Cardiovascular disease (CVD) is the leading cause of mortality worldwide [1
]. A growing body of evidence suggests that inflammation is a key feature in CVD and its risk factors, such as abdominal obesity, metabolic syndrome and type 2 diabetes (T2D) [2
]. The changes in the degree of inflammation could be reflected in the fluctuations in the levels of C-reactive protein (CRP), a sensitive marker of inflammation. According to meta-analyses of long-term prospective studies, increased levels of inflammatory marker CRP were strongly positively associated with CVD risk [3
]. Several dietary factors, such as plant sterols, fiber, isoflavones and omega-3 (n
-3) polyunsaturated fatty acids (PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-linolenic acid (ALA)) have been shown to be cardiovascular protective based on accumulating evidence from randomized controlled trials (RCTs) [5
]. Reducing inflammation has been recognized as one of the numerous mechanisms by which they may reduce the risk of CVD [6
]. Flaxseed (linseed, Linum usitatissimum), an edible oil seed/grain, is emerging as an attractive functional food with the richest plant source of ALA (50%–62% of flaxseed oil, or 22% of whole flaxseed) and lignans (a class of phytoestrogen, range: 0.2–13.3 mg/g flaxseed) [9
]. In addition, flaxseed contains abundant dietary fiber (28% by weight), a third of which is soluble fiber [9
ALA has been shown to have anti-inflammatory effects through the downregulation of the expression of hepatic inflammatory genes in diabetic rats and a remarkable reduction of plasma CRP levels in rats fed with a high-fat diet [12
]. Whole flaxseed supplementation has been shown to mitigate pathophysiology of atherosclerosis in myocardial ischemia rat models through decreasing levels of inflammatory markers [14
The special composition of flaxseed and its possible mechanisms in CVD protection inspire many researchers to perform clinical trials to determine the outcomes of flaxseed intervention (whole flaxseed, flaxseed oil, or lignans) on various cardiovascular risk factors, particularly inflammation status reflected in inflammatory marker levels of CRP [11
]. However, the findings from those clinical trials were inconsistent, and the discrepancies may be attributable to aspects of the study design (e.g., study power, the patient recruited, sample size, study duration, flaxseed or its derivatives dose used). Therefore, we performed a meta-analysis of published RCTs to evaluate whether administration of flaxseed or its derivatives could ameliorate inflammation status.
This meta-analysis provides evidence of no general benefit of flaxseed or its derivatives supplementation on decreasing CRP levels. However, the supplementation significantly decreased CRP levels in studies, where the recruited participants’ BMI were over 30 kg/m2.
Many studies have repeatedly shown that obese [42
] or elderly [43
] people tend to have higher blood levels of CRP, and people with chronically elevated levels of inflammation may be most likely to benefit from this intervention [44
]. This has been confirmed in the subgroup analysis that CPR level was significantly reduced in studies with mean BMI over 30 kg/m2
). Additionally, we found a trend toward a greater reduction of CPR in age over 50 years (Table 2
). Three of the included studies needed to be mentioned individually. The participants recruited by Faintuch et al.
] were morbidly obese with BMIs over 40 kg/m2
. The participants recruited by Nordstrom et al.
] were subjects with rheumatoid arthritis. CRP levels were over 10 mg/L in these 3 studies. Clinically, CRP over 10 mg/L is suggestive of active inflammation or infection [45
]. Because the SDs of the net change of CRP were large and sample sizes were very small (around 10 in each group), the weight of these 3 studies is negligible (less than 1%). An exclusion of these 3 studies from the meta-analysis did not significantly change the pooled results (Table 2
). Whether flaxseed intervention could decrease CRP levels in these active inflammatory situations needs to be further studied.
Intake of n
-3 PUFAs (EPA and DHA) has been shown to have beneficial effects on CVD, diabetes, and other obesity-related diseases [46
]. A recent meta-analysis showed that marine-derived n
-3 PUFAs supplementation had a significant lowering effect on CRP levels [47
]. However, it is unclear whether ALA, as a plant-based source of n
-3 PUFA, has similar effects on chronic diseases and inflammation. Unlike fish oil, ALA is more readily available and quite inexpensive. Flaxseed was considered as an alternative source of marine-derived omega-3 fatty acid, and some studies were conducted to examine its beneficial role in patients with T2D, rheumatoid arthritis, and chronic hemodialysis [24
]. However, in our current meta-analysis, we showed that flaxseed oil did not have a significant CRP-lowering effect. One of the plausible explanations for this null result is that the conversion from ALA to EPA or DHA was considered negligible (conversion rate has been suggested to be as low as 5%) [49
]; thus, the biologically effective dose may not be reached through such a conversion. Another explanation for the null findings is that the effects of flaxseed oil may have been masked by the use of MUFA- or n
-6 PUFA-enriched oils as the control regimen in these studies. Previous studies have shown that, compared to saturated fatty acids, MUFAs and n
-6 PUFAs also have an inflammation-lowering effect [50
]. Whether a replacement of MUFAs or n
-6 PUFAs for saturated or trans fatty acids as the control regimen could lower CRP remains to be elucidated.
Our findings from the meta-analysis showed that whole flaxseed reduced CRP levels and the statistical result was borderline significant. Besides n
-3 fatty acid, flaxseed is a good source of dietary fiber (28% by weight), in particular soluble fiber [9
]. Dietary fiber can be partially or completely fermented to short chain fatty acids (acetate, propionate, and butyrate). One study showed that propionate downregulated the pro-inflammatory cytokine TNF-αin adipose tissue [52
]. Recently, Jiao et al.
] conducted a meta-analysis and showed that dietary fiber (total fiber intake 8 g/day higher) significantly reduced CRP levels in overweight and obese adults. Thus, this CRP-lowering effect might be due to the fiber component in whole flaxseed. Lignans are a group of polyphenols with antioxidant prosperities and are abundant in flaxseed (range: 0.2–13.3 mg/g) [35
]. Although lignans are not classified as dietary fibers, they share some of the chemical characteristics of lignin, which is an insoluble fiber. However, human studies that examine the role of lignans on inflammation are still limited, and whether lignans alone have a CRP-lowering effect needs to be confirmed or refuted.
This meta-analysis included studies that had a relatively high Jadad score. However, it was limited by a potential publication bias, which is revealed by the asymmetry of the funnel plot and the Egger’s model. Publication bias suggests that some small studies with negative findings may have been missed or unpublished. Including these studies would further promote our results to a null effect. In addition, there is considerable heterogeneity across studies, which complicated the interpretation of our findings. Given the variation in study characteristics, it is not surprising that there is substantial heterogeneity among individual studies. The participants in these studies are overweight/obese adults, hemodialysis patients with dyslipidaemia, patients with renal failure, patients with rheumatoid arthritis, T2DM or metabolic syndrome, and adults who are defined “healthy”. A healthy status may influence the effect of flaxseed or its derivatives on inflammatory response differently. The intestinal microbiota composition varies between healthy and diseased individuals [54
]. As the components of flaxseed need to be fermented or metabolized by human intestinal bacteria to exert their biological effects, gut microbiota may also change the effect of flaxseed on inflammatory response [38
]. Subgroup analysis results indicated a significantly larger reduction of CRP in subjects with BMIs over 30 kg/m2
. This finding was also supported by meta-regression analysis that BMI was a source of heterogeneity among trials. This result is important because obesity, an established risk factor for CVD, is associated with elevated levels of CRP [55
]. A decrease in CRP by flaxseed supplementation is helpful for alleviating the risk of CVD [55
]. Although our meta-analysis did not find sufficient evidence that flaxseed and its derivatives have a beneficial effect on reducing circulating CRP in unstratified populations, their CVD prevention role cannot be denied. As is well known, in addition to inflammation, high blood pressure and dyslipidemia are also risk factors of CVD. Recent meta-analysis showed that supplementation with various flaxseed products decreased both systolic blood pressure (BP) and diastolic BP [56
]. In additon, a meta-analysis by Pan et al.
found that flaxseed reduced circulating total and LDL-cholesterol concentrations [7
]. The intervention of whole flaxseed reduced total or LDL cholesterol by ≈0.2 mmol/L, which is estimated to have resulted in a reduction of ≈3% in all-cause mortality and of 6% in both coronary heart disease–related mortality and total events [7
]. Therefore, the effects of flaxseed on CVD prevention appear to be clinically significant. Thus, functional foods/nutraceutials such as garlic [58
], green tea [59
], astaxanthin [60
] and flaxseed [7
. that have been demonstrated to reduce the risk of CVD, are encouraged to be incorporated into our diet, as they might reduce the drug dose, such as statins, the commonly prescribed drugs to prevent cardiovascular events or drug-related side effects as an adjuvant therapy [61
]. Our data suggest that future well-designed studies with large sample sizes and adequate durations are needed to investigate the effectiveness of whole flaxseed on inflammatory factors amelioration, particularly in obese populations.