Asthma is a chronic inflammatory disease of the airways, affecting 2.5 million Australians in 2014–2015 [1
]. Globally, it is estimated that 334 million people have asthma [2
]. Airway inflammation in asthma is triggered by exposures such as allergens and viruses, and causes airway hyper-responsiveness (AHR), airway smooth muscle contraction and excess mucous production [3
]. This results in the hallmark symptoms of asthma including breathlessness, wheezing, chest tightness and persistent cough [2
]. Systemic inflammation is also a feature of asthma, with circulating C-reactive protein (CRP) levels shown to be elevated in people with asthma [4
], which is associated with poorer lung function and more severe airway inflammation [6
Current treatment for asthma predominantly involves inhaled corticosteroid (ICS) medication, which helps to control symptoms and exacerbations and to improve lung function and quality of life by reducing airway inflammation [7
]. However, dietary patterns are also being investigated for their potential preventative or therapeutic role. It has been suggested that a Western dietary pattern, high in energy, saturated fats, sugars and salt, may increase the prevalence and severity of asthma, independent of socioeconomic and lifestyle factors [9
]. Additionally, a Mediterranean dietary pattern, which is nutrient dense and high in fish, fruit and vegetables, could be protective, reducing the incidence and the severity of asthma symptoms [9
One such way that the Mediterranean diet might be effective in reducing asthma symptoms is due to the high intake of omega-3 polyunsaturated fatty acids (n-3 PUFA). n-3 PUFA include eicosapentaenoic acid (EPA, C20:5n-3), docosapentaenoic acid (DPA, C22:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) and are commonly found in significant amounts in marine sources such as salmon, herring and sardines [10
]. These fatty acids have been found to inhibit inflammatory processes within the body, with benefits in cardiovascular disease well established [10
]. These include suppression of transcription factors that control the production of circulating inflammatory cytokines CRP, tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β and IL-6 [11
]. n-3 PUFA also compete with omega-6 polyunsaturated fatty acids (n-6 PUFA), resulting in the downregulation of arachidonic acid-derived immune and inflammatory mediators including 3- and 5-series prostaglandins, thromboxanes, leukotrienes and lipoxins [3
]. These same pathways and inflammatory mediators are involved in AHR in people with asthma [11
]. Hence, it is possible that n-3 PUFA could play a role in the prevention or treatment of asthma.
Various studies have investigated n-3 PUFA in asthma. Mouse models have shown that increased DHA intake is associated with reduced eosinophil infiltration into the lungs [13
] and that by increasing the ratio of n-3:n-6 in lung tissue, interleukins can be downregulated [14
]. In humans, research is conflicting. Some studies have found that supplementation with n-3 PUFA can decrease inflammatory markers and improve asthma symptoms [15
], while others found no changes to AHR or airway inflammation [17
]. A Cochrane meta-analysis conducted in 2000, and updated in 2011 with nil changes, including 9 randomised control trials (RCTs) of both adults and children, concluded that there was no benefit or risk for the use of dietary marine fatty acids in people with asthma [18
]. Furthermore the European Academy of Allergy and Clinical Immunology have released a position statement emphasizing that until more standardized trials with assessment of pre-intervention fatty acid levels have been conducted, there is no recommendation for n-3 PUFA in asthma and other allergic diseases [20
The conflicting evidence highlights a need for more research in this area. Hence, this study aimed to examine the relationship between n-3 PUFA status and clinical outcomes in Australian adults with asthma. Firstly, it is unclear whether n-3 PUFA status is impaired in Australian subjects with asthma compared to health controls, thus an aim of this project was to investigate and describe the differences between these two groups. We hypothesized that individuals with asthma would have poorer n-3 PUFA status compared to those without asthma. Furthermore we hypothesized that subjects with asthma and a high n-3 PUFA status would have better clinical outcomes than those with low n-3 PUFA status. These aims were examined using the omega-3 index (O3I), which has been validated as a reliable measure of dietary n-3 PUFA intake and reflects long-term n-3 PUFA status [21
]. O3I is the sum of erythrocyte EPA and DHA, expressed as a percentage of total erythrocyte membrane fatty acids [23
]. A secondary aim of this project was to examine the effects of obesity on O3I in adults with asthma. Obesity in asthma is associated with poorer asthma control, greater severity, higher medication doses and more frequent exacerbations than healthy weight individuals [24
]. One mechanism suggested to underpin this relationship is the chronic low-grade inflammation associated with obesity [25
]. Considering the anti-inflammatory properties attributed to n-3 PUFA, it is possible that n-3 PUFA may attenuate this inflammation. Whether these interactions exist in obese asthmatic subjects is unknown. Therefore, we hypothesized that in an obese asthmatic population, those with a lower O3I would have poorer clinical and biochemical outcomes compared to those with a higher O3I.
To the best of our knowledge, this is the first study reporting that a lower omega-3 index is associated with poorer asthma control in adults with asthma. Additionally, a higher O3I was associated with a lower maintenance ICS dose. Interestingly, this was most significant in the subjects who were also obese, showing a similar dose range of maintenance ICS to nonobese subjects with asthma. Considering the high medication burden and reduced quality of life in people with asthma, our study suggests that higher levels of n-3 PUFA could be utilised as an adjunct therapy in the treatment of asthma.
Our first aim was to investigate the differences in erythrocyte fatty acid levels and O3I between subjects with and without asthma in an Australian population. Contrary to our hypothesis there was no difference in O3I, subjects with asthma had a better fatty acid profile, with lower saturated fatty acids, higher monounsaturated and n-3 fatty acids and a lower n-6 PUFA to n-3 PUFA ratio. This is in contrast to the results of Zhou et al. [38
], who found that subjects in China with asthma had a fatty acid profile composed mostly of SFAs, while those without asthma contained more PUFAs. Similar to our study, supplement and dietary intake data were not available to determine whether these differences were reflective of different dietary or supplement patterns or an effect of asthma. In severe asthma, dysregulation of lipid metabolism pathways has been observed; in particular, n-3 PUFA pathways are impaired, while n-6 PUFA pathways remain unaffected [39
]. This may explain the differences between the two studies, as our population had mild to moderate asthma while Zhou et al. did not present data on the severity in their population and potentially had more severe asthma phenotypes. Furthermore, the subjects with asthma were older than the control group (mean 58 years old versus 25 years old), and without adjusting for this may have been a confounder explaining the differences between the two groups.
This study demonstrated that a lower omega-3 index is associated with poorer asthma control in adults. Subjects with uncontrolled asthma had a significantly lower O3I than those with well controlled or partially controlled asthma. Our findings are supported by a cross-sectional study conducted in 2011, which observed a significant positive relationship between EPA and DHA consumption (measured using a Food Frequency Questionnaire (FFQ)) with asthma control and lung function (FEV1
]. Our study reinforces this finding, using the objective and longer-term measure of O3I, which provides stronger evidence for this relationship.
Another significant finding was the relationship between O3I and maintenance ICS dose. Subjects with a higher O3I had a significantly lower range of maintenance ICS dose. A similar finding has been shown in a recent RCT by Papamichael et al. [41
], where children with asthma were prescribed a Mediterranean diet supplemented with two meals of 150 g cooked fatty fish per week for 6 months, compared to a control group following their normal diet. They found that while there was no difference between lung function, asthma control and quality of life scores, there was a significant reduction in medication use for children in the intervention group [41
]. In a study examining exercise-induced bronchoconstriction, n-3 PUFA supplementation (3200 mg EPA + 200 mg DHA for eight weeks) has also been demonstrated to reduce bronchodilator use in adults [42
]. Given irregular reporting of respiratory outcomes such as ICS dose and asthma control in the available literature, systematic reviews on n-3 PUFA in asthma have highlighted the need for more high quality research in this area [19
]. In particular, the relationship between n-3 PUFA and medication use would be of great interest for future research, given our results. Our findings suggest that achieving an O3I ≥ 8% could be a beneficial target for people with asthma in order to reduce maintenance ICS dose. This target also corresponds with cardioprotective recommendations [22
]. Nutritionally, to achieve this O3I, it would equate to consuming ≥800 mg EPA and DHA per day, or 4–5 serves of mostly oily fish per week [44
]. Intervention studies are required to confirm our observations, particularly to elucidate the ideal dose and duration needed to achieve this status in an asthmatic population, as well as the most effective pathway (supplementation versus whole foods).
As obesity is generally associated with increased asthma severity, poorer asthma control and more frequent exacerbations, it was important to analyse the relationship between O3I, obesity and asthma outcomes [24
]. When we examined obese and nonobese asthmatics according to O3I, obese asthmatics with a higher O3I had a lower range of maintenance ICS doses compared with obese asthmatics with a lower O3I. This is particularly important, as obesity is associated with a reduced response to ICS medication, requiring higher doses to achieve protective effects [45
]. Our findings suggest that omega-3 fatty acids could be a potential nonpharmacological approach to assist in the management of asthma, however our findings require confirmation by intervention studies. A recent study by Lang et al. found that supplementing with 4 g/day of fish oil over 24 weeks did not affect asthma control, lung function, exacerbations or have any impact on medication use in overweight and obese adolescents and young adults with asthma [46
]. This study did not investigate inflammation. Rather, it reported fatty acid status within inflammatory cells such as monocytes and granulocytes, so without confirmation that the supplementation was reducing inflammatory pathways it may be possible that the dose or length of treatment was not sufficient to affect clinical changes in asthma.
Interestingly, we did not find any differences in systemic inflammatory markers between asthmatics with lower and higher O3I, after adjusting for age, gender and BMI. This has been confirmed in other studies investigating the association between n-3 PUFA and inflammatory markers in asthma [47
]. However, one study used a semiquantitative FFQ rather than objectively measuring n-3 PUFA [47
]. Another study trialed a fish oil supplement for eight weeks (800 mg or 3400 mg per day), with neither dose producing a reduction in CRP [48
However, other studies have found positive effects of n-3 PUFA on systemic inflammatory markers in asthma. Farjadian et al. [15
] studied children with asthma and demonstrated a reduction in TNF-α and IL-17A in 72% of subjects after n-3 PUFA supplementation (180 mg EPA and 120 mg DHA daily) for 3 months [15
]. This study also demonstrated an improvement in asthma symptoms, while Mickleborough et al. [16
] found that supplementing n-3 PUFA (3.2 g EPA and 2.2 g DHA) in elite athletes over three weeks suppressed exercise-induced bronchoconstriction and inflammatory markers such as TNF-α and IL-1β.
A review examining the impact of n-3 PUFA supplementation on inflammatory biomarkers across a variety of diseases found that, particularly in cardiac populations and the critically ill, omega-3 fatty acid supplementation can reduce a variety of inflammatory biomarkers including CRP, IL-6 and TNF-α [50
]. However systematic inflammation is not reported in systematic reviews on n-3 PUFA and asthma due to irregularity in reporting [19
]. Considering the heterogeneity between studies with pathway, dose and duration, further research is needed to further elucidate this relationship.
A recent review by Kumar et al. [51
] highlighted a need for further research involving n-3 PUFA in specific asthma sub-populations, as there is a gap in knowledge for the use of n-3 PUFA in obese subjects with asthma. Considering our findings, which demonstrate that a higher O3I in obese asthmatics is associated with lower CRP and maintenance ICS dose, n-3 PUFA supplementation may provide a unique nonpharmacological approach to treating asthma in this population and demands further research.
As expected, subjects with asthma had poorer lung function and increased airway inflammation compared to those without asthma. Airway inflammation is a key feature of asthma and is characterised by increased levels of eosinophils, neutrophils, or both, in the airways [25
]. While increased systemic inflammation has been reported in some studies of asthma, this was only significant in CRP between our two groups. This may be related to the higher erythrocyte percentage of n-3 fatty acids that we observed in asthma compared to controls. We are unsure why this occurred in our cohort, but we suspect this must be due to higher dietary intake or supplement use by the asthma group.
Strengths of our study include the use of O3I. O3I is an objective and validated measure of n-3 PUFA intake, as erythrocyte fatty acids represent habitual intake and individual bioavailability as opposed to plasma fatty acids, which reflect shorter term intake [12
]. Erythrocyte fatty acids are more accurate than subjective measures such as FFQs, which rely on accurate recounting of dietary intake, as well as interpretation.
There were some limitations to the study. This was an older cohort, limiting our study’s ability to be generalised to younger populations. In addition, subjects with and without asthma were not matched for sex or BMI. However, where differences existed, analyses have been adjusted for sex, age and BMI. Another limitation was that fish oil supplementation and dietary intake of fish were not recorded across the studies. It would be important to account for this in future research to determine which pathway more effectively changes n-3 PUFA status in this population. Dietary intake data would also be able to address possible confounding by other anti- or proinflammatory foods or nutrients, which we were not able to account for in this study. Lastly, socioeconomic status data for subjects were not available. Considering the established relationship between education and financial status with n-3 PUFA status [53
] it would have been beneficial to investigate this relationship in a population with asthma, and would be important to assess in future studies. Furthermore, this cohort may be more representative of subjects with high socioeconomic advantage. The higher median O3I in our asthmatic and nonasthmatic subjects was higher than expected for average Australians. Previous research suggests that, on average, Australians consume 395 mg of n-3 PUFA per day [55
], equivalent to an O3I of approximately 4–5%.
The cross-sectional study design cannot determine causality; as such, further intervention studies are needed. Nevertheless, our study adds important insight into the relationship between n-3 PUFA and asthma outcomes.