This is the first large-scale study to explore and compare the effects of omega-3 fatty acid supplement use on CRP levels following the induction of a sterile inflammatory response by strenuous physical exercise in healthy individuals. There are several novel and important findings. First, use of omega-3 fatty acid supplements was common in the present cohort, with about two-thirds of subjects reporting either regular or sporadic use of these supplements. Second, subjects who reported regular use of omega-3 fatty acid supplements had lower baseline and exercise-induced CRP levels compared with other subjects. Third, in subgroup analysis only regular use of CLO was associated with lower baseline- and exercise-induced CRP levels. Fourth, in multiple regression models, the beneficial effects of regular CLO consumption, was evident in all models explored. These findings imply that omega-3 fatty acid supplements, and particularly CLO, are associated with a reduction in both basal and exercise-induced inflammation in recreational athletes.
Use of supplements
The use of dietary supplements in the general population is common. Bailey et al. found that 49% of the general population in the US uses dietary supplements . Among athletes, the use of dietary supplements seems to be even higher, but exact estimates are difficult and approximately 14% of athletes use omega-3 fatty acid supplements . In Norway, there is a long tradition of CLO supplement use. The main manufacturer reports yearly sales of about 2.5 million bottles of CLO in Norway (population: 5.4 million) . Three studies reporting on the use of CLO in the 1990–2000 found between 18 and 45% of their cohorts reported regular use of CLO supplements [15,16,17]. To our knowledge, there are no previous studies on the use of CLO in athletic cohorts.
The CRP response in relation to regular use of omega-3 fatty acid supplement
In this present analysis, regular use of omega-3 fatty acid supplements, and in particular regular use of CLO, was associated with lower CRP levels both at baseline and following exercise. The difference in CRP levels following exercise was most pronounced in the least fit subjects and in the subjects with the highest BMI levels (Fig. 3).
The association between intake of omega-3 fatty acid supplements and inflammation has been studied in several cohorts, but the results have been conflicting. Omega-3 fatty acid supplementation has been found to reduce inflammatory biomarkers in populations with various chronic inflammatory or non-inflammatory diseases [10, 18, 19]. Importantly, the Vitamin D and Omega-3 trial (VITAL) found no decrease in inflammatory markers in subjects that used either 1 g omega-3 or 50 μg vitamin D daily for 1 year .
The anti-inflammatory properties of CLO are less explored. Our study showed that the anti-inflammatory effect was largest in CLO users. One earlier randomized controlled trial found that supplementation with CLO was associated with a decrease in CRP in a cohort of women with gestational diabetes. The authors attributed this to the content of omega-3 PUFAs in CLO . The possible impact of the other components of CLO, such as vitamins A, E and D, were not discussed . These vitamins, present both in CLO and some other omega-3 fatty acid supplements, may contribute to anti-inflammatory effects. Vitamin E is an antioxidant, which theoretically could be beneficial in neutralizing the effects of oxygen free radicals, but prior studies have been conflicting [22, 23]. PUFAs are important components of cell membranes . Oxygen free radicals react more quickly with vitamin E than with PUFAs, hence the presence of vitamin E may protect the integrity of the cell membranes, in turn preventing cell damage [25, 26]. Furthermore, the vitamin A precursor, beta-carotene, and vitamin E have been associated with reduction in muscle damage and enhanced recovery from exercise . Vitamin D is mostly considered to be important in regulating calcium and phosphate metabolism, however, some studies also report on anti-inflammatory effects of vitamin D supplements [28, 29]. Whether the presence of these vitamins and possible differences in vitamin content between supplements may contribute to the attenuation of the exercise-induced CRP response found in the present analysis, should be explored in future studies.
The impact of quality, quantity and content
The observed anti-inflammatory differences between users of CLO and other omega-3 fatty acid supplements in the present study may relate to the quality of the supplement, in particular the degree of oxidation of the fatty acids [30, 31]. The Global Organization for EPA and DHA Omega-3 s has recommended a maximal limit of total oxidation value (TOTOX) of 26 . Recent studies have suggested that high-quality fish oil supplements may have more favourable effects than similar doses of more oxidized PUFAs [33, 34]. More than 39% of omega-3 fatty acid supplements exceeds the limit of excess oxidation [34,35,36]. Moreover, in a Norwegian study of over-the-counter omega-3 fatty acid supplements the median TOTOX value in 54 available supplements was 29.0 (minimum-maximum: 8.1–113.6) . The main CLO manufacturer in Norway (Möller’s, Oslo) reports a TOTOX value of 4.1 . The degree of oxidation might therefore be of importance when interpreting these results.
The quantity of PUFA intake might further explain some of the difference in effect observed in the present study. As outlined in Table 1, the recommended daily dose of CLO (5 ml) contains 1.2 g of PUFAs. For other omega-3 fatty acid supplements, intake is commonly recommended as 1–4 capsules per day, making the exact dose consumed difficult to assess. Furthermore, the specific content of EPA and DHA is also not always available. Conversely, some of the omega-3 fatty acid products might yield lower PUFA intake as compared to that of CLO supplements, particularly since CLO is often consumed in a tablespoon, which contains 2–3 times the recommended daily dose .
EPA and DHA are usually both present in omega-3 fatty acid supplements. Emerging evidence suggests that the two fatty acids have different health benefits. In the Reduction of Cardiovascular Events with Icasopent Ethyl-Intervention Trial (REDUCE-IT), use of 4 g of PUFAs (icosapent ethyl) was found to lower the risk of ischemic events in subjects with hypertriglyceridemia. This product consists of 100% EPA, and corresponds to 10 times more EPA than the contents in a recommended daily dose of CLO . DHA has also been shown to lower triglyceride levels, but might also increase levels of low-density lipoprotein (LDL), and high-density lipoprotein (HDL) [40, 41]. Furthermore, in the Comparing EPA to DHA study (ComparED), DHA and EPA were compared head-to-head and against placebo in healthy subjects with abdominal obesity and subclinical systemic inflammation, and results indicate that DHA at a dose of 3 g/day for 10 weeks may be more effective than a similar dose of EPA in attenuating inflammation . However, a meta-analysis by Li et al. concluded that a higher daily dose of EPA lead to greater lowering effect on CRP in healthy subjects, as compared to DHA or omega-3 fatty acid supplements. DHA, on the other hand, was found to have a dose-dependent decrease of the level of the pro-inflammatory cytokine IL-6 . These underlying differences among supplements used by the current study participants may explain some of the observed differences in effect.
In the present analysis, the least fit subjects with the highest BMI had the highest exercise-induced CRP levels. This is in line with our previous study demonstrating a strong correlation between fitness and post-exercise CRP levels . In the present study, regular use of CLO was associated with lower CRP levels both at baseline and following exercise compared with all other groups. Importantly, the largest benefits of CLO use on CRP levels, were found in the least fit subjects and in subjects with the highest BMI levels (Fig. 3). Obesity is characterized by a low-grade chronic inflammation . In line with our findings at rest, prior studies have demonstrated significant reductions in baseline inflammatory markers such as IL-6 (up-stream of CRP) in obese subjects receiving EPA and DHA [44, 45]. To our knowledge the present study is the first to suggest that there may be an increased beneficial effect of CLO on exercise-induced inflammation in moderately obese individuals with reduced fitness. The reason for the difference in CRP levels between CLO and other omega-3 supplements is not clear. The difference may relate to amount, quality or balance of the different PUFAs and other contents of CLO compared with the other supplements as discussed above. The present findings suggest that regular use of CLO may have a beneficial effect by attenuating post-exercise inflammation, potentially reducing the post-exercise discomfort, and thereby increasing the motivation to increase exercise in overweight and obese individuals with reduced fitness.
There are several limitations to the present study. The main limitations relate to the observational study design, and the lack of information on supplement manufacturer, content, duration and quantity of supplement used. In previous studies, intake of CLO has been reported to be significantly lower in people with lower socioeconomic rank and education . In our material, however, 63.6% of non- and sporadic users of omega-3 fatty acid subjects reported higher education, vs 60.6% among regular users of omega-3 fatty acid supplements, p = 0.24.