Review: The Nutritional Management of Multiple Sclerosis With Propionate.

Over the last 15 years there has been an accumulation of data supporting the concept of a gut-brain axis whereby dysbiosis of the gut microbiota can impact neurological function. Such dysbiosis has been suggested as a possible environmental exposure triggering multiple sclerosis (MS). Dysbiosis has been consistently shown to result in a reduction in short-chain fatty acid (SCFA) producing bacteria and a reduction in stool and plasma levels of propionate has been shown for MS patients independent of disease stage and in different geographies. A wealth of evidence supports the action of propionate on T-cell activity, resulting in decreased T-helper cell 1 (Th1) and T-helper cell 17 (Th17) numbers/activity and increased regulatory T cell (Treg cell) numbers/activity and an overall anti-inflammatory profile. These different T-cell populations play various roles in the pathophysiology of MS. A recent clinical study in MS patients demonstrated that supplementation of propionate reduces the annual relapse rate and slows disease progression. This review discusses this data and the relevant mechanistic background and discusses whether taming of the overactive immune system in MS is likely to allow easier bacterial and viral infection.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Ethyl-Ester Omega-3 Fatty Acid in Taiwanese Hypertriglyceridemic Patients.

AIM: Information regarding the effects of omega-3 fatty acid on hypertriglyceridemic patients in Chinese is still limited. This study aimed to investigate the efficacy and safety of Omacor®, a prescription ethyl-ester omega-3 fatty acid for the treatment of hypertriglyceridemia, administered at doses of 2 g/day and 4 g/day to Taiwanese hypertriglyceridemic patients. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel study in adults with hypertriglyceridemia was conducted. After a five-week diet lead in period patients with triglycerides =200-1000 mg/dL were randomized to receive Omacor®, a concentrated preparation of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in a dose of 1 g twice daily (2 g Omacor®), 2 g twice daily (4 g Omacor®) or placebo, for eight weeks. The primary endpoint was the percentage change in triglyceride serum levels from baseline to the end of treatment. RESULTS: A total of 253 Taiwanese patients were randomized, of which 65.6% (166) were men. At the end of the treatment, the percentage change in triglyceride serum levels in both the Omacor® 4 g/day (－32.1%) and 2 g/day (－29.7%) groups was larger than in the placebo group (－5.4%) (p＜0.001). The incidence of drug-related adverse events was as follows: 0.0%, 1.2%, and 0.0% in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Omacor® may be a feasible option to treat hypertriglyceridemia in Taiwanese patients.

Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia.

OBJECTIVES: To evaluate the efficacy and safety of icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. METHODS: The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. RESULTS: With icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. CONCLUSIONS: Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerated.

Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week clinical trial.

BACKGROUND: Icosabutate is a structurally enhanced omega-3 fatty acid molecule developed with the aim of achieving improved triglyceride (TG)-lowering efficacy, increased potency, and preserved safety compared with conventional prescription omega-3 fatty acid. OBJECTIVE: To evaluate the efficacy and safety of icosabutate 600 mg once daily in patients with very high TGs. METHODS: After a 6-8 week run-in period, men and women with TG levels ≥ 500 mg/dL and ≤ 1500 mg/dL were randomized to double-blind treatment with placebo or icosabutate 600 mg for 12 weeks. The primary end point was % change from baseline in TGs at 12 weeks. RESULTS: A total of 87 subjects were randomized. At baseline, median TG (interquartile range) levels were 611 (543-878) and 688 (596-892) mg/dL, and the median change after 12 weeks of treatment was -51% and -17%, respectively, for a placebo-corrected change of -33% (P < .001). Adjusted for placebo, icosabutate significantly reduced very low-density lipoprotein cholesterol (-36%, P < .001), remnant lipoprotein cholesterol (-34%, P < .001), apolipoprotein (Apo) C-III (-35%, P < .001), trended toward reduced non-high-density lipoprotein cholesterol (-7%, P = .064); significantly increased high-density lipoprotein cholesterol (18%, P < .001) and low-density lipoprotein cholesterol (28%, P < .001), with a trend of an increased lipoprotein (a; 10%, P = .054). No changes were observed in total cholesterol, apolipoprotein B, or apolipoprotein A1. Fasting plasma glucose was unchanged, whereas fasting plasma insulin was reduced (P = .001) with icosabutate. Icosabutate was generally well tolerated. CONCLUSION: Treatment with icosabutate once daily significantly reduced TG, very low-density lipoprotein cholesterol, and Apo C-III levels in patients with very high TG levels. This trial was registered at www.clinicaltrials.gov as NCT01893515.

Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability.

OBJECTIVE: To examine n-3 polyunsaturated fatty acid (PUFA) incorporation into atherosclerotic plaques and the association with plaque inflammation and stability. METHODS AND RESULTS: Patients awaiting carotid endarterectomy (n=121) were randomised to consume control capsules or n-3 PUFA ethyl ester capsules until surgery (median 21 days). The fatty acid compositions of plasma and carotid plaque phospholipids, plaque features, and expression of inflammatory genes were determined. The proportion of eicosapentaenoic acid (EPA) was higher (P<0.0001) in carotid plaque phospholipids in patients in the n-3 PUFA group. Plaques from patients in the n-3 PUFA group had fewer foam cells (P=0.0390). There were no other differences between plaques in the two groups with regard to histological characteristics or morphology. Plaque stability was not different between the two groups. However, the EPA content of plaque phospholipids was inversely associated with plaque instability (P=0.0209), plaque inflammation (P=0.0108), the number of T cells in the plaque (P=0.0097) and a summary score considering a range of plaque features (P=0.0425). Plaques from patients who received n-3 PUFAs had significantly lower levels of mRNA for matrix metalloproteinases (MMP)-7 (P=0.0055), -9 (P=0.0048) and -12 (P=0.0044) and for interleukin-6 (P=0.0395) and intercellular adhesion molecule 1 (P=0.0142). CONCLUSIONS: Atherosclerotic plaques readily incorporate EPA. A higher plaque EPA content is associated with a reduced number of foam cells and T cells, less inflammation and increased stability.

Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study.

Patients on antiretroviral therapy are reported to have an increased risk of cardiovascular disease. We aimed to investigate the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy. We randomized 51 patients in a placebo-controlled, double-blind trial to receive either 2 capsules of Omacor twice daily or 2 capsules of placebo. Compliance was measured by determining levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neutrophils. Plasma triglycerides were reduced in the n-3 PUFA group by 0.14 mmol/l after 12 weeks of treatment (n=26), while plasma triglycerides increased by 0.36 mmol/l in the control group (n=25). The difference between groups was significant, p=0.03. No significant effect of treatment was found for total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol or apolipoproteins. There was a significant increase in leukotriene B5 (LTB5) and LTB5/LTB4 ratio in the n-3 PUFA group compared to the control group. Baseline values for intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM) and highly sensitive C-reactive protein (hsCRP) were comparable at baseline, and the intervention did not change these parameters significantly. The present study showed that treatment with n-3 PUFA slightly decreased plasma triglycerides and induced anti-inflammatory effects by increasing formation of anti-inflammatory LTB5.