We therefore wondered whether intestinal myeloid cells might be a key player in mediating the beneficial CLA effect on systemic immune responses. Based on these findings we evaluated whether CLA might directly enhance anti-inflammatory and suppressive properties of myeloid cells.

First, we determined CLA-induced changes in pro- and anti-inflammatory gene expression patterns in unstimulated isolated murine splenic myeloid cells by RT 2 profiler array and observed differential gene expression upon CLA exposure 50 µM cis - 9 , trans and 50 µM trans , cis isomer as depicted in Fig.

Downregulated genes comprised pro-inflammatory markers, such as Nos2 iNos , Ccr2 Cd , Ifng and Il6 , whereas significantly upregulated genes included the anti-inflammatory cytokine Il10 Fig. Accordingly, quantification of key cytokines and chemokines in supernatants of CLA-exposed unstimulated bone-marrow-derived myeloid cells BMM revealed that IL10 secretion was significantly enhanced upon CLA exposure, whereas secretion of IFNγ and CCL2 MCP-1 was significantly reduced Fig.

Moreover, CLA altered the oxidative capacities of myeloid cells, as the production rate of reactive oxygen species was significantly reduced by CLA treatment, whereas levels of the reactive oxygen species scavenger glutathione were increased Fig.

Analysis of the mitochondrial respiratory capacity of myeloid cells by real-time measurement of the oxygen consumption rate revealed a highly significant reduction of both basal as well as maximal respiration by CLA Fig.

Overall, these data indicate that CLA inhibited a range of pro-inflammatory functions of myeloid cells and enhanced the production of the anti-inflammatory cytokine IL10, which all represent common features of MDSC-like cells.

CLA treatment enhances anti-inflammatory and suppressive features of myeloid cells in vitro. B — G BMMs were differentiated without or with 50 µM CLA-mix over 7 days.

At least three independent experiments were performed for each readout. B Concentrations of secreted cytokines in cell supernatants were assessed by ELISA. Dotted lines indicate the detection limit. E and F Real-time measurement of oxygen consumption rate OCR in BMMs is shown as E graph of one example oxygen consumption rate measurement as well as F dot plots of basal and maximal respiration of one example experiment out of three independent experiments with in total six mice, whereas one dot represents one technical replicate.

Dot plots depict mean ± SD. Taken together, we were able to demonstrate that CLA exerts direct effects on myeloid cells, limiting their pro-inflammatory capacities and promoting suppressive functions of these cells. Based on our data generated in the murine system, we next aimed to address whether CLA might also exert anti-inflammatory effects on human myeloid cells.

As depicted in Fig. In particular, CLA exposure elicited a transcriptional signature known to be associated with a myeloid suppressive phenotype, i.

downregulation of genes involved in T-cell activation, antigen presentation, interferon- and TNF-signalling as well as genes for pro-inflammatory cytokines and chemokines [namely CCL3 MIP1A , CXCL10 IP , IL1B , IL18 ], whereas anti-inflammatory genes [ IL4I1 FIG1 , MMP9 , PPARG ] were upregulated.

Dietary CLA supplementation in multiple sclerosis patients alters blood myeloid cell composition by enhancing anti-inflammatory and suppressive subsets and functional properties.

B Study design of proof-of-concept trial CLAiMS is shown. C — G Frozen PBMC of study subjects at baseline BL and 6 months 6M after CLA supplementation as depicted in B , were stained with monocyte-specific antibodies and analysed by multi-colour flow cytometry.

Significantly upregulated clusters are depicted in orange and downregulated clusters are displayed in blue. Clusters with a high continuous line and low dotted line cytokine expression profile CCL2, IFNγ, IL1β, IL6, IL8 are highlighted. Each dot represents one individual patient at baseline or 6 months; in E — G only, dots belonging to the same patient are connected by a line.

This encouraged us to perform a small open-label proof-of-concept study in 15 stable RRMS patients to investigate the immunomodulatory effects of standardized dietary CLA supplementation as an add-on to their first-line disease-modifying treatment for 6 months study design in Fig.

A detailed analysis of monocyte signatures by an unbiased single-cell dimensionality reduction approach confirmed that inflammatory cytokine-producing monocyte clusters were already significantly downregulated in an unstimulated state after 6 months of CLA supplementation Fig.

Upon monocyte stimulation, we found significantly upregulated clusters lacking pro-inflammatory signatures on CLA supplementation Fig. In particular, dietary CLA supplementation also led to a reduction of IL1B , IL18 and HLA-DR expression.

Taken together, dietary CLA supplementation in RRMS patients results in broad changes within the monocyte compartment with a downmodulation of pro-inflammatory subsets and functional properties, accompanied by an increase in anti-inflammatory subsets and functions.

Here, we report that dietary supplementation with CLA exerts strong protective effects in a spontaneous mouse model of CNS autoimmunity. This was accompanied by a reduction of intestinal inflammation and a notable shift within the intestinal myeloid cell population with a decrease in mature macrophages and a concomitant increase in myeloid suppressor-like cells, suggesting a key role of local innate immune regulation for CLA-mediated beneficial effects on CNS autoimmunity.

In recent years, the relevance of local immune modulation within the intestine for shaping a variety of autoimmune diseases, including CNS autoimmunity, has been highlighted by experimental studies, some of which addressed the gut—CNS axis.

However, it should be noted that CLA supplementation in our mouse model was started in utero by feeding the mothers. In light of the central role of the gut microbiota, especially during development of the immune system, an indirect modulation of intestinal myeloid cells by the microbiota early in life cannot be excluded by our approach.

Notably, some of the observed alterations of myeloid cells in vitro are hallmarks of MDSCs, and accordingly, we observed a significant increase in MDSC-like cells in the intestine of OSE CLA mice, which suggests that dietary CLA supplementation might at least partly act via induction of myeloid cells with suppressive properties.

Moreover, there was no significant difference in the frequencies of MSDC-like cells in the bone marrow of OSE CLA mice Supplementary Fig.

It has been shown that targeted induction of MDSC-like cells alleviates intestinal 70 and rheumatoid inflammation, 71 , 72 as well as experimental autoimmune myasthenia gravis. In the field of cancer research, where the role of MDSCs for suppression of anti-tumour immune responses has been well-established, dietary effects on MDSC frequencies or function have already been described.

A high salt diet, for example, inhibits tumour growth by blocking MDSC functions in several tumour models. Dietary CLA supplementation has already been shown to exert beneficial effects in the context of experimental inflammation-induced colorectal cancer 79 and inflammatory bowel disease.

All these studies are well in line with our findings: First, they underline that dietary CLA supplementation ameliorates intestinal inflammation, and we now extend these findings by providing evidence that this mechanism might be relevant for the control of CNS autoimmunity.

This is of particular interest since intestinal barrier disruption and inflammation have already been linked to experimental CNS autoimmunity and more recently to multiple sclerosis.

Second, they provide further evidence that dietary CLA supplementation can promote the anti-inflammatory properties of myeloid cells in various organs.

In light of this pilot study, we decided to perform a proof-of-concept trial of dietary CLA supplementation in 15 patients with RRMS to evaluate whether we can replicate some of our key immunological findings from our preclinical dataset in humans.

Notably, we observed changes within the peripheral blood myeloid cell compartment with a relative increase in anti-inflammatory subsets and a decrease in pro-inflammatory cell subsets. Furthermore, the cytokine profile of monocytes from CLA-treated patients was substantially altered, and CLA supplementation also modulated the metabolic properties of monocytes by interfering with mitochondrial respiration, suggesting that CLA interferes with the metabolic reprogramming necessary for full activation as has been shown for other anti-inflammatory approaches.

Although the precise site of action of this myeloid cell-mediated modulation of adaptive immune responses is not clear, several previous studies support the hypothesis of a peripheral immune regulation by these cells, 48 , 89 which is in line with our results from animal experiments.

While we did not observe significant changes in CNS-located myeloid cell subset composition within the CNS of OSE CLA mice Supplementary Fig. The size of our pilot trial precludes any reliable conclusions with regard to the clinical efficacy of dietary CLA supplementation in multiple sclerosis patients, and this definitely needs to be explored in a larger randomized and placebo-controlled trial, ideally using a classical MRI-based end point as an established surrogate marker of disease activity in RRMS.

In our opinion, the performance of such a trial is feasible, in particular considering our pilot data demonstrating high tolerability and treatment adherence over 6 months. Furthermore, we did not observe any clinical relapses in those patients adhering to the combination of CLA supplementation and first-line immune modulatory treatment of multiple sclerosis.

Especially in light of the still unsolved problems of treatment adherence as well as side-effects of immunomodulatory treatment, complementary treatment via targeted dietary modification represents a highly attractive therapeutic approach in the multiple sclerosis treatment landscape and putatively also in other autoimmune diseases with a key role of the intestinal immune system in immune dys regulation, such as systemic lupus erythematosus, inflammatory bowel disease and rheumatoid arthritis.

Taken together, our study provides evidence that dietary CLA supplementation is a promising novel strategy for the control of CNS autoimmunity as a complementary approach to conventional treatment. Future studies, especially with regard to targeted dietary intervention in RRMS patients, are warranted to characterize the therapeutic potential of this novel approach in humans.

We thank Annika Engbers, Andrea Pabst, Claudia Kemming, Elke Hoffmann, Luzia Buchholz, Janine Meyer and Maj Lisa Frankenberg for excellent technical support. This study was supported by the German Research Foundation DFG grant number CRC SFB TR A08 to L.

and D. and C. and T. and L. as well as HE to L. and P. received support from the DFG SFB C2 and the RU P3. and M. received travel support from Novartis.

received speaker honoraria and travel support from Sanofi Genzyme. received travel support from Biogen. received research funding support from Biogen and honoraria from Sanofi, Esai, and Genzyme.

received research funding from the German Cancer Aid Deutsche Krebshilfe , German Research Foundation DFG , Innovative Medical Research program Medical Faculty, University of Münster , Wilhelm Sander-Stiftung, Maria Möller Stiftung, and NanoString. He received compensation for serving on scientific advisory boards for Bristol-Myers Squib and Novartis.

receives research support from the German Research Foundation DFG and the European Union. She received speaker honoraria from MyLan, Bayer Health Care and Genzyme and travel expenses for attending meetings from Biogen, Euroimmun, Genzyme, MyLan, Novartis Pharma GmbH and Bayer Health Care.

received research funding from the German Research Foundation, Interdisciplinary Center for Clinical Studies IZKF Münster, National MS Society, European Leukodystrophy Association, Progressive MS Alliance, European Commission HMSCA-ITN and Novartis.

She received compensation for serving on scientific advisory boards Frequency Therapeutics, Inc. and speaker honoraria from Novartis. received honoraria for acting as a member of Scientific Advisory Boards for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG and Sanofi-Aventis as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F.

Hoffmann-La Roche Ltd. received compensation for serving on Scientific Advisory Boards for Alexion, Genzyme, Janssen, Merck Serono, Novartis and Roche. She received speaker honoraria and travel support from Bayer, Biogen, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva.

She receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Novartis and Merck Serono. Supplementary material is available at Brain online.

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Willebrand R , Hamad I , Van Zeebroeck L , et al. For example, 10trans,12cis-CLA is involved in catabolic processes such as lipolysis and fat oxidation, whereas 9cis,11trans-CLA seems to be the active anabolic agent.

In addition, based on the evidence, 10trans,12cis-CLA is thought to be anticarcinogenic, antiobesity, and antidiabetic, whereas 9cis,11trans-CLA is mainly anti-inflammatory CLA is formed via biohydrogenation by bacterial enzymes known as catalyst, present in the intestine microbiota of ruminant mammals; hence, CLA is mainly found in their flesh and milk Nonetheless, it is present in foods only in finite amounts; therefore, commercialized CLA supplements have been provided to offer potential benefits, such as reduction of body weight and total fat mass, anticancer effects including reducing tumor growth 15 , 16 , reducing insulin resistance, lipid disorders, and oxidative stress, improving liver function in nonalcoholic fatty liver 17 , and immunomodulatory effects 18 — A large number of studies have investigated the effect of CLA supplementation on inflammatory cytokines and adipokines.

However, the results of these studies are contradictory. For instance, some studies have reported that CLA supplementation had no significant effect on leptin levels 21 , 22 , whereas others found a significant decrease in serum leptin during CLA supplementation 23 , CLA supplementation has even been shown to significantly increase serum leptin levels Also, some studies have reported that CLA supplements lead to a decrease in adiponectin levels 26 , while another study has reported that CLA supplements have little or no effect on adiponectin levels However, Sneddon et al.

Furthermore, while one study has found that CLA supplementation may increase CRP and tumor necrosis factor-alpha TNF-α and marginally decrease interleukin-6 IL-6 , indicating a proinflammatory state 29 , 30 , a recent review article suggests that CLA may have an anti-inflammatory effect by reducing inflammatory mediators such as cytokines, particularly IL-6, TNF-α, IFN-γ, and IL-1β Therefore, due to the inconsistencies in previous studies, the present study sought to update previous meta-analyses in light of the plethora of new studies.

Thus, the current meta-analysis sought to investigate the effects of CLA on inflammatory cytokines and adipokines in adults. This systematic review has been conducted according to the PRISMA statement The present study was registered at PROSPERO CRD There were no restrictions on the length of time or language of publications.

By reading the titles, abstracts, and full text of the papers as needed, two researchers independently FS and OA chose the appropriate articles. The effects of CLA supplementation on inflammatory cytokines and adipokines variables in adults with different health statuses in all human randomized clinical trials RCTs.

The searches were limited to human studies with no language restrictions. Animal studies, reviews, in vitro research, research on kids and teenagers, grey literature, conference abstracts, opinion pieces, books, and RCTs without a placebo or control group were excluded.

Studies that used CLA in combination with vitamins or minerals were also excluded. In the present study, we searched for studies that assessed the effects of CLA supplementation on all inflammatory cytokines. After screening and finding eligible studies, we found that most studies evaluated CRP, IL-6, and TNF.

In addition, a limited number of studies have evaluated other inflammatory factors such as IL-1 and IL Therefore, we included studies that evaluated the effects of CLA on CRP, IL-6, and TNF.

After quickly skimming the titles, abstracts, and full text to choose the most pertinent research following a separate review of each qualifying RCT, the following data were gleaned by two independent researchers OA and FS. Name of the first author, country of origin, year of publication, type of clinical trial, participant characteristics mean age, body mass index BMI , sex , randomization, blinding, sample size, number of participants in the intervention and control groups, type and dosage of supplemented CLA, duration of the study, and related data were extracted for additional measurements.

The CLA dosages were converted to milligrams per day, whether they were given in grams per day or another unit. To rate the quality of the studies, the Cochrane Collaboration technique was utilized Two researchers SR and GS independently assessed the methods, and any disagreements between their assessments were resolved through discussion.

Each study was evaluated for any bias, including those caused by randomized sequence generation, allocation concealment, participant and staff blindness, outcome assessor blindness, insufficient outcome data, selective reporting, and other biases.

Stata The pooled weighted mean difference WMD was calculated using a random-effects model to take into account any existing heterogeneity due to the different intervention doses, duration, participant health, sample sizes, and length of intervention developed by Der Simonian and Laird We computed the mean differences in CRP, IL-6, TNF-α, adiponectin, and leptin between the CLA supplementation and control groups from the preintervention to the postintervention.

Other subgroup analyses were performed according to gender man, woman , baseline BMI normal We used the leave-one-out approach to do a sensitivity analysis to identify how many inferences were dependent on a single sample to examine the influence of each study on the pooled effect size The flow chart presented in Figure 1 describes the selection process and the references retrieved from the database.

Figure 1 Flow chart of study selection for inclusion trials in the systematic review. Out of studies, 62 did not have the desired data. Finally, 42 studies 11 , 12 , 16 , 18 , 19 , 27 , 28 , 42 — 76 were included in the present meta-analysis, and their characteristics are illustrated in Table 1.

The risk of bias assessment is summarized in Table 2. All of these studies were RCTs published between and Study design characteristics are presented in Table 1. The two studies were conducted in the USA 42 , 67 , three in Sweden 43 , 45 , 49 , three in the Netherlands 44 , 52 , 65 , four in Canada 12 , 14 , 46 , 68 , two in Norway 27 , 47 , four in the UK 28 , 48 , 51 , 56 , two in France 50 , 53 , two in Turkey 11 , 72 , one in Japan 55 , one in Ireland 57 , one in Korean 58 , one in Finland 59 , one in Denmark 61 , one in China 62 , three in Germany 62 , 69 , 70 , one in Italy 64 , one in Spain 16 , one in Poland 75 , and the others in Iran 18 , 19 , 60 , 66 , 71 , 73 , 74 , Thirteen studies included only men and seven women, and 22 included both sexes.

The duration of the intervention varied from 4 to weeks. The CLA supplements were used in doses of 1. The mean age and baseline BMI ranged from 20 to Iwata et al. used two different CLA doses in their studies.

Out of the 42 studies, CRP, IL-6, TNF-α, adiponectin, and leptin were reported in 20, 15, 16, 12, and 20, respectively. For supplementation, 47 study arms used mixed isomers 9cis,11trans-CLA and 10trans,12cis-CLA , four study arms used 9cis,11trans-CLA isomer, and five study arms used 10trans,12cis-CLA isomer.

In these studies, detection methods of CRP were Behring latex-enhanced high-sensitivity assays, Eckman Synchron CX7 System, enzyme-linked immunosorbent assay, enhanced turbidimetric immunoassay, highly sensitive immunoassay with a monoclonal antibody coated with polystyrene particles, immunoturbidimetric assay, and rabbit antihuman.

Diamonds represent pooled estimates from random-effects analysis. WMD, weighted mean difference; CI, confidence interval; CLA, conjugated linoleic acid; CRP, C-reactive protein; IL-6, interleukin 6; TNF-α, tumor necrosis factor-alpha.

Overall, 24 effect sizes from 20 studies for CRP were included in the analysis. In the other subgroups, the effect of CLA supplementation on serum concentrations of CRP was not significant Table 3.

Table 3 Subgroup analyses of CLA supplementation on inflammatory cytokines and adipokines. In the other subgroups, the effect of CLA supplementation on serum concentrations of IL-6 was not significant Table 3. In the other subgroups, the effect of CLA supplementation on serum concentrations of TNF-α was not significant Table 3.

The present study conducted a nonlinear dose—response regression to analyze the dose—response relationship between CLA supplementation and inflammatory cytokines and adipokines.

Meta-regression analyses were performed to assess whether inflammatory cytokines and adipokines were affected by CLA supplementation doses and intervention duration.

WMD, weighted mean difference; CI, confidence interval; CRP, C-reactive protein; IL-6, interleukin 6; TNF-α, tumor necrosis factor-alpha. The sensitivity analysis demonstrated that no study had a significant impact on the overall findings. Although the overall result of studies reporting data on TNF-α was sensitive to the study by Song et al.

In the case of CRP, some studies had an impact on the overall effect size, including that of Whigham et al. It was shown that the exclusion of every individual study by the sensitivity analysis could not change the direction of the correlation but eliminated the significant effect of CLA on CRP.

Table 4 displays the Grading of Recommendations Assessment, Development, and Evaluation GRADE profile of CLA supplementation on inflammatory cytokine and adipokine variables together with the certainty in outcomes. For CRP, because of serious limitations in inconsistency, the quality of evidence was moderate.

In the case of IL-6, because of very serious limitations in inconsistency and for TNF-α because of very serious limitations in inconsistency ad serious limitations for publication bias, the quality of evidence was low.

For both outcomes, including leptin and adiponectin, because of very serious limitations in inconsistency and serious limitations in imprecision, the quality of evidence was very low.

Table 4 GRADE profile of CLA supplementation for inflammatory cytokines and adipokines. Using the GRADE methodology, which was previously outlined, the total degree of evidence certainty across the studies was evaluated and summarized In this review, an analysis of pooling 42 studies indicated that CLA supplementation increased CRP concentrations, decreased IL-6 and TNF-α values, and had no effect on adiponectin and leptin levels.

Taking CLA decreased IL-6 in male individuals and unhealthy subjects if the trial duration was less than 12 weeks and when a mixture of two isomers was used. However, in subgroup analyses based on isomer type, 10trans12cis- CLA isomer significantly increased TNF-α.

Supplementation with CLA reduced adiponectin in women. It also decreased leptin in women and unhealthy adults but increased in those with normal baseline BMI. Moreover, the results of the meta-regression analysis showed that there was no significant linear association between intervention doses and duration of supplementation with inflammatory cytokines and adipokines.

The majority of studies included in this meta-analysis used supplements consisting of mixed amounts of CLA isomers. Therefore, since CLA isomers have shown different effects on inflammation 30 , 78 , it is suggested that this issue be considered in research.

It is also important to consider the contents of the placebo used in studies. Some included RCTs have used vegetable oils as a placebo, such as safflower and olive oils.

One study has indicated the reduced effect of safflower oil on CRP levels compared to CLA Another study has elucidated the anti-inflammatory effect of olive oils through the prevention of lipooxygenase and enzymes that synthesize leukotriene In other words, prescribing these vegetable oils as a placebo might misinterpret results.

Diet and physical activity can play an important role in inflammatory conditions It is better to consider the effects of these two factors in the result of the present meta-analysis. Although, in some studies, the confounding variables of physical activity and diet were controlled, in some trials, these factors were not considered.

Diet is an important regulatory factor in the immune response. Malnutrition leads to suppression of the immune system, whereas overnutrition leads to immune activation. Some foods have anti-inflammatory effects, and there are still controversies about others Also, a high-fat diet causes excessive body fat accumulation and impairs the immune system.

On the other hand, it has been reported that trans and saturated fatty acids are significantly associated with the inflammatory state Although ruminant trans fatty acids have different effects than industrial trans fatty acids, several studies show that industrial trans fatty acids promote inflammation, whereas ruminant trans fatty acids have been reported to be harmless or even beneficial to health, as well as also having anti-inflammatory properties One study reported that sedentary subjects had higher levels of inflammatory factors such as IL-6 and TNF-α compared to subjects with higher physical activity Other confounding factors that can affect inflammatory markers are sleep duration and sleep quality.

In addition, a study on healthy subjects reported that higher IL-6 levels were associated with lower sleep quality Here, we showed CLA consumption increased CRP concentrations, decreased IL-6 and TNF-α, and did not change adiponectin and leptin levels.

There are some meta-analyses that have investigated the effect of CLA on the abovementioned markers. For example, Derakhshandeh-Rishehri et al. A meta-analysis conducted by Haghighatdoost et al.

Another meta-analysis conducted on 19 RCTs demonstrated that CLA intake had a small but not significant decline in plasma leptin. However, it significantly decreased leptin in obese individuals, with trials lasting for less than 24 weeks A study carried out by Mazidi et al.

By combining previous and current results, it can be acknowledged that except for the effect of CLA in increasing CRP levels, there is no consensus on other markers i. Moreover, it is noteworthy to state that exercise, dietary intake, sleep duration, and sleep quality can alter the effects of CLA.

Therefore, further well-designed studies may clarify the role of CLA on the abovementioned markers. In the present study, the gender-dependent impact of CLA has also been shown in the reduction of IL-6, TNF-α, adiponectin, and leptin.

Based on evidence, CLA can induce testosterone biosynthesis 91 , and subsequently, testosterone is able to decrease IL-6 expression It has also been stated that circulating CLA concentrations are greater in women than in men Therefore, the aforementioned evidence can justify the different effects seen between men IL-6 and TNF-α reduction and women adiponectin and leptin reduction after taking CLA.

The effect of CLA on inflammatory responses has generated inconsistent results. This may be due to isomers and tissue-specific responses of CLA.

Moreover, across the included RCTs, administration doses of CLA varied from 1. Health characteristics, inflammation status, and even gut microbiome composition of the recruited individuals were also different These variations in the studies can influence the results and interpretations. For example, in relation to isomer and tissue-specific response, 9cis,11trans-CLA isomer exerts its anti-inflammatory effect by activating the peroxisome proliferator-activated receptor-γ PPAR-γ -dependent pathway and ultimately reducing the production of proinflammatory cytokines such as TNF-α and IL-6 However, the 10trans,12cis-CLA isomer has been reported to have a proinflammatory effect in adipose tissue, in contrast to its effects on innate immunity and vascular cells.

In addition, in adipose tissue, activation of PPAR­γ is contrary to the physiological effects of 10trans,12cis-CLA in vitro and in vivo This isomer downregulates PPAR-γ gene expression and increases TNF-α, IL-6, and CRP production in adipose tissue 78 , It seems that the reason for this inconsistency is cytokines secreted from adipocytes, which in turn alter PPAR­γ expression and activity in the fat cell.

Therefore, inconclusive results regarding the anti-inflammatory properties of CLA are likely due to the subtle proinflammatory effects of the 10trans,12cis-CLA isomers in specific tissues 30 , Overall, it appears that CLA can elicit both anti-inflammatory and proinflammatory features.

Some proposed mechanisms for the effects of CLA isomers on inflammation include the following: 1 Modulation of eicosanoid signaling. This means that CLA reduces the production of inflammatory eicosanoids derived from arachidonic acid AA through the inhibition of several steps in the AA cascade.

Also, it suppresses the expression of the inducible NO synthase iNOS gene, which leads to a decrease in IL-6 production. This meta-analysis has some limitations that should be addressed. Most of the included studies had a relatively small sample size, which can cause an overestimation of the results.

Observation of publication bias for TNF-α findings suggests overestimation of CLA efficiency on TNF-α. Moreover, TNF-α, IL-6, and CRP results were sensitive to some studies.

In conclusion, it is suggested that CLA supplementation can have both proinflammatory and anti-inflammatory roles. It can enhance CRP concentrations while reducing TNF-α and IL-6 levels.

Furthermore, CLA is able to decrease adiponectin and leptin in women. It can also decrease leptin in unhealthy adults and increase it in subjects with a normal baseline BMI. Finally, in order to improve the quality of studies, future clinical trials are encouraged to carefully consider CLA-isomer-specific regulation of inflammatory markers and take notice of the contents of the placebo used in their control groups.

It is also important to keep in mind the gender-dependent impact of CLA. Further inquiries can be directed to the corresponding authors. OA and SR contributed to the conception and design of the study.

DA-L, MZ, and GS contributed to data extraction. FS and AK screened articles for inclusion criteria. OA contributed to the data analysis. SR, MY, and EG contributed to manuscript drafting, OA and MZ supervised the study. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Asbaghi O, Ashtary-Larky D, Bagheri R, Moosavian SP, Nazarian B, Afrisham R, et al.

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Correspondence to H M Roche. Contributors : APN analysed the data and wrote the paper. HMR, EJN, AL, DKK and MJG provided consultation on the interpretation of the results and commented on the paper.

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nature european journal of clinical nutrition original communication article. Abstract Objective: To assess the effects of dietary supplementation using two isomeric blends of conjugated linoleic acid CLA on immune function in healthy human volunteers.

Design: Double-blind, randomised, placebo-controlled intervention trial. hyperplasia and mucosal follicle formation, and the extent of inflammatory cell infiltration in the lamina propria or submucosa were rated from 0 none to 5 extensive pathological changes.

Mononuclear cells were isolated from CNS, blood, bone marrow, and inguinal lymph nodes as previously described. All antibodies, if not otherwise stated were obtained from BioLegend. Surface marker staining using antibodies against murine CD3 clone: 17A2 , CD4 clone: GK1. The acquisition was performed with the flow cytometer Gallios Beckman Coulter.

Results were analysed with FlowJo software BD Life Science. Faecal samples were dissolved in µl PBS containing 0. After centrifugation, total protein content was measured in the supernatant by the colourimetric DC Protein Assay Kit Bio-Rad with bovine serum albumin as standard.

The concentration of IgM in faecal lysates was assessed with the Ready-Set-Go! The 16S rDNA gene variable region V3 of the extracted faecal DNA was amplified and sequenced with the MiSeq Reagent Kit v2 Illumina at the Institute for Hygiene, Münster.

The Illumina reads obtained were analysed with the mother software package v1. Bacterial sequences were then classified into operational taxonomic units; the relative abundance and Bray-Curtis distance-based principal coordinates analysis were visualized with phyloseq v1.

For in vitro experiments, murine myeloid cells were treated without and with CLA-mix containing 50 µM cis-9 , trans CLA-isomer and 50 µM trans , cis CLA-isomer Sigma-Aldrich. RNA was isolated using the RNeasy ® Micro Kit Qiagen and cDNA synthesis was performed from ng total RNA using RT 2 FirstStrand Kit Qiagen.

Bone marrow-derived macrophages BMMs were generated as previously described 45 and treated with CLA-mix during a differentiation period of 7 days.

Cytokine concentrations were measured in the supernatant of mature BMMs after 72 h IFNγ and CCL2 and 96 h IL10 using Ready-Set-Go! For analysis of intracellular glutathione levels, BMMs were stained with monochlorobimane mBCI, 50 μM; Invitrogen at 37°C for 30 min.

Intracellular reactive oxygen species production was measured in living BMMs using dihydroethidium fluorescence measurements according to a protocol outlined in Kovac et al. To measure the metabolic activity, mature BMMs were harvested, seeded to poly- d -lysine-coated Seahorse plates, and incubated overnight at 37°C.

As described in Klotz et al. The suppression assay was performed according to Hucke et al. Blood sampling of treatment-naïve RRMS patients diagnosed according to the current McDonald criteria was approved by the local ethics committee of the Westfälische Wilhelms-Universität Münster f-S.

The study protocol for the proof-of-concept study CLAiMS was approved by the ethics committee of the Ärztekammer Westfalen-Lippe and the Westfälische Wilhelms-Universität Münster f-S, approved on All participants provided written informed consent for the planned procedures prior to entry into the study, in accordance with the Declaration of Helsinki.

Around 40 ml blood was obtained from treatment-naïve RRMS patients or patients participating in the proof-of-concept trial CLAiMS via vein puncture and collected into S-Monovette ® syringes containing EDTA Sarstedt. Peripheral blood mononuclear cells PBMCs were isolated immediately from the fresh blood by Lymphoprep TM Stemcell Technologies density gradient centrifugation as described in Klotz et al.

Patients were included in the clinical study at the Department of Neurology with the Institute of Translational Neurology at University Hospital Münster according to the inclusion and exclusion criteria listed in Supplementary Table 1. The study cohort consisted of 15 RRMS patients meeting the current McDonald criteria.

Only patients without relapses within the last 3 months and a stable first-line immunomodulatory medication for at least 3 months were included. Study subjects were predominantly female Demographics for all patients from our clinical trial including baseline disease characteristics are described in Supplementary Table 2.

Daily dietary supplementation with 2. For data analysis, all patients were included. PBMCs were analysed by multicolour flow cytometry and monocyte subsets were identified using the following markers as defined by Mukherjee et al.

For intracellular staining of IFNγ clone: 4S. No: L for 2 h. Dead cells were discriminated using Zombie NIR TM BioLegend. Flow cytometric measurement was performed with Navios or CytoFLEX both Beckman Coulter.

Data were analysed using Kaluza software Beckman Coulter. In addition, unbiased data analysis was performed by a dimensionality reduction approach, as described previously. The phenograph algorithm was applied to identify local phenotypic similarities.

Overnight resting and oxygen consumption rate measurement were performed as described above for murine cells, but assessment was perfomed with the Seahorse XFe96 Extracellular Flux Analyzer Agilent Technologies. Measurement of the nCounter ® Human Myeloid Innate Immunity Panel was performed with the nCounter ® FLEX Dx NanoString Technologies at the Division of Translational Pathology, Münster.

Quality control, normalization, and differential expression analysis were performed with nSolver Analysis Software 4. Undetectable genes were excluded from further analysis.

Adjustment of P- values was performed according to the Benjamini-Yekutieli correction. GraphPad Prism 6 software and R version 3. All results illustrated in dot plots are shown as the mean ± standard deviation unless stated otherwise.

Unpaired, two-sided Mann-Whitney U-tests were used as non-parametric tests to compare two groups. Data and full code of all scripts are available upon reasonable request from the corresponding author. There is no restriction on the availability of materials described in the study.

Because of the spontaneous occurrence of disease and independence from any exogenous triggers, this model is particularly suitable for analysis of modifying factors of disease induction. Furthermore, OSE CLA mice exhibited a significant delay in disease onset median onset on Day 30 in OSE CLA mice as compared to Day 24 in OSE ctrl mice; Fig.

This disease amelioration was accompanied by a highly significant reduction in immune cell infiltrates within the spinal cords of OSE CLA mice as illustrated by detailed immune cell quantification of histological specimens from OSE CLA mice compared to OSE ctrl mice Fig.

As dietary modifications have a profound impact on the intestinal immune system, and since organ-specific autoimmune diseases including CNS autoimmunity are affected by intestinal immune responses, 14 we next evaluated the impact of dietary CLA supplementation on the gut.

As described in other mouse models of CNS autoimmunity, 14 , 53 diseased OSE ctrl mice displayed notable immune cell infiltrations in the intestinal lamina propria; however, this was diminished in OSE CLA mice Fig. Quantification of intestinal inflammation Fig.

Enhanced immune cell infiltration is often associated with altered intestinal barrier function, which is accompanied by enhanced levels of the surrogate marker IgM in the faeces.

Analysis of the gut microbiome in CLA-supplemented mice revealed profound changes in overall microbiome composition, as illustrated by principal component analysis and relative abundance of genera Fig.

To investigate whether CLA-mediated effects on EAE disease course depend on the gut microbiome, we temporarily eradicated the gut microbiome by short-term antibiotic treatment of OSE CLA and OSE ctrl mice for 3 days after weaning Days 28—34 after birth.

CLA supplementation reduces intestinal inflammation in OSE mice. Scatter dot plots depict mean ± SD, whereas each dot represents one individual mouse.

Statistics: H two-way ANOVA with Bonferroni correction; B — E and I Mann-Whitney U-test. Taken together, our data illustrate that dietary supplementation with CLA modulates intestinal immune responses with a downmodulation of pro-inflammatory myeloid cells and a concomitant increase in MDSC-like cells.

We therefore wondered whether intestinal myeloid cells might be a key player in mediating the beneficial CLA effect on systemic immune responses. Based on these findings we evaluated whether CLA might directly enhance anti-inflammatory and suppressive properties of myeloid cells.

First, we determined CLA-induced changes in pro- and anti-inflammatory gene expression patterns in unstimulated isolated murine splenic myeloid cells by RT 2 profiler array and observed differential gene expression upon CLA exposure 50 µM cis - 9 , trans and 50 µM trans , cis isomer as depicted in Fig.

Downregulated genes comprised pro-inflammatory markers, such as Nos2 iNos , Ccr2 Cd , Ifng and Il6 , whereas significantly upregulated genes included the anti-inflammatory cytokine Il10 Fig.

Accordingly, quantification of key cytokines and chemokines in supernatants of CLA-exposed unstimulated bone-marrow-derived myeloid cells BMM revealed that IL10 secretion was significantly enhanced upon CLA exposure, whereas secretion of IFNγ and CCL2 MCP-1 was significantly reduced Fig.

Moreover, CLA altered the oxidative capacities of myeloid cells, as the production rate of reactive oxygen species was significantly reduced by CLA treatment, whereas levels of the reactive oxygen species scavenger glutathione were increased Fig.

Analysis of the mitochondrial respiratory capacity of myeloid cells by real-time measurement of the oxygen consumption rate revealed a highly significant reduction of both basal as well as maximal respiration by CLA Fig. Overall, these data indicate that CLA inhibited a range of pro-inflammatory functions of myeloid cells and enhanced the production of the anti-inflammatory cytokine IL10, which all represent common features of MDSC-like cells.

CLA treatment enhances anti-inflammatory and suppressive features of myeloid cells in vitro. B — G BMMs were differentiated without or with 50 µM CLA-mix over 7 days. At least three independent experiments were performed for each readout. B Concentrations of secreted cytokines in cell supernatants were assessed by ELISA.

Dotted lines indicate the detection limit. E and F Real-time measurement of oxygen consumption rate OCR in BMMs is shown as E graph of one example oxygen consumption rate measurement as well as F dot plots of basal and maximal respiration of one example experiment out of three independent experiments with in total six mice, whereas one dot represents one technical replicate.

Dot plots depict mean ± SD. Taken together, we were able to demonstrate that CLA exerts direct effects on myeloid cells, limiting their pro-inflammatory capacities and promoting suppressive functions of these cells. Based on our data generated in the murine system, we next aimed to address whether CLA might also exert anti-inflammatory effects on human myeloid cells.

As depicted in Fig. In particular, CLA exposure elicited a transcriptional signature known to be associated with a myeloid suppressive phenotype, i. downregulation of genes involved in T-cell activation, antigen presentation, interferon- and TNF-signalling as well as genes for pro-inflammatory cytokines and chemokines [namely CCL3 MIP1A , CXCL10 IP , IL1B , IL18 ], whereas anti-inflammatory genes [ IL4I1 FIG1 , MMP9 , PPARG ] were upregulated.

Dietary CLA supplementation in multiple sclerosis patients alters blood myeloid cell composition by enhancing anti-inflammatory and suppressive subsets and functional properties. B Study design of proof-of-concept trial CLAiMS is shown. C — G Frozen PBMC of study subjects at baseline BL and 6 months 6M after CLA supplementation as depicted in B , were stained with monocyte-specific antibodies and analysed by multi-colour flow cytometry.

Significantly upregulated clusters are depicted in orange and downregulated clusters are displayed in blue. Clusters with a high continuous line and low dotted line cytokine expression profile CCL2, IFNγ, IL1β, IL6, IL8 are highlighted. Each dot represents one individual patient at baseline or 6 months; in E — G only, dots belonging to the same patient are connected by a line.

This encouraged us to perform a small open-label proof-of-concept study in 15 stable RRMS patients to investigate the immunomodulatory effects of standardized dietary CLA supplementation as an add-on to their first-line disease-modifying treatment for 6 months study design in Fig.

A detailed analysis of monocyte signatures by an unbiased single-cell dimensionality reduction approach confirmed that inflammatory cytokine-producing monocyte clusters were already significantly downregulated in an unstimulated state after 6 months of CLA supplementation Fig. Upon monocyte stimulation, we found significantly upregulated clusters lacking pro-inflammatory signatures on CLA supplementation Fig.

In particular, dietary CLA supplementation also led to a reduction of IL1B , IL18 and HLA-DR expression. Taken together, dietary CLA supplementation in RRMS patients results in broad changes within the monocyte compartment with a downmodulation of pro-inflammatory subsets and functional properties, accompanied by an increase in anti-inflammatory subsets and functions.

Here, we report that dietary supplementation with CLA exerts strong protective effects in a spontaneous mouse model of CNS autoimmunity. This was accompanied by a reduction of intestinal inflammation and a notable shift within the intestinal myeloid cell population with a decrease in mature macrophages and a concomitant increase in myeloid suppressor-like cells, suggesting a key role of local innate immune regulation for CLA-mediated beneficial effects on CNS autoimmunity.

In recent years, the relevance of local immune modulation within the intestine for shaping a variety of autoimmune diseases, including CNS autoimmunity, has been highlighted by experimental studies, some of which addressed the gut—CNS axis.

However, it should be noted that CLA supplementation in our mouse model was started in utero by feeding the mothers. In light of the central role of the gut microbiota, especially during development of the immune system, an indirect modulation of intestinal myeloid cells by the microbiota early in life cannot be excluded by our approach.

Notably, some of the observed alterations of myeloid cells in vitro are hallmarks of MDSCs, and accordingly, we observed a significant increase in MDSC-like cells in the intestine of OSE CLA mice, which suggests that dietary CLA supplementation might at least partly act via induction of myeloid cells with suppressive properties.

Moreover, there was no significant difference in the frequencies of MSDC-like cells in the bone marrow of OSE CLA mice Supplementary Fig.

It has been shown that targeted induction of MDSC-like cells alleviates intestinal 70 and rheumatoid inflammation, 71 , 72 as well as experimental autoimmune myasthenia gravis. In the field of cancer research, where the role of MDSCs for suppression of anti-tumour immune responses has been well-established, dietary effects on MDSC frequencies or function have already been described.

A high salt diet, for example, inhibits tumour growth by blocking MDSC functions in several tumour models. Dietary CLA supplementation has already been shown to exert beneficial effects in the context of experimental inflammation-induced colorectal cancer 79 and inflammatory bowel disease.

All these studies are well in line with our findings: First, they underline that dietary CLA supplementation ameliorates intestinal inflammation, and we now extend these findings by providing evidence that this mechanism might be relevant for the control of CNS autoimmunity.

This is of particular interest since intestinal barrier disruption and inflammation have already been linked to experimental CNS autoimmunity and more recently to multiple sclerosis.

Second, they provide further evidence that dietary CLA supplementation can promote the anti-inflammatory properties of myeloid cells in various organs. In light of this pilot study, we decided to perform a proof-of-concept trial of dietary CLA supplementation in 15 patients with RRMS to evaluate whether we can replicate some of our key immunological findings from our preclinical dataset in humans.

Notably, we observed changes within the peripheral blood myeloid cell compartment with a relative increase in anti-inflammatory subsets and a decrease in pro-inflammatory cell subsets. Furthermore, the cytokine profile of monocytes from CLA-treated patients was substantially altered, and CLA supplementation also modulated the metabolic properties of monocytes by interfering with mitochondrial respiration, suggesting that CLA interferes with the metabolic reprogramming necessary for full activation as has been shown for other anti-inflammatory approaches.

Although the precise site of action of this myeloid cell-mediated modulation of adaptive immune responses is not clear, several previous studies support the hypothesis of a peripheral immune regulation by these cells, 48 , 89 which is in line with our results from animal experiments.

While we did not observe significant changes in CNS-located myeloid cell subset composition within the CNS of OSE CLA mice Supplementary Fig. The size of our pilot trial precludes any reliable conclusions with regard to the clinical efficacy of dietary CLA supplementation in multiple sclerosis patients, and this definitely needs to be explored in a larger randomized and placebo-controlled trial, ideally using a classical MRI-based end point as an established surrogate marker of disease activity in RRMS.

In our opinion, the performance of such a trial is feasible, in particular considering our pilot data demonstrating high tolerability and treatment adherence over 6 months. Furthermore, we did not observe any clinical relapses in those patients adhering to the combination of CLA supplementation and first-line immune modulatory treatment of multiple sclerosis.

Especially in light of the still unsolved problems of treatment adherence as well as side-effects of immunomodulatory treatment, complementary treatment via targeted dietary modification represents a highly attractive therapeutic approach in the multiple sclerosis treatment landscape and putatively also in other autoimmune diseases with a key role of the intestinal immune system in immune dys regulation, such as systemic lupus erythematosus, inflammatory bowel disease and rheumatoid arthritis.

Taken together, our study provides evidence that dietary CLA supplementation is a promising novel strategy for the control of CNS autoimmunity as a complementary approach to conventional treatment. Future studies, especially with regard to targeted dietary intervention in RRMS patients, are warranted to characterize the therapeutic potential of this novel approach in humans.

We thank Annika Engbers, Andrea Pabst, Claudia Kemming, Elke Hoffmann, Luzia Buchholz, Janine Meyer and Maj Lisa Frankenberg for excellent technical support. This study was supported by the German Research Foundation DFG grant number CRC SFB TR A08 to L.

and D. and C. and T. and L. as well as HE to L. and P. received support from the DFG SFB C2 and the RU P3. and M. received travel support from Novartis.

received speaker honoraria and travel support from Sanofi Genzyme. received travel support from Biogen. received research funding support from Biogen and honoraria from Sanofi, Esai, and Genzyme. received research funding from the German Cancer Aid Deutsche Krebshilfe , German Research Foundation DFG , Innovative Medical Research program Medical Faculty, University of Münster , Wilhelm Sander-Stiftung, Maria Möller Stiftung, and NanoString.

He received compensation for serving on scientific advisory boards for Bristol-Myers Squib and Novartis. receives research support from the German Research Foundation DFG and the European Union.

She received speaker honoraria from MyLan, Bayer Health Care and Genzyme and travel expenses for attending meetings from Biogen, Euroimmun, Genzyme, MyLan, Novartis Pharma GmbH and Bayer Health Care. received research funding from the German Research Foundation, Interdisciplinary Center for Clinical Studies IZKF Münster, National MS Society, European Leukodystrophy Association, Progressive MS Alliance, European Commission HMSCA-ITN and Novartis.

She received compensation for serving on scientific advisory boards Frequency Therapeutics, Inc. and speaker honoraria from Novartis. received honoraria for acting as a member of Scientific Advisory Boards for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG and Sanofi-Aventis as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F.

Hoffmann-La Roche Ltd. received compensation for serving on Scientific Advisory Boards for Alexion, Genzyme, Janssen, Merck Serono, Novartis and Roche. She received speaker honoraria and travel support from Bayer, Biogen, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva.

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The inconclusive results in human supplementation trials are due to the use of mixed isomers, which may negate one another, resulting in no net change in adiposity; moreover, doses used in human trials were much lower than those used in animal studies [ 62 ].

These paradoxical findings may arise from the use of mixed isomers of CLA or the difference in experimental models used. In any event, isomer-specific dose-titrated clinical studies combined with mechanistic studies in cultures of primary cells should provide the much needed insight on potential human applications for CLA.

Within various rodent species and strains, dietary CLA exerts varying potencies; therefore, the differences in species' sensitivities are of great importance when trying to extrapolate rodent data to the human situation [ 2 , 15 ].

Of late, over a hundred clinical studies regarding the efficacy of CLA as functional food are available in literature. A brief survey on the outcome of such studies shows that the overwhelming beneficial effects of CLA impart positive outlook. Table 2 [ , — ] gives some of the notable effects of CLA in humans, as evidenced by clinical studies.

It seems that 9- and CLA are having contrasting biological functions, but CLA with more detrimental effects. However a ratio of these isomers may give better effect, as effected in immune function [ ]. Normal CLA concentration in human body is 0. Studies reveal that an intake of about g per day for 6 to 12 months by an adult would impart optimum biological effects, which would be long lasting too [ ].

According to Fernie et al. Very recently Kelley et al. demonstrated in mice that some adverse effects like insulin resistance and non-alcoholic fatty liver disease attributed to CLA may be due to the deficiency of n-3 PUFA and that such adverse effects can be corrected by a concomitant increase in the intake of α-linolenic acid, an n-3 PUFA and flax seed oil, a rich natural source for this fatty acid [ ].

Considering the reported adverse events and safety concerns, Gaullier at al. assessed the effects of supplementation of 3. The data revealed that CLA supplementation for 24 months in healthy, overweight adults was well tolerated as revealed by the decreased body weight and body fat mass, and increased circulating lipoprotein, thrombocytes, and aspartate amino transferase.

There was no change in fasting blood glucose. Plasma total cholesterol and LDL cholesterol were reduced, whereas HDL cholesterol and triglycerides were unchanged. The reported adverse effect rate was decreased considerably in the 2-years long study, compared with the initial 12 months of the study [ ].

These results indicate that most of the reported adverse effects are related to the short-term studies in humans [ ]. Apparently, many of the physiological adverse effects like hyperinsulinemia and fatty liver in mice were ameliorated with the inclusion of increasing amounts of fish oil in the diets, which is a rich source for very long-chain fatty acids [ ].

These results indicate that a mixture comprising all n-3, n-6 CLA and n-9 fatty acids in an appropriate proportion on humans would be a better answer to avoid the reported adverse effects of CLA. Obese people are likely to consume more of these minor lipid nutrients, irrespective of their high cost.

Although comparatively few human clinical studies exist, it appears to date that CLA are beneficial for human health. More focused world-wide network clinical trials involving probands and patients from all continents are required to arrive at conclusive evidence. Another important aspect is contrasting functionalities of CLA isomers and the fact that a majority of clinical trials use a crude mixture of CLA predominated by 9- and CLAs.

Moreover, the reported negative effects like fatty liver and spleen, induction colon carcinogenesis, are yet to be proved beyond doubt. Furthermore, apart from PPAR-mediated signalling, more conclusive evidences are necessary to unravel other molecular mechanisms and complex signalling pathways triggered by dietary CLA.

Strictly controlled studies as performed in animals or in culture models may not be maintained in clinical trials, however, most of human studies are based on blood, blood cells, milk or biopsy specimens - all these would cause probable variations in the general data generated.

Thus, conclusive studies focused on parameters such as type of CLA isomer administered, variables measured, mode of administration eg. To this end, a positive result is that recent studies emphasise a combination of CLA with PUFA to be best formula to ameliorate the adverse effects observed so far.

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Download references. Department of Biochemistry, University of Münster, Münster, Germany. Biotechnology Division, Department of Botany, University of Calicut, Kerala, , India. Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, , Graz, Austria.

You can also search for this author in PubMed Google Scholar. Correspondence to Sailas Benjamin. Both authors contributed equally to this article, read and approved the final version of the manuscript.

This article is published under license to BioMed Central Ltd. Reprints and permissions. Benjamin, S. Conjugated linoleic acids as functional food: an insight into their health benefits. Nutr Metab Lond 6 , 36 Download citation. Received : 15 July Accepted : 18 September Published : 18 September Anyone you share the following link with will be able to read this content:.

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Search all BMC articles Search. Download PDF. Download ePub. Abstract This review evaluates the health benefits of the functional food, conjugated linoleic acids CLA - a heterogeneous group of positional and geometric isomers of linoleic acid predominantly found in milk, milk products, meat and meat products of ruminants.

Introduction Conjugated linoleic acids CLA represent a heterogeneous group of positional and geometric isomers of linoleic acid, which are predominantly found in milk, milk products, meat and meat products of ruminants [ 1 , 2 ].

Figure 1. Full size image. CLA isomers Positive health effects attributed to CLA are mainly based on cell culture models and animal studies with comparatively less scientific evidences from direct studies on humans [ 4 ].

Figure 2. Anti-obesity Considering anti-obesitic and hypolipidemic effects, it is possible to modify body composition by supplementing CLA to the diet. Table 1 Major biochemical actions of CLA on lipid metabolism.

Full size table. Anti-carcinogenesis CLA inhibits cancer by blocking the growth and metastatic spread of tumours. Anti-atherosclerosis Atherosclerosis is a progressive disease of medium and large arteries by the accumulation of lipids in the inflammatory cells foam-cell formation , cellular proliferation, platelet adherence and aggression, and calcium deposition [ 91 , 92 ].

Anti-diabetes Diabetes can be caused by too little insulin type I , resistance to insulin type II , or by both. Immunomodulation In vitro studies of the use of immune cells and in vivo animal models demonstrate that CLA modulate immune function.

Bone formation Mixed CLA isomers have been shown to have variable effects on bone formation ostheosynthesis and resorption in animals. Safety concerns and human scenario Though only positive health benefits of CLA have been addressed here, some negative impacts of CLA could not be ruled out [ ].

Table 2 Important biological effects of CLA in human subjects. References Steinhart H, Rickert R, Winkler K: Identification and analysis of conjugated linoleic acid isomers CLA. CAS Google Scholar Benjamin S, Hanhoff T, Börchers T, Spener F: A molecular test system for the screening of human PPAR transactivation by conjugated linoleic acid isomers and their precursor fatty acids.

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Further investigation showed that CLA — the conjugated form of linoleic acid — was abnormally low both in mice with a typical microbiome fed a minimal diet or in germ-free mice fed a rich diet, suggesting that bacteria were necessary to convert linoleic acid into CLA.

Conversely, when the researchers colonized them with bacteria that had been genetically modified to not produce LAI, they did not develop these immune cells, showing that CLA produced by this bacterial enzyme was essential for these immune cells to grow. When CLA attached to these receptors, the cells produced a different protein called interleukin 18R ILR , which in turn lowered the production of a third protein called ThPOK.

This complex pathway has clear implications for immunity to infection, Kasper said. Authorship, funding, disclosures.

Co-authors included Haohao Zhang, Yanbo Zhang, Byongsook Goh, Bin Bao, Suelen S. Mello, Ximei Sun, Wen Zheng, Francesca S. Gazzaniga, Meng Wu, Fangfang Qu, Qiangzong Yin, Michael S. Gilmore, and Sungwhan F. New study findings could inform the design of treatments for a range of viruses that replicate in News Topic Menu News Topics Research Awards and Achievements Care Delivery HMS Community Education Stay Up to Date.

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By CHRISTY BROWNLEE June 28, Research 4 min read. At a glance: Research in mice shows gut bacteria feed on common fatty acids, and the byproduct of this process stimulates the rise of immune cells in the gut.

Immune cascade spurred by fatty acid consumption shielded the mice against disease-causing gut bacteria. Study offers striking demonstration of how diet and gut microbes work together to build the human immune system. Get more HMS news here Now, a study led by Harvard Medical School researchers sheds light on this process, pinpointing a critical intermediary between food and health — the gut bacteria that make up our microbiome, or the collection of microorganisms that live in symbiosis with humans.

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