A dietary intervention with conjugated linoleic acid enhances microstructural white matter reorganization in experimental stroke

 Your doctor can tell you the difference between linoleic acid and conjugated linoleic acid, and should know EXACTLY the amount of CLA to take! Of course your competent? doctor will ensure that human testing gets done before your children and grandchildren have strokes!

• linoleic acid (5 posts to November 2014)

A dietary intervention with conjugated linoleic acid enhances microstructural white matter reorganization in experimental stroke

Frederike A. Straeten^1†Jan-Kolja Strecker¹Anna-Lena Börsch^1†Bastian Maus^2,3†Maike Hoppen¹Birgit Schmeddes¹Lucia Härtel¹Ann-Katrin Fleck¹Stephanie van Zyl¹Tabea Straeten¹Carolin Beuker¹Mailin Koecke¹Louisa Mueller-Miny^1†Cornelius Faber^2,3†Gerd Meyer zu Hörste^1†Luisa Klotz¹Jens Minnerup¹Antje Schmidt-Pogoda^1*

• ¹Department of Neurology, University Hospital Münster, University of Münster, Münster, Germany
• ²Translational Research Imaging Center, University of Münster, Münster, Germany
• ³Clinic of Radiology, University Hospital Münster, University of Münster, Münster, Germany

Background: A dietary supplementation with conjugated linoleic acid (CLA) was shown to attenuate inflammation and increase the proportions of circulating regulatory T cells (T_regs) and M2-type macrophages in disease models such as autoimmune encephalitis and arteriosclerosis. Since T_regs and anti-inflammatory (M2-type) macrophages were found to enhance stroke recovery, we hypothesized that CLA-supplementation might improve stroke recovery via immune modulatory effects.

Methods: Functional assessment was performed over 90 days after induction of experimental photothrombotic stroke in wild type mice (n = 37, sham n = 10). Subsequently, immunological characterization of different immunological compartments (n = 16), ex vivo magnetic resonance (MR, n = 12) imaging and immunohistochemical staining (n = 8) was performed. Additionally, we tested the effect of CLA in vitro on peripheral blood mononuclear cells from human stroke patients and healthy controls (n = 12).

Results: MR diffusion tensor imaging (DTI) demonstrated enhanced microstructural reorganization of interhemispheric white matter tracts, dependent on lesion size. Functional recovery over 90 days remained unaffected. Detailed immunological analyses across various compartments revealed no significant long-term immunological alterations due to CLA. However, analyses of human blood samples post-stroke showed reduced levels of pro-inflammatory interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNF-α) release by T-lymphocytes following in vitro treatment with CLA.

Conclusion: We aimed to explore the efficacy of a dietary intervention with minimal known side effects that could be accessible to human stroke patients, regardless of the degree of disability, and without the risks associated with aggressive immunomodulatory therapies. Our main findings include improved microstructural reorganization in small infarcts and a reduced inflammatory response of human T cells in vitro.

1 Introduction

There is emerging evidence that not all impairments after stroke can be attributed to the primary ischemic lesion, but also to a secondary local and sustained inflammation, resulting in impaired connectivity and regional excitotoxicity due to deregulated neuronal coupling (1, 2).

While an initial immune response and recruitment of activated immune cells such as T_H1-cells and neutrophils are needed at the acute stage of CNS injury, the sustained compartmentalized neuroinflammation hinders neuroregeneration and contributes to secondary deterioration (2, 3). This can largely be attributed to the secretion of pro-inflammatory cytokines by microglia and lymphocytes, including IFN-γ, TNF-α and IL-1β. T_regs counteract this detrimental cytokine elevation and contribute, mediated by IL-10, to the regulation of the deranged immune reaction (4).

Conjugated linoleic acid (CLA) encompasses a group of linoleic acid isomers with two conjugated double bonds, while immunomodulatory effects have been demonstrated predominantly for the cis-9,trans-11 (c9,t11) and trans-10,cis-12 (t10,c12) isoforms of CLA (5). CLA exerted an anti-inflammatory effect in vivo via activation of the peroxisome proliferator activator receptor (PPAR)-γ in immune cells, thereby skewing monocyte function to a more anti-inflammatory phenotype via induction of IL-10 in vitro and in vivo. This phenotype and its associated effects were beneficial in existent atherosclerosis (6). CLA has ameliorated the disease course of various experimental autoimmune diseases, especially of inflammatory bowel disease (7). Fleck et al. (8) showed beneficial effects of a CLA-rich diet in a mouse model of multiple sclerosis and attributed these effects to enhanced IL-10 production by murine myeloid cells and a suppressed T cell proliferation. For primary prevention of stroke, a 5% higher intake of linoleic acid accompanied by a lower intake of saturated fatty acids was associated with a reduced risk of ischemic stroke (9). Following stroke, the diversity of the gut microbiome is decreased and diversity of the gut microbiota is associated with an attenuated proinflammatory immune response (10). Omega-3 polyunsaturated fatty acids promoted white matter tract integrity in the corpus callosum as well as microglia-differentiation into anti-inflammatory (M2-)phenotypes and ameliorated long-term sensorimotor recovery in experimental stroke (11). The effect of CLA on stroke recovery has not been investigated so far.

To conclude, T_regs as well as a regulatory subset of myeloid cells are crucial for controlling the immune response after stroke and are thereby pivotal for stroke recovery. In myeloid cells, CLA has been shown to upregulate IL-10 production and to reduce secretion of IFN-γ (8). Supplementation of conjugated linoleic acid might be capable of suppressing the secretion of pro-inflammatory cytokines including TNF-α, IFN-γ, IL-17 and IL-6, and enhancing the secretion of anti-inflammatory cytokines, thereby polarizing myeloid and T cells into a more regulatory phenotype. This could bear the potential to counteract secondary local and sustained inflammation, which impairs stroke recovery and contributes to secondary neurodegeneration (2). In this exploratory study we aim to investigate a potential immune-modulating and neuro-regenerative effect of a CLA-rich diet in an experimental mouse model of ischemic stroke.

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