly- and doubly-labelled ion fragments. Thus, the DMOX spectrum in Fig. 4 clearly indicates a label located on C-9 of VA. Furthermore, the relative abundance of ions at m/z 264, 265 and 266 also suggests additional enrichment at C-13, which would have arisen from reduction of the labelled VA precursor. Comparison of the ratio of ions at m/z 211/210 and 265/264 is consistent with this conclusion.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Eckburg et al., 2005), and the presence of an additional route of RA synthesis via a HFA in the human intestine (Devillard et al., 2007), the final labelling patterns of CLA isomers formed by the two ecosystems are similar.
Evidence of CLA formation by intestinal bacteria was first obtained indirectly in the experiments of Chin et al. (1994), who noted that germ-free rats had a lower incorporation of CLA in liver, lung, kidney, skeletal muscle and abdominal adipose tissue than conventional animals. Kamlage et al. (1999, 2000) measured the ability of faecal suspensions to produce CLA from LA, but did not identify the structure of CLA isomers formed. This study provides unequivocal evidence that RA is the main CLA produced during LA metabolism by the human intestinal microbiota, with lower amounts of trans-9,trans-11-CLA also being formed. Other isomers, including trans-10,cis-12-CLA, were only minor products. This is a significant finding, since the anti-proliferative and anti-inflammatory properties of RA are well established (Ha et al., 1987; Pariza, 2004; Wahle et al., 2004; Bauman et al., 2005), while the physiological effects of trans-10,cis-12-CLA on gut health are potentially less beneficial (Kritchevsky, 2000; Pariza, 2004). Far fewer data are available on the role of trans-9,trans-11-CLA, but in vitro studies with various human cell lines point towards this isomer exhibiting activity similar to or higher than RA (Coakley et al., 2006).
CLA formation has been studied in three other groups of bacteria, namely ruminal bacteria, lactic acid producers predominantly from dairy products, and Propionibacterium acnes. RA, trans-9,trans-11-CLA and trans-10,cis-12-CLA were the major CLA intermediates formed from LA in ruminal digesta, with traces of trans-9,cis-11-CLA, cis-9,cis-11-CLA and cis-10,cis-12-CLA (Wallace et al., 2007). In contrast, trans-10,cis-12-CLA was formed in only trace quantities by the human intestinal microbiota. In the rumen, the ratio of isomers formed seems to depend on pH (Choi et al., 2005), possibly because different bacterial species producing various isomers have specific ranges in pH for optimal growth. It is possible that this may also hold true for bacteria in the human intestine. The CLA isomers formed by human intestinal bacteria contrast even more with those produced during LA metabolism by Lactobacillus plantarum and related species, where trans-9,trans-11-CLA is often the most abundant isomer formed (Ogawa et al., 2001, 2005). P. acnes, by contrast, produces only trans-10,cis-12 CLA (Liavonchanka et al., 2006). The formation of CLA by P. freudenreichii subsp. shermanii reported here appears to be unique thus far, in that both 9,11 and 10,12 geometric isomers are formed, indicating that the two mechanisms of CLA formation are not mutually exclusive. It would be important to understand the regulation of both synthetic pathways in the same organism.
Mass spectrometric analysis indicated that a deuterium atom from deuterated water was incorporated into C-13 of RA and trans-9,trans-11-CLA in both mixed human microbiota and pure cultures. Bacteria that converted LA to VA had a labelling pattern suggesting that this was derived via the reduction of a C-13-labelled RA intermediate. Concentrations of trans-10,cis-12-CLA were too low in the mixed microbiota to make an assessment of labelling, but data from incubations of LA with pure cultures indicated that the labelling of trans-10,cis-12-CLA was much lower compared with RA. This is a pattern that has been observed previously in pure and mixed cultures of ruminal bacteria (Kepler et al., 1971; Wallace et al., 2007).
The labelling pattern provides an indication of the enzymic mechanism of CLA formation. CLA could be formed by a direct isomerization (Liavonchanka et al., 2006), a hydration/dehydration mechanism (Ogawa et al., 2001, 2005), or a hydrogen-abstraction mechanism involving a radical intermediate (Wallace et al., 2007). From the data presented here and from elsewhere (Liavonchanka et al., 2006; Wallace et al., 2007), it seems clear that 10,12 CLA isomers are formed by an isomerase mechanism that does not involve proton exchange with water. The mechanism of RA formation remains uncertain, however. Our original interpretation of the labelling pattern from ruminal bacteria (Wallace et al., 2007), which is very similar to that found here with human intestinal bacteria, was that RA synthesis proceeded with no hydroxy intermediate, resulting in labelling on C-13 (Fig. 5A). The fatty acid that we considered the most likely intermediate of a hydration/dehydration mechanism, ricinoleic acid (12-OH-18 : 1), was not converted to RA in the rumen. A hydrogen-abstraction mechanism with a radical intermediate was therefore proposed (Wallace et al., 2007). That the same pattern occurs in the mixed intestinal microbiota, where some species form 10-OH-18 : 1 that in turn other species convert to RA, is consistent with two possible interpretations. One is that the direct mechanism predominated over the cross-species hydration/dehydration one, with the latter being undetectable. The other is that the 10-OH-18 : 1 is metabolized also by a hydrogen-abstraction mechanism (Fig. 5B). Indeed, it is tempting to speculate that, in those species that form RA and/or VA, 10-OH-18 : 1 is a transient intermediate that has not yet been detected. Thus, the unlikely scenario that some species of Roseburia metabolize LA by one route (the ‘direct’ route to RA then VA), while others metabolize LA by another (to 10-OH-18 : 1) (Devillard et al., 2007), would no longer be required. In the latter case, all Roseburia spp. would form 10-OH-18 : 1, with only some species continuing the metabolism further by the rearrangement mechanism. However, the finding that VA-producing species do not metabolize 10-OH-18 : 1 to RA or VA tends to favour the former interpretation, of a predominant direct mechanism.
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) but not the latter species (Devillard et al., 2007). Whether this indicates that the systems are fundamentally different, or only that L. plantarum has additional enzymic potential to metabolize ricinoleic acid to another precursor of CLA formation, is unclear at this stage. It is concluded that, even though the microbial species responsible for LA metabolism in the human intestine and the rumen are significantly different, and more than one route for RA synthesis is known in the former, the predominant mechanisms of CLA and VA formation in the two gut ecosystems are similar. RA formation in both ecosystems may involve the action of radical enzymes that abstract H atoms from the conjugated double bond system.
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ACKNOWLEDGEMENTS |
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Edited by: D. M. Gordon
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Received 4 August 2008;
revised 2 October 2008;
accepted 6 October 2008.
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