M.S. Mukherjee, Health Sciences (N118) GPO Box 2100, Adelaide 5001, South Australia. E-mail: mitali.mukherjee@flinders.edu.au.
Search for other works by this author on: Chad Y Han , Chad Y Han are with the Caring Futures Institute, College of Nursing and Health Sciences, Flinders University , Bedford Park, South Australia, Search for other works by this author on: Shawgi Sukumaran , Shawgi Sukumaran are with the College of Medicine and Public Health, Flinders University , Bedford Park, South Australia, is with the Department of Medical Oncology, Flinders Medical Centre, Bedford Park , South Australia, Search for other works by this author on: Christopher L Delaney , Christopher L Delaney are with the College of Medicine and Public Health, Flinders University , Bedford Park, South Australia, is with the Department of Vascular Surgery, Flinders Medical Centre , Bedford Park, South Australia, Search for other works by this author on: Michelle D Miller Michelle D Miller are with the Caring Futures Institute, College of Nursing and Health Sciences, Flinders University , Bedford Park, South Australia, Search for other works by this author on:Nutrition Reviews, Volume 81, Issue 1, January 2023, Pages 55–74, https://doi.org/10.1093/nutrit/nuac045
13 July 2022Mitali S Mukherjee, Chad Y Han, Shawgi Sukumaran, Christopher L Delaney, Michelle D Miller, Effect of anti-inflammatory diets on inflammation markers in adult human populations: a systematic review of randomized controlled trials, Nutrition Reviews, Volume 81, Issue 1, January 2023, Pages 55–74, https://doi.org/10.1093/nutrit/nuac045
Navbar Search Filter Mobile Enter search term Search Navbar Search Filter Enter search term SearchChronic inflammation, characterized by prolonged elevated inflammation markers, is linked to several chronic conditions. Diet can influence the levels of inflammation markers in the body.
The aim of this systematic review was to assess the effects of anti-inflammatory diets on 14 different inflammation markers in adults.
Data SourcesThis systematic review conducted searches using Medline, PubMed, EMCare, Cochrane, and CINAHL, to locate randomized controlled trials (RCTs).
Data ExtractionTwo researchers independently screened 1537 RCTs that measured changes in inflammation markers after prescription of an intervention diet.
Data AnalysisIn total, 20 RCTs were included and assessed qualitatively. The results demonstrated that a Mediterranean diet can bring about statistically significant and clinically meaningful between-group differences in interleukins -1α, -1β, -4, -5, -6, -7, -8, -10, and -18, interferon γ, tumor necrosis factor α, C-reactive protein, and high-sensitivity C-reactive protein, as compared with a control diet.
ConclusionsThere may be a link between diet, inflammation markers, and disease outcomes in various adult populations. However, further research using consistent RCT protocols is required to determine correlations between diet, specific inflammation markers, and clinically relevant outcomes.
Inflammation is the body’s defense mechanism against harmful stimuli such as injury, toxins, or irradiation. It is characterized by redness, pain, heat, swelling, or loss of tissue function, which results from the activation of inflammatory pathways and the secretion of inflammatory markers, such as C-reactive protein (CRP), interleukins (ILs) and tumor necrosis factor (TNF). While acute inflammation is useful in restoring tissues and minimizing injury via cellular and molecular events, allowing the inflammation to continue uncontrolled can lead to chronic inflammatory states and result in irreversible DNA and tissue damage. 1 Several chronic conditions such as obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, and certain cancers have been linked to chronic inflammation. 2 , 3 Inflammation has also been implicated in the perpetuation of neuroinflammatory processes that can increase the risk of cognitive decline and lead to the development of neurodegenerative conditions such as dementia and Alzheimer’s disease. 4 , 5
Diet can have an impact on the pro- and anti-inflammatory cytokines and chemokines in the body. A diet consisting of large amounts of simple carbohydrates, saturated fats, processed meats, and fried foods, has been associated with a pro-inflammatory state in the body. 6 In contrast, a diet that is rich in fruits and vegetables, spices, herbs, wholegrains, and fish has been associated with a higher likelihood of an anti-inflammatory state in the body. 6 While the definition of an “anti-inflammatory diet” needs further clarity in the current literature, common examples are the Mediterranean diet and the dietary advice to stop hypertension (DASH). The Mediterranean diet is characterized by high intakes of wholegrains, fruits, vegetables, nuts, and legumes; moderate intake of poultry, fish, and red wine; low intake of processed foods and red meat; and use of olive oil as the main fat source. 7 Similar to the Mediterranean diet, the DASH diet also consists of high intakes of wholegrains, fruits, vegetables, and nuts; however, in contrast, the DASH diet recommends intake of low-fat dairy, low sodium intake, and minimal alcohol. 5 , 8
Traditionally, “diet and disease”–related studies have primarily focused on determining the effects of isolated nutrients on disease risk factors and health outcomes. However, this approach tends to overlook the synergistic effects of correlated nutrients. Therefore, it is vital to undertake holistic research that examines combinations of foods and dietary patterns, as opposed to isolated nutrients, to address this limitation. 2
Various observational studies have identified associations of dietary patterns with inflammation markers and subsequent risk of developing chronic diseases. From the Nurse’s Health Study (NHS), consisting of nested case–control (n = 732) and cohort study designs (n = 35 340 and n = 89 311), a positive association was found between higher quintiles of dietary pattern score (represented by a diet high in sugar-sweetened drinks, processed meat, and refined grains and low in fruit and vegetables) and increased risk of developing type 2 diabetes and elevated inflammation markers. 9
A review of dietary patterns suggests that adherence to a Mediterranean diet was negatively associated with inflammation. A Mediterranean diet is a dietary pattern explored by observational studies that has shown a consistent and inverse relationship between adherence and inflammation. 6 The ATTICA study (with 3042 participants) suggested that greater adherence to a Mediterranean diet was associated with lower levels of CRP and IL-6. 10
The Vasterbotten Intervention Programme was a population-based prospective cohort study conducted on 100 881 people to determine associations between dietary patterns and cancer risk. Dietary patterns were measured via the dietary inflammatory index (DII) and the Mediterranean diet score. 11 Briefly, the DII is a scoring system used to categorize the inflammatory potential of diet in a continuum, with more positive scores indicating a pro-inflammatory diet and, conversely, more negative scores indicating a more anti-inflammatory diet. This index was developed after using data from 1943 articles and reviewing the effect of diet (45 food parameters) on inflammatory biomarkers such as IL-1β, IL-4, IL-6, IL-10, TNF-α, and CRP. 12 , 13 The Mediterranean diet score is a 14-item tool that evaluates adherence to a Mediterranean diet. 10 A higher score indicates better adherence to the Mediterranean diet. The hazards ratio and 95% confidence interval (CI) were 0.97 (0.94–0.99) for a lower DII and 0.97 (0.94–1.00) for a higher Mediterranean diet score. Therefore, the results of this study showed that a lower DII (0.97 [0.94–0.99]) and higher Mediterranean diet score (0.97 [0.94–1.00]) were weakly associated with a lower risk of all cancers after a median 15-year follow-up. 14
Observational studies have also demonstrated that greater adherence to Mediterranean diet and DASH diets could be protective against cognitive decline and hence play a role in reducing the risk of neurodegenerative diseases. 5 , 15 , 16
A previous systematic review and meta-analysis explored the effect of various diets on inflammation markers (mainly CRP) in patients with metabolic syndrome. 17 The current systematic review examined a wider and pertinent scope: the effects of diets classified as “anti-inflammatory” on various inflammation markers in wider adult population groups using the inclusion and exclusion criteria set for this systematic review.
The primary aim of this review was to determine the effects of an anti-inflammatory diet on inflammation markers in the body. The secondary aim of this study was to determine the constituents of an “anti-inflammatory” diet. Additional outcomes explored are relevant disease-related outcomes, to briefly determine clinical relevance.
This systematic review has been conducted in accordance with the PRISMA guidelines. 18
The PICOS criteria used to define the research question and the inclusion and exclusion criteria set for this review have been described in Table 1. Five electronic databases (Medline, PubMed, EMCare, Cochrane, and CINAHL) were searched using translated search strategies from inception to August 2020. The search strategies were reviewed by research librarians from the Flinders University Library Services. This systematic review was registered and published on PROSPERO on October 25, 2020. A flow diagram of article selection has been depicted in Figure 1.
PICOS criteria for inclusion and exclusion of studies
| Parameter . | Inclusion criterion . | Exclusion criterion . |
|---|---|---|
| Participants | Studies conducted on humans aged 18 years and above, with or without chronic health condition(s) | Studies conducted on ages below 18, or on pregnant or lactating individuals |
| Interventions | Studies that use whole foods such as an anti-inflammatory, Mediterranean, DASH, or a low inflammatory diet as the intervention | Studies that test medications or exercise alongside chosen interventionsStudies that include immunonutrient oral supplements or capsules as the interventionStudies that include other types of diets, eg, weight-loss or ketogenic diets alongside the anti-inflammatory dietary intervention |
| Comparisons | Control or habitual diets | |
| Outcomes | Studies that use wholefood such as an anti-inflammatory, Mediterranean, DASH, or low inflammatory diet as the intervention | Studies that do not measure pre– and post–dietary intervention levels of inflammatory markers as primary or secondary outcomes |
| Study design | Studies that have a randomized controlled trial design or interventional design with a control | Retrospective studies |
| Parameter . | Inclusion criterion . | Exclusion criterion . |
|---|---|---|
| Participants | Studies conducted on humans aged 18 years and above, with or without chronic health condition(s) | Studies conducted on ages below 18, or on pregnant or lactating individuals |
| Interventions | Studies that use whole foods such as an anti-inflammatory, Mediterranean, DASH, or a low inflammatory diet as the intervention | Studies that test medications or exercise alongside chosen interventionsStudies that include immunonutrient oral supplements or capsules as the interventionStudies that include other types of diets, eg, weight-loss or ketogenic diets alongside the anti-inflammatory dietary intervention |
| Comparisons | Control or habitual diets | |
| Outcomes | Studies that use wholefood such as an anti-inflammatory, Mediterranean, DASH, or low inflammatory diet as the intervention | Studies that do not measure pre– and post–dietary intervention levels of inflammatory markers as primary or secondary outcomes |
| Study design | Studies that have a randomized controlled trial design or interventional design with a control | Retrospective studies |
PICOS criteria for inclusion and exclusion of studies
| Parameter . | Inclusion criterion . | Exclusion criterion . |
|---|---|---|
| Participants | Studies conducted on humans aged 18 years and above, with or without chronic health condition(s) | Studies conducted on ages below 18, or on pregnant or lactating individuals |
| Interventions | Studies that use whole foods such as an anti-inflammatory, Mediterranean, DASH, or a low inflammatory diet as the intervention | Studies that test medications or exercise alongside chosen interventionsStudies that include immunonutrient oral supplements or capsules as the interventionStudies that include other types of diets, eg, weight-loss or ketogenic diets alongside the anti-inflammatory dietary intervention |
| Comparisons | Control or habitual diets | |
| Outcomes | Studies that use wholefood such as an anti-inflammatory, Mediterranean, DASH, or low inflammatory diet as the intervention | Studies that do not measure pre– and post–dietary intervention levels of inflammatory markers as primary or secondary outcomes |
| Study design | Studies that have a randomized controlled trial design or interventional design with a control | Retrospective studies |
| Parameter . | Inclusion criterion . | Exclusion criterion . |
|---|---|---|
| Participants | Studies conducted on humans aged 18 years and above, with or without chronic health condition(s) | Studies conducted on ages below 18, or on pregnant or lactating individuals |
| Interventions | Studies that use whole foods such as an anti-inflammatory, Mediterranean, DASH, or a low inflammatory diet as the intervention | Studies that test medications or exercise alongside chosen interventionsStudies that include immunonutrient oral supplements or capsules as the interventionStudies that include other types of diets, eg, weight-loss or ketogenic diets alongside the anti-inflammatory dietary intervention |
| Comparisons | Control or habitual diets | |
| Outcomes | Studies that use wholefood such as an anti-inflammatory, Mediterranean, DASH, or low inflammatory diet as the intervention | Studies that do not measure pre– and post–dietary intervention levels of inflammatory markers as primary or secondary outcomes |
| Study design | Studies that have a randomized controlled trial design or interventional design with a control | Retrospective studies |
Flow diagram depicting the process involved in the identification, screening, and inclusion of articles chosen for the systematic review. Abbreviations: RCT, randomized controlled trial
The search results were exported to Covidence software. Duplicates were eliminated. All titles and abstracts were independently screened by 2 reviewers (M.S.M. and C.Y.H.) against the inclusion and exclusion criteria. Any conflicts that arose were resolved through arriving at a consensus. Full-text articles were also independently assessed, and any conflicts that arose were resolved by reaching a consensus involving a third reviewer (M.D.M.).
Data extraction and quality assessment of all articles deemed appropriate to include were independently completed by 2 reviewers (M.S.M. and C.Y.H.). Information such as author details, country, study design, population characteristics (age, gender ratio, and disease state), sample size, intervention and control characteristics, dietary intake measure, compliance measure, involvement of dietitian, pre- and post-intervention outcome values (for inflammation markers), in conjunction with their statistical significance and relevant disease-related outcomes, was extracted from all articles in 2 separate Excel sheets. The data were then collated, and any conflicts in data extracted were resolved via another review of the original articles.
The Cochrane Risk-of-Bias 2.0 tool was utilized for quality assessment of the chosen articles by 2 independent reviewers (M.S.M. and C.Y.H.). 19 Five key domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results were explored. Within each domain, the assessment classified studies as “high risk,” having “some concern,” or “low risk.” An overall rating of “high risk,” having “some concern,” or “low risk” was given to each study, based on the ratings in the 5 aforementioned domains.
Out of the 2278 studies imported for screening, 741 duplicates were removed. The remaining 1537 studies were screened for title and abstract, and 45 were deemed appropriate for full-text review. Finally, 20 articles were deemed eligible for inclusion in this systematic review. Reasons for excluding articles were: inclusion of intervention consisting of a single food item in place of a diet; hypocaloric interventions; inflammatory markers not measured at baseline and follow-up; provision of intervention in a supplement, pill, capsule, or syrup or as a 1-time meal; unpublished results; studies conducted in pediatric, pregnant, or lactating populations; and inclusion of multiple interventions, such as exercise programs.
The study characteristics have been summarized in Table 2 20–39 and Table 3. 20–39
Demographic characteristics and inflammation markers measured in 20 randomized controlled trials examining the effects of anti-inflammatory diet interventions on inflammation markers in adult populations
C: control; CRP: C-reactive protein; CR: crossover study; DAS-28: disease activity score-28; DASH: dietary action to stop hypertension; EVOO: extra virgin olive oil; hs-CRP: high-sensitivity C-reactive protein; HL: hyperlipidemia; hs: high-sensitivity; HT: hypertension; I: intervention; I1: Mediterranean diet + extra virgin olive oil; I2: Mediterranean diet + nuts; I2X: Mediterranean diet with washed olive oil; IFN: interferon; IL: interleukin; NR: not reported; PR: parallel study; RCT: randomized controlled trial; T2DM: type 2 diabetes mellitus; TNF: tumor necrosis factor; W: wash-out period; β: beta; γ: gamma.
Demographic characteristics and inflammation markers measured in 20 randomized controlled trials examining the effects of anti-inflammatory diet interventions on inflammation markers in adult populations
C: control; CRP: C-reactive protein; CR: crossover study; DAS-28: disease activity score-28; DASH: dietary action to stop hypertension; EVOO: extra virgin olive oil; hs-CRP: high-sensitivity C-reactive protein; HL: hyperlipidemia; hs: high-sensitivity; HT: hypertension; I: intervention; I1: Mediterranean diet + extra virgin olive oil; I2: Mediterranean diet + nuts; I2X: Mediterranean diet with washed olive oil; IFN: interferon; IL: interleukin; NR: not reported; PR: parallel study; RCT: randomized controlled trial; T2DM: type 2 diabetes mellitus; TNF: tumor necrosis factor; W: wash-out period; β: beta; γ: gamma.
Of the 20 studies included in this systematic review, 7 studies were conducted in Spain 20–22 , 26 , 28 , 29 , 33 ; 4 studies in Australia 23 , 27 , 31 , 38 , 40 ; 3 studies in the United States 25 , 35 , 39 ; 2 studies in Poland 30 , 36 ; 1 study each in the United Kingdom 24 ; Sweden 37 ; Iran 34 ; and Algeria. 32 Only 3 studies had a crossover design, 27 , 37 , 38 and all other studies had a parallel design. The earliest study included in this article was conducted in 2003, 25 while the latest studies were conducted in 2020. 30 , 34 , 37 The sample sizes in the studies ranged from a minimum of 30 people 39 to a maximum of 772 people. 26 The duration of the intervention was: 3 months 25 , 27 , 28 , 32–34 for 6 studies; 6 months for 6 studies 23 , 30 , 31 , 35 , 36 , 38 ; 5 years 20 , 22 for 2 studies; 1 year 21 , 29 for 2 studies; 1.5 months, 39 4 months, 24 2.5 months, 37 and 4 years 26 for 1 study each. Mixed population groups consisting of participants with or without: type 2 diabetes, hypertension, or dyslipidemia 20–22 , 26 , 29 , 33 , 38 were included in 7 studies; chronic disease 23 , 25 , 28 in 3 studies; diabetes and prediabetes 27 , 39 in 2 studies; osteoarthritis in 1 study 24 ; rheumatoid arthritis 37 in 1 study; multiple sclerosis 34 in 1 study; chronic renal failure 32 in 1 study; kidney transplant recipients 36 in 1 study; patients at risk of colon cancer 35 in 1 study; and individuals with coronary artery disease in 2 studies. 30 , 31
Fifteen of the studies included used a Mediterranean diet as their intervention. 20–24 , 26–29 , 31–33 , 35 , 36 , 38 Of these, 7 studies included a total of 3 arms. 20–22 , 26 , 28 , 29 , 33 Six of these 7 studies included interventions such as a Mediterranean diet supplemented with extra virgin olive oil (EVOO) in 1 arm, a Mediterranean diet supplemented with nuts in another arm, and a low-fat diet in the control arm. 20 , – 22 , 26 , 29 , 33 The seventh study included a Mediterranean diet supplemented with EVOO in 1 arm, a Mediterranean diet supplemented with washed olive oil in the second arm, and a low-fat diet in the control arm. 28
Three studies included a type of “anti-inflammatory” diet as the intervention, 34 , 37 , 39 and 2 studies included a DASH diet as the intervention. 25 , 30
For the studies included in this review, the control group were administered a low-fat diet in 9 studies, 20–22 , 26 , 29 , 31 , 33 , 36 , 38 their habitual diet or an unmodified diet in 6 studies, 23 , 24 , 27 , 28 , 30 , 32 the American Diabetes Association diet in 1 study, 39 healthy diet recommendations in 2 studies, 34 , 35 and the Swedish diet in 1 study. 37
The Mediterranean diet intervention promoted inclusion of EVOO, vegetables, nuts, wholegrains, legumes, and fish, and suggested limiting of processed foods and red meat. 20–24 , 26–29 , 31–33 , 35 , 36 , 38 DASH diets promoted consumption of fruits, vegetables, and low-fat dairy products. 25 , 30 Two 34 , 37 of the 3 dietary interventions described as “anti-inflammatory” diets had similar features to the Mediterranean dietary intervention, whereas the third 39 prescribed exclusion and inclusion of specific foods items as shown in Table 3.
Intervention characteristics of and compliance in 20 randomized controlled trials examining the effects of anti-inflammatory diet interventions on inflammation markers in adult populations
Mediterranean diet supplemented with nuts
Common features in both interventions
Mediterranean diet supplemented with nuts
Common features in both interventions
DASH: dietary action to stop hypertension; EVOO: extra virgin olive oil; FFQ: food frequency questionnaire; HL: hyperlipidemia; HT: hypertension; MDS: Mediterranean diet score; MUFAs: monounsaturated fatty acids; T2DM: type 2 diabetes mellites.
Intervention characteristics of and compliance in 20 randomized controlled trials examining the effects of anti-inflammatory diet interventions on inflammation markers in adult populations
Mediterranean diet supplemented with nuts
Common features in both interventions
Mediterranean diet supplemented with nuts
Common features in both interventions
DASH: dietary action to stop hypertension; EVOO: extra virgin olive oil; FFQ: food frequency questionnaire; HL: hyperlipidemia; HT: hypertension; MDS: Mediterranean diet score; MUFAs: monounsaturated fatty acids; T2DM: type 2 diabetes mellites.
Measurement of the following inflammatory markers was reported in the included studies: CRP 21 , 25–28 , 32 , 33 , 35 , 36 , 38 or high-sensitivity (hs)-CRP, 20 , 23 , 30 , 31 , 34 , 39 (16 studies); IL-6 ( 9 studies) 20–22 , 24 , 26 , 31 , 33 , 35 , 39 ; TNFα (6 studies) 20 , 22 , 24 , 29 , 35 , 39 ; IL-10 (4 studies) 21–23 , 28 , 35 ; IFNγ (4 studies) 21 , 22 , 24 , 35 ; IL-1β and IL-8 22 , 24 , 35 (3 studies); IL-4 (3 studies) 24 , 34 , 35 ; IL-18 (2 studies) 21 , 22 ; IL-13 (2 studies) 22 , 35 ; IL-1α and IL-2 (1 study) 24 ; IL-5, IL-12, IL-7, and IL-17 (1 study). 22
A summary of the changes observed in the inflammation markers has been summarized in Table 4.
Summary of results illustrating the type of cytokines measured, number of studies that measured respective cytokine levels, and number of studies that demonstrated a statistically significant increase or decrease in respective cytokine levels in intervention and control groups
| Cytokine measured . | Number of studies that measured cytokine levels . | Number of studies demonstrating statistically significant cytokine levels ↑ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↓ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↑ in control group . | Number of studies demonstrating statistically significant cytokine levels ↓ in control group . |
|---|---|---|---|---|---|
| CRP/hsCRP | 16 | 1 | 8 | 1 | 0 |
| IL-1α | 1 | 0 | 1 | 0 | 0 |
| IL-1β | 3 | 0 | 1 | 0 | 0 |
| IL-2 | 1 | 0 | 0 | 0 | 0 |
| IL-4 | 3 | 0 | 1 | 0 | 0 |
| IL-5 | 1 | 0 | 1 | 0 | 0 |
| IL-6 | 9 | 0 | 5 | 1 | 0 |
| IL-7 | 1 | 0 | 1 | 0 | 0 |
| IL-8 | 3 | 0 | 1 | 1 | 0 |
| IL-10 | 4 | 2 | 0 | 0 | 0 |
| IL-13 | 1 | 1 | 0 | 0 | 0 |
| IL-17 | 1 | 0 | 0 | 0 | 0 |
| IFNγ | 4 | 0 | 2 | 0 | 0 |
| TNFα | 6 | 0 | 3 | 1 | 0 |
| Cytokine measured . | Number of studies that measured cytokine levels . | Number of studies demonstrating statistically significant cytokine levels ↑ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↓ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↑ in control group . | Number of studies demonstrating statistically significant cytokine levels ↓ in control group . |
|---|---|---|---|---|---|
| CRP/hsCRP | 16 | 1 | 8 | 1 | 0 |
| IL-1α | 1 | 0 | 1 | 0 | 0 |
| IL-1β | 3 | 0 | 1 | 0 | 0 |
| IL-2 | 1 | 0 | 0 | 0 | 0 |
| IL-4 | 3 | 0 | 1 | 0 | 0 |
| IL-5 | 1 | 0 | 1 | 0 | 0 |
| IL-6 | 9 | 0 | 5 | 1 | 0 |
| IL-7 | 1 | 0 | 1 | 0 | 0 |
| IL-8 | 3 | 0 | 1 | 1 | 0 |
| IL-10 | 4 | 2 | 0 | 0 | 0 |
| IL-13 | 1 | 1 | 0 | 0 | 0 |
| IL-17 | 1 | 0 | 0 | 0 | 0 |
| IFNγ | 4 | 0 | 2 | 0 | 0 |
| TNFα | 6 | 0 | 3 | 1 | 0 |
A P value of Abbreviations: ↑: increase; ↓: decrease; CRP: C-reactive protein; hsCRP: high-sensitivity C-reactive protein; IL-1α: interleukin 1 alpha; IL-1β: interleukin 1 beta; IL-2: interleukin 2; IL-4: interleukin 4; IL-5: interleukin 5; IL-6: interleukin-6; IL-7: interleukin 7; IL-8: interleukin 8; IL-10: interleukin 10; IL-13: interleukin 13; IL-17: interleukin 17; IFNγ: interferon gamma; TNFα: tumor necrosis factor alpha.
Summary of results illustrating the type of cytokines measured, number of studies that measured respective cytokine levels, and number of studies that demonstrated a statistically significant increase or decrease in respective cytokine levels in intervention and control groups
| Cytokine measured . | Number of studies that measured cytokine levels . | Number of studies demonstrating statistically significant cytokine levels ↑ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↓ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↑ in control group . | Number of studies demonstrating statistically significant cytokine levels ↓ in control group . |
|---|---|---|---|---|---|
| CRP/hsCRP | 16 | 1 | 8 | 1 | 0 |
| IL-1α | 1 | 0 | 1 | 0 | 0 |
| IL-1β | 3 | 0 | 1 | 0 | 0 |
| IL-2 | 1 | 0 | 0 | 0 | 0 |
| IL-4 | 3 | 0 | 1 | 0 | 0 |
| IL-5 | 1 | 0 | 1 | 0 | 0 |
| IL-6 | 9 | 0 | 5 | 1 | 0 |
| IL-7 | 1 | 0 | 1 | 0 | 0 |
| IL-8 | 3 | 0 | 1 | 1 | 0 |
| IL-10 | 4 | 2 | 0 | 0 | 0 |
| IL-13 | 1 | 1 | 0 | 0 | 0 |
| IL-17 | 1 | 0 | 0 | 0 | 0 |
| IFNγ | 4 | 0 | 2 | 0 | 0 |
| TNFα | 6 | 0 | 3 | 1 | 0 |
| Cytokine measured . | Number of studies that measured cytokine levels . | Number of studies demonstrating statistically significant cytokine levels ↑ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↓ in intervention group/s . | Number of studies demonstrating statistically significant cytokine levels ↑ in control group . | Number of studies demonstrating statistically significant cytokine levels ↓ in control group . |
|---|---|---|---|---|---|
| CRP/hsCRP | 16 | 1 | 8 | 1 | 0 |
| IL-1α | 1 | 0 | 1 | 0 | 0 |
| IL-1β | 3 | 0 | 1 | 0 | 0 |
| IL-2 | 1 | 0 | 0 | 0 | 0 |
| IL-4 | 3 | 0 | 1 | 0 | 0 |
| IL-5 | 1 | 0 | 1 | 0 | 0 |
| IL-6 | 9 | 0 | 5 | 1 | 0 |
| IL-7 | 1 | 0 | 1 | 0 | 0 |
| IL-8 | 3 | 0 | 1 | 1 | 0 |
| IL-10 | 4 | 2 | 0 | 0 | 0 |
| IL-13 | 1 | 1 | 0 | 0 | 0 |
| IL-17 | 1 | 0 | 0 | 0 | 0 |
| IFNγ | 4 | 0 | 2 | 0 | 0 |
| TNFα | 6 | 0 | 3 | 1 | 0 |
A P value of Abbreviations: ↑: increase; ↓: decrease; CRP: C-reactive protein; hsCRP: high-sensitivity C-reactive protein; IL-1α: interleukin 1 alpha; IL-1β: interleukin 1 beta; IL-2: interleukin 2; IL-4: interleukin 4; IL-5: interleukin 5; IL-6: interleukin-6; IL-7: interleukin 7; IL-8: interleukin 8; IL-10: interleukin 10; IL-13: interleukin 13; IL-17: interleukin 17; IFNγ: interferon gamma; TNFα: tumor necrosis factor alpha.
A total of 9 studies measured IL-6 levels 20–22 , 24 , 26 , 31 , 33 , 35 , 39 ; of these, 8 studies used a Mediterranean diet as the intervention, while 1 used an anti-inflammatory diet as the intervention. 39
There were statistically significant differences between the intervention groups and the control groups with respect to changes in IL-6 levels. In 5 of the 9 studies, IL-6 decreased in the intervention groups (provided the Mediterranean diet was supplemented with nuts or EVOO), whereas no decrease in IL-6 was observed in the respective control groups. 20–22 , 26 , 33 The remaining studies demonstrated no differences between groups. 24 , 31 , 35 , 39 All of the studies that demonstrated a decrease in IL-6 levels administered a Mediterranean diet as the intervention. Statistically significant decreases could be noticed after an intervention duration of as little as 3 months, within and between groups. 33
Sixteen studies measured pre– and post–dietary intervention levels of either CRP or hs-CRP; of these 16, 12 provided a Mediterranean diet as the intervention, 20 , 21 , 23 , 26–28 , 31–33 , 35 , 36 , 38 2 provided an anti-inflammatory diet as the intervention, 34 , 39 and 2 provided a DASH diet as the intervention. 25 , 30 Six of the 16 studies demonstrated a statistically significant decrease in CRP or hsCRP levels in the intervention group/s as compared with the control group. 20 , 21 , 26 , 28 , 33 , 35 One study demonstrated a greater decrease after an intervention of a Mediterranean diet supplemented with EVOO than after a Mediterranean diet supplemented with nuts. 33 Statistically significant decreases between and within groups could be noticed after an intervention duration of as little as 3 months in 2 studies. 28 , 33
Of the 6 studies that measured pre– and post–dietary intervention levels of TNFα, 5 provided a Mediterranean diet as the intervention, 20 , 22 , 24 , 29 , 35 and 1 study provided an anti-inflammatory diet as the intervention. 39 Two studies demonstrated a statistically significant decrease in TNFα levels in the arm specifically providing a Mediterranean diet supplemented with EVOO, as compared with a control arm. 20 , 22 No differences were noticeable in any of the other groups.
All 4 studies that measured IFNγ provided a Mediterranean diet as the intervention. 21 , 22 , 24 , 35 In 1 of these 4 studies, the IFNγ level decrease was greater in the Mediterranean diet arm supplemented with EVOO than that in the Mediterranean diet arm supplemented with nuts. 22 In another study, although a statistically significant decrease in IFNγ (level) was seen in the Mediterranean diet arm providing EVOO, no changes were noticeable in the intervention arm providing a Mediterranean diet with nuts or in the control arm. 28 Overall, no changes were observable in the control groups in any of the studies that measured IFNγ. Statistically significant decreases within the intervention group could be noticed after an intervention duration of as little as 3 months. 28
Only 1 study (which administered a Mediterranean diet as the intervention) measured IL-1α. That study demonstrated a statistically significant decrease in IL-1α levels at follow-up in the intervention group as compared with the control group. 24
Only 1 22 out of 3 studies 22 , 24 , 35 (which provided a Mediterranean diet as the intervention) measured pre– and post–dietary intervention IL-1β levels. That study found a statistically significant decrease in the IL-1β levels at follow-up in the intervention group as compared with the control group.
Only 1 study (which provided a Mediterranean diet as the intervention) measured IL-2 levels. No significant within-group changes or between-group differences were found for the intervention or control groups in that study. 24
Three studies 24 , 34 , 35 measured pre– and post–dietary intervention levels of IL-4, 2 of which provided a Mediterranean diet 24 , 35 as the intervention, and the other an anti-inflammatory diet 34 . The study with the anti-inflammatory diet intervention demonstrated a statistically significant increase in IL-4 levels at follow-up 34 in the intervention group as compared with the control group. No significant changes were observed in the remaining studies. A statistically significant decrease between and within groups could be noticed after an intervention duration of 3 months. 34
All 3 studies that measured IL-8 levels provided a Mediterranean diet as the intervention. 24 , 34 , 35 In 1 study, a statistically significant decrease in IL-8 levels was observable in the intervention groups as compared with the control group, 22 but no within- or between-group changes were observed in the other 2 studies. 24 , 35 Similar decreases in IL-8 levels were seen in the Mediterranean diet intervention arms supplemented with either EVOO or nuts, with a 0.88 pg/mL vs 0.82 pg/mL decrease, respectively. However, in the same study, the control group showed a 0.73 pg/mL increase in IL-8 levels. 22
All 4 studies that measured IL-10 levels provided a Mediterranean diet as the intervention. 21 , 22 , 24 , 35 Only 1 of those 4 studies demonstrated a greater decrease in the intervention group as compared with the control group that was statistically significant. 24
Only 1 study (which provided a Mediterranean diet as the intervention) measured IL-5 levels. In that study, a similar statistically significant decrease in the IL-5 level was observed in the Mediterranean diet supplemented with EVOO intervention arm to that observed in the arm with a Mediterranean diet supplemented with nuts (0.25 pg/mL vs 0.17 pg/mL, respectively), whereas no changes were observable in the control group. 22
Only 1 study (which provided a Mediterranean diet as the intervention) measured IL-7. In that study, statistically significant decreases in the IL-7 levels were observed in the Mediterranean diet intervention arms that supplied either EVOO or nuts, as compared with the control group. The IL-7 magnitude of decrease was comparable in those 2 arms, being 0.44 pg/mL vs 0.36 pg/mL, respectively. No changes were observed in the control group. 22
Two studies, both providing a Mediterranean diet as the intervention, measured IL-13 levels. 22 , 35 No statistically significant between-group changes were observable in either study.
Only 1 study (which provided an anti-inflammatory diet as the intervention) measured pre– and post–dietary intervention IL-17 levels. However, no significant within- or between-group changes were found in either of the intervention arm or the control arm in that study. 34
Only 1 study (which administered a Mediterranean diet as the intervention) measured IL-12 levels, and no significant differences between the intervention and control groups were found. 22
Two studies (which provided a Mediterranean diet as the intervention) measured IL-18, and they both observed statistically significant changes between baseline and follow-up values. 21 , 22 An arm that provided a Mediterranean diet with EVOO showed a greater decrease in IL-18 levels compared with an arm not supplemented with EVOO and a control arm. 22
The Mediterranean diet intervention brought about a statistically significant decrease in IL-1α levels in the osteoarthritis population group in 1 study. 24 In addition, a meaningful reduction in serum cartilage oligomeric matrix protein (sCOMP) levels, elevated in patients with knee osteoarthritis, was observed in the group receiving the Mediterranean diet. No changes in inflammation markers or sCOMP levels were noticeable in the control group. 24 Another study that implemented an anti-inflammatory diet in the rheumatoid arthritis population found no differences in Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) or in disease activity in the intervention and control groups. 37
Implementation of an anti-inflammatory diet demonstrated no statistically significant changes in inflammation markers in participants with prediabetes / type 2 diabetes in 1 study. Statistically significant reductions in glucose were noticed in either the intervention group or the control group. There were no statistically significant differences between the intervention and control groups. 39 Another study, which provided the Mediterranean diet to people with diabetes and measured CRP, found no changes in CRP levels post–dietary intervention in the intervention arm and the control arm. However, there was a statistically significant decrease in HbA1c levels in the intervention group, compared with the control group. 27
In populations that were either heathy or living with chronic conditions such as hypertension, type 2 diabetes mellitus, or hyperlipidemia, the PREDIMED study demonstrated statistically significant changes in inflammation markers and differences between post–dietary intervention inflammation markers in the intervention and control groups. In addition, statistically significant reductions in cardiovascular risk factors were observed in groups receiving the interventions, as compared with the control group. 20–22 , 26 , 29 , 33 In the same population, 1 study providing a Mediterranean diet supplemented with pork found no significant changes in cardiovascular risk factors or inflammation markers in either the intervention or control groups. 38
In 1 study conducted in the multiple sclerosis population, while no significant changes were observable in the inflammation markers measured in either the intervention group or the control group, statistically significant improvements were observed in relation to fatigue and quality of life in the group receiving the intervention as compared with the control. 34
In the coronary artery disease population, 1 study that measured DII and cardiovascular risk outcomes did not see a statistically significant decline in inflammation markers or cardiovascular risk factors; however, a positive correlation between decline in DII scores and declines in triglyceride and hs-IL-6 levels was observed in participants who received the Mediterranean diet intervention. 31 In the same population, another study observed a statistically significant decline in blood platelet factor 4 in the group that received the DASH diet intervention, as compared with the control group, but no changes in the inflammation markers measured were observed. 30
One study conducted in the chronic renal failure population found statistically significant reductions in dyslipidemia, inflammation markers, and thiobarbituric acid reactive substances (TBARS) in the intervention group that received an adapted Mediterranean diet, as compared with control. 32 Similarly, another study, conducted in kidney graft recipients patients, also observed a decrease in TBARS and in addition, a statistically significant increase in antioxidant enzyme activities in the intervention group receiving an adapted Mediterranean diet; in that study, however, no changes in the inflammation marker measured (CRP) were observed. 36
In populations free of chronic disease, a Mediterranean diet brought about a statistically significant decline in cardiovascular risk factors as compared with those consuming habitual diet. However, no changes in the inflammation markers measured were observed. 23 Similarly, another study demonstrated that a DASH diet brought about a decline in cardiovascular risk factors, while no changes in the inflammation markers measured were observed. 25
The risk of bias assessment has been summarized in Table 5. 20–39 Overall, 8 studies were judged to have a low risk of bias 20–23 , 26 , 31 , 33 , 37 ; 9 studies demonstrated some concerns of bias 24 , 27 , 28 , 30 , 32 , 34–36 , 38 ; and 3 studies demonstrated a high risk of bias. 25 , 29 , 39 All studies were randomized; however, some studies did not provide details pertaining to the exact method of randomization, resulting in a risk of bias concerning the randomization process. 24 , 27 , 32 , 35 , 36 , 39 In 1 study, due to unequal allocation of participants to the intervention and control arms in the ratio of 2:1, concerns of bias arose in the randomization process; there was also concern over the level of statistical power as the sample size was small. 39 In another study, there were statistically significant differences in baseline values of IFN-y between intervention and control groups leading to concerns regarding the randomization process. 28
Methodological Quality Assessment of 20 randomized controlled trials examining the effect of anti-inflammatory diet interventions on inflammatory markers in adults using Cochrane Risk-of-Bias 2.0 tool
| Study . | Revised Cochrane risk-of-bias tool for randomized trials . | |||||
|---|---|---|---|---|---|---|
| Randomization process . | Deviations from intended interventions . | Missing outcomes . | Measurement of the outcome . | Selection of the reported result . | Overall . | |
| Low risk | ||||||
| Vadell et al (2020) 37 | + | + | + | + | + | + |
| Casas et al (2017) 22 | + | + | + | + | + | + |
| Casas et al (2016) 20 | + | + | + | + | + | + |
| Casas et al (2014) 21 | + | + | + | + | + | + |
| Mena et al (2009) 33 | + | + | + | + | + | + |
| Mayr et al (2018) 31 | + | + | + | + | + | + |
| Estruch et al (2006) 26 | + | + | + | + | + | + |
| Davis et al (2017) 23 | + | + | + | + | + | + |
| Some concern | ||||||
| Dyer et al (2017) 24 | ! | + | + | + | ! | ! |
| Wade et al (2019) 38 | + | + | + | + | ! | ! |
| Mekki et al (2010) 32 | ! | ! | + | + | ! | ! |
| Stachowska et al (2005) 36 | ! | ! | + | + | ! | ! |
| Sidahmed et al (2014) 35 | ! | ! | + | + | + | ! |
| Konstantinidou et al (2010) 28 | ! | + | + | + | ! | ! |
| Itsiopoulos et al (2010) 27 | ! | + | + | + | ! | ! |
| Mousavi-Shirazi-Fard et al (2020) 34 | + | + | + | + | ! | ! |
| Makarewicz-Wujec et al (2020) 30 | + | + | + | + | ! | ! |
| High risk | ||||||
| Zwickey et al (2019) 39 | – | ! | + | + | ! | – |
| Lasa et al (2014) 29 | ! | + | + | + | – | – |
| Erlinger et al (2003) 25 | + | + | + | + | – | – |
| Study . | Revised Cochrane risk-of-bias tool for randomized trials . | |||||
|---|---|---|---|---|---|---|
| Randomization process . | Deviations from intended interventions . | Missing outcomes . | Measurement of the outcome . | Selection of the reported result . | Overall . | |
| Low risk | ||||||
| Vadell et al (2020) 37 | + | + | + | + | + | + |
| Casas et al (2017) 22 | + | + | + | + | + | + |
| Casas et al (2016) 20 | + | + | + | + | + | + |
| Casas et al (2014) 21 | + | + | + | + | + | + |
| Mena et al (2009) 33 | + | + | + | + | + | + |
| Mayr et al (2018) 31 | + | + | + | + | + | + |
| Estruch et al (2006) 26 | + | + | + | + | + | + |
| Davis et al (2017) 23 | + | + | + | + | + | + |
| Some concern | ||||||
| Dyer et al (2017) 24 | ! | + | + | + | ! | ! |
| Wade et al (2019) 38 | + | + | + | + | ! | ! |
| Mekki et al (2010) 32 | ! | ! | + | + | ! | ! |
| Stachowska et al (2005) 36 | ! | ! | + | + | ! | ! |
| Sidahmed et al (2014) 35 | ! | ! | + | + | + | ! |
| Konstantinidou et al (2010) 28 | ! | + | + | + | ! | ! |
| Itsiopoulos et al (2010) 27 | ! | + | + | + | ! | ! |
| Mousavi-Shirazi-Fard et al (2020) 34 | + | + | + | + | ! | ! |
| Makarewicz-Wujec et al (2020) 30 | + | + | + | + | ! | ! |
| High risk | ||||||
| Zwickey et al (2019) 39 | – | ! | + | + | ! | – |
| Lasa et al (2014) 29 | ! | + | + | + | – | – |
| Erlinger et al (2003) 25 | + | + | + | + | – | – |
Key: low risk: +; some concern: !; high risk: –.
Methodological Quality Assessment of 20 randomized controlled trials examining the effect of anti-inflammatory diet interventions on inflammatory markers in adults using Cochrane Risk-of-Bias 2.0 tool
| Study . | Revised Cochrane risk-of-bias tool for randomized trials . | |||||
|---|---|---|---|---|---|---|
| Randomization process . | Deviations from intended interventions . | Missing outcomes . | Measurement of the outcome . | Selection of the reported result . | Overall . | |
| Low risk | ||||||
| Vadell et al (2020) 37 | + | + | + | + | + | + |
| Casas et al (2017) 22 | + | + | + | + | + | + |
| Casas et al (2016) 20 | + | + | + | + | + | + |
| Casas et al (2014) 21 | + | + | + | + | + | + |
| Mena et al (2009) 33 | + | + | + | + | + | + |
| Mayr et al (2018) 31 | + | + | + | + | + | + |
| Estruch et al (2006) 26 | + | + | + | + | + | + |
| Davis et al (2017) 23 | + | + | + | + | + | + |
| Some concern | ||||||
| Dyer et al (2017) 24 | ! | + | + | + | ! | ! |
| Wade et al (2019) 38 | + | + | + | + | ! | ! |
| Mekki et al (2010) 32 | ! | ! | + | + | ! | ! |
| Stachowska et al (2005) 36 | ! | ! | + | + | ! | ! |
| Sidahmed et al (2014) 35 | ! | ! | + | + | + | ! |
| Konstantinidou et al (2010) 28 | ! | + | + | + | ! | ! |
| Itsiopoulos et al (2010) 27 | ! | + | + | + | ! | ! |
| Mousavi-Shirazi-Fard et al (2020) 34 | + | + | + | + | ! | ! |
| Makarewicz-Wujec et al (2020) 30 | + | + | + | + | ! | ! |
| High risk | ||||||
| Zwickey et al (2019) 39 | – | ! | + | + | ! | – |
| Lasa et al (2014) 29 | ! | + | + | + | – | – |
| Erlinger et al (2003) 25 | + | + | + | + | – | – |
| Study . | Revised Cochrane risk-of-bias tool for randomized trials . | |||||
|---|---|---|---|---|---|---|
| Randomization process . | Deviations from intended interventions . | Missing outcomes . | Measurement of the outcome . | Selection of the reported result . | Overall . | |
| Low risk | ||||||
| Vadell et al (2020) 37 | + | + | + | + | + | + |
| Casas et al (2017) 22 | + | + | + | + | + | + |
| Casas et al (2016) 20 | + | + | + | + | + | + |
| Casas et al (2014) 21 | + | + | + | + | + | + |
| Mena et al (2009) 33 | + | + | + | + | + | + |
| Mayr et al (2018) 31 | + | + | + | + | + | + |
| Estruch et al (2006) 26 | + | + | + | + | + | + |
| Davis et al (2017) 23 | + | + | + | + | + | + |
| Some concern | ||||||
| Dyer et al (2017) 24 | ! | + | + | + | ! | ! |
| Wade et al (2019) 38 | + | + | + | + | ! | ! |
| Mekki et al (2010) 32 | ! | ! | + | + | ! | ! |
| Stachowska et al (2005) 36 | ! | ! | + | + | ! | ! |
| Sidahmed et al (2014) 35 | ! | ! | + | + | + | ! |
| Konstantinidou et al (2010) 28 | ! | + | + | + | ! | ! |
| Itsiopoulos et al (2010) 27 | ! | + | + | + | ! | ! |
| Mousavi-Shirazi-Fard et al (2020) 34 | + | + | + | + | ! | ! |
| Makarewicz-Wujec et al (2020) 30 | + | + | + | + | ! | ! |
| High risk | ||||||
| Zwickey et al (2019) 39 | – | ! | + | + | ! | – |
| Lasa et al (2014) 29 | ! | + | + | + | – | – |
| Erlinger et al (2003) 25 | + | + | + | + | – | – |
Key: low risk: +; some concern: !; high risk: –.
All studies collected baseline and follow-up dietary intake data at the minimum, therefore ensuring that information relating to adherence to the intervention was collected. Due to this, deviation from intended interventions was not a major concern for these studies. However, in 2 studies, due to the population groups being chronic kidney disease populations, non-protocol interventions were a potential risk of bias. 32 , 36 Missing outcome data was not a major concern for any of the studies included in this review, because data of all or nearly all patients was reported in the analyses.
As the measurement of outcome was completed using an objective measure such as blood tests, all studies demonstrated a low risk of bias in this aspect. This is because outcome assessor bias and participant-reported bias were not relevant for this study design.
Selection of the reported result was a concern in studies that did not provide information about any pre-specified outcomes in the form of a clinical trial registry, protocol paper, or statistical analysis paper. 24 , 28 , 30 , 34 , 38 , 39 In another study, selection of reported results was a concern, because the study was a post hoc analysis that included additional exclusion criteria, 29 and yet another study was an ancillary study that displayed CRP values according to convenience, instead of providing baseline and follow-up values. 25
The results demonstrated that dietary intervention could reduce inflammatory markers such as IL-6, CRP, hsCRP, IL-1α, IL-1β, IL-8, IFNγ, TNFα, IL-5, IL-7, IL-12, and IL-18 and increase anti-inflammatory markers such as IL-4, IL-10, and IL-13 in the blood. Differences between intervention and control groups were evident for inflammation markers such as IL-6, CRP, hsCRP, IL-1α, IL-1β, IL-4, IL-8, IL-10, IFNγ, TNFα, IL-5, IL-7, and IL-18. These differences between groups were evident in studies providing a Mediterranean diet as the intervention.
Diseases such as cardiovascular disease, cancer, chronic respiratory diseases, heart disorders, obesity, arthritis, neurodegenerative disorders, and diabetes are associated with chronic inflammation. Therefore, the outcomes derived from this systematic review are relevant for several disorders resulting from inflammation; however, further research is indicated in a variety of population groups to determine whether the results are clinically meaningful.
Elevated levels of IL-1β, IL-6, TNF-α, and IFN-γ have been associated with cardiovascular disease. It is believed that these proinflammatory cytokines contribute to atherosclerosis. 41–43 Many cancer patients show an incidence of elevated levels of IL-2, IL-6, IL-10, and TNF. In in vitro studies, IL-6, IL-2, and IL-1 have also been shown to induce tumor proliferation. 44 An increased production of IL-6, TNF-α, and IL-1β is seen in people with diabetes, which may have a role in decreasing insulin sensitivity. 45 TNF and IL-1 are implicated in the inflammation process in joints that leads to erosion of cartilage and bones, contributing to arthritis. 46
The PREDIMED study, conducted on 7447 participants, demonstrated that the incidence of major cardiovascular events was lower in participants that were assigned a Mediterranean diet with either EVOO or nuts as compared with a low-fat diet. 47 In a randomized controlled crossover study consisting of 27 participants, administration of a Mediterranean diet brought about a statistically significant decrease in HbA1c in the intervention group as compared with the control group. 27 sCOMP, 48 which tends to be elevated in patients with knee osteoarthritis and is related to disease progression, showed a statistically significant decrease in the Mediterranean diet intervention group as compared with the control in a randomized control trial consisting of 124 participants with osteoarthritis. 24 Anti-inflammatory dietary intervention was also found to be associated with improvements in fatigue and quality of life levels in multiple sclerosis participants receiving the intervention as compared with the control group. 34 Studies conducted in the chronic renal disease patients also demonstrated improvements in lipidemia and oxidative status in participants receiving a Mediterranean diet. 32 , 36
The results demonstrated that there may be potential correlations between diet, inflammation, and disease outcomes. However, only 1 study employed the use of DII to find correlations between diet, inflammation markers, and disease outcomes. 31 As DII calculates inflammatory load attributable to the diet, it can be a useful measure in studies trying to determine the effect of diet on inflammation and disease outcomes. 13
A traditional Mediterranean diet is rich in antioxidants, phytochemicals, and minerals, and typically provides 6000 μg/day of beta carotene, 17 mg/day of vitamin E, 400 μg/day of folate, 300 mg/day of flavonoid, and 120 μg/day of selenium. 49 The Mediterranean diet lacks trans fatty acids, which are associated with elevated levels of inflammation markers. The presence of phytochemicals in wholegrains and EVOO contributes to anti-inflammatory and antioxidant effects. Olive oil contains hydroxytyrosol and oleuropein, which inhibit oxidation of low-density lipoproteins in a dose-dependent manner in in vitro studies. 50 It also contains oleocanthal, a phytochemical that mimics the activity of ibuprofen in exerting COX-inhibitory activity. 51 The aleurone layer (outermost layer of endosperm) of wheat bran is rich in ferulic acid, lignans, phytic acid, alkylresorcinols, and apigenin, all of which have demonstrated anticarcinogenic and anti-inflammatory activities in animal studies. 52 Spermidine is a polyamine present in the germ of whole grains. It can inhibit histone acetyltransferases and provide resistance against oxidative stress. 53 Potent antioxidants such as alpha tocopherol, carotenoids, oleuropein, and phytosterols are present in 25 mg, 1–2 mg, 20–500 mg, and 98–185 mg quantities, respectively, in 100 g of EVOO. Therefore, Mediterranean diet can play a role in reducing inflammation and oxidative stress. 47 PREDIMED study has shown that a Mediterranean diet, especially 1 that includes extra virgin olive oil aids in reducing plasma inflammation markers. 54 , 55
In the interventions included, the diets defined as “Mediterranean” had common features. These included increased consumption of EVOO, nuts, fatty fish, legumes, fruits, vegetables, and lean meat, and reduction in the consumption of red meat and refined food products. On the other hand, the diets classified as “anti-inflammatory” diets did not demonstrate consistent features across all studies. For instance, 1 study that provided an anti-inflammatory diet as an intervention included similar features as per a Mediterranean diet, such as inclusion of EVOO or canola oil, nuts, legumes and lentils, abundant fruit and vegetables, and limited consumption of processed foods. However, in addition to this, it encouraged consumption of spices, white and green tea, and dark chocolate in moderate amounts. 34 Another anti-inflammatory diet included advice to the participants to exclude wheat, gluten, corn, soy, dairy items, certain vegetables such as eggplant and bell peppers, citrus foods, red meat, shellfish, pork, and trans-fat; and encouraged inclusion of fish, nuts, and dark-colored berries. 39 Another diet claiming to contain anti-inflammatory components encouraged consumption of salmon, vegetarian dishes incorporating legumes, fruits, low-fat dairy, spices, pomegranate, nuts, oil or margarine, and limiting of intake of meats. 37 The differences in the features of the 3 anti-inflammatory diets demonstrated that, unlike the Mediterranean diet, the “anti-inflammatory” diet is not well defined. Only 2 studies that measured inflammatory markers utilized a DASH diet as an intervention (which encouraged abundant consumption of fruit, vegetables, and low-fat dairy products). 25 , 30
The definition of an “anti-inflammatory” diet may continue to evolve as more randomized controlled trials (RCTs) determine what type of intervention brings about a favorable change in inflammation markers and subsequent disease outcomes.
The majority of the studies utilized a Mediterranean diet as the intervention, while only a few used a DASH or an “anti-inflammatory” diet as the intervention. More RCTs need to be conducted using all these different types of diet in different population groups to enable meaningful comparisons. Furthermore, research focusing on sustainable interventions that provide individualized diets maximizing intake of anti-inflammatory components could be conducted in relevant populations.
From the data available in the included studies, the Mediterranean diet could be judged to be effective in reducing inflammation markers based on the statistically significant changes observed in the inflammation markers. The Mediterranean diet, furthermore, also contributed to favorable outcomes in diseases. Therefore, diets that include the consumption of wholegrains as compared with refined grains, lean meats as compared with red and processed meats, oily fish containing omega 3 fatty acids, fruits, vegetables, nuts, legumes, and healthy fats such as EVOO, can be considered as providing anti-inflammatory benefits.
All PREDIMED studies were successful in demonstrating a significant change in inflammatory markers. These studies prescribed a specific quantity of foods. For instance, 50 g of EVOO per day or 30 g of nuts per day. Furthermore, specific portions of other food groups were also prescribed. Australian studies with a similar design to PREDIMED but with a reduced prescription of the quantity of EVOO 38 or unspecific portions of other food groups 31 did not successfully demonstrate changes in inflammatory markers. This suggests that the quantity of foods, in this instance, EVOO, consumed per day may play a role in the effect on inflammation markers. However, an additional consideration in relation to the results is the effect of the sample size. In the studies reviewed, the sample sizes of the participants in each arm were comparable between the studies conducted in Spain and Australia. To determine whether results are dependent on dose, further studies that include additional arms with different quantities of EVOO, nuts, or portions of food groups would be beneficial. A minimum of 22 participants in each arm would be recommended. 22
From the studies included in this review, 3 months was the shortest duration of intervention. Statistically significant changes were observed in inflammatory markers after as little as 3 months of administration of a Mediterranean diet. 33 Further research is warranted in areas such as the minimum intervention duration required for a change in levels of inflammatory markers to be noticed. This would provide an indication of the time frame for prophylaxis.
Some key strengths of this review include the conduction of a systematic search through 5 databases (Medline, PubMed, Emcare, CENTRAL, and CINAHL), which were reviewed by 2 different librarians from Flinders University. Data extraction and quality assessment being completed by 2 independent reviewers also adds to the accuracy and rigor of the data compiled in this review. In addition to this, the quality assessment showed that the majority of the studies included in this review have either a low risk of bias or posed some concerns of bias, indicating that the study results can be accepted with confidence. This review made it clear that an “anti-inflammatory” diet is currently not well defined, but that a Mediterranean diet is well defined, demonstrating consistent features across studies.
Due to the inclusion of several different populations groups, the findings of the results from individual studies are not externally valid. In addition, the type of inflammation marker measured varied between studies, so making comparisons and drawing conclusions about relationships between specific inflammation markers and disease outcomes is difficult. We acknowledge that, due to the heterogeneity in prescribed interventions and population groups across the articles, a meta-analysis, at this stage, would not provide an accurate quantitative representation of the effect of Anti-inflammatory diets that is valid for all population groups. Another limitation of this review is that, while it reports on the effects of diet on inflammatory markers, it does not a provide a detailed report on all other disease outcomes measured within the respective studies. In order to determine the clinical relevance of the results, a detailed analysis of the effect of the intervention on all disease outcomes is imperative. Another noteworthy limitation is that 6 articles out of the 20 articles included in this systematic review included data from the same cohort (the PREDIMED study). 20–22 , 26 , 29 , 33
In future studies, design factors that may yield optimal and meaningful results include using a consistent RCT protocol; measurement of a variety of inflammation markers, DII, dietary compliance, relevant disease outcomes, and correlations between measured outcomes; utilization of low risk-of-bias intention-to-treat models; sustainable, tailored nutritional advice; and provision of the intervention to an adequate sample size for a minimum duration of 3 months.
Diet can play a role in reducing inflammation markers in the body. A Mediterranean diet, including components such as EVOO, nuts and fish in specific quantities can play a role in altering inflammation markers. The results demonstrated that the link between diet, inflammation and disease outcomes is currently unclear. Further research using intervention studies is potential and strongly warranted to determine correlations between diet (DII), inflammation markers and disease outcomes. Further research in this area may be of benefit in designing a therapeutic diet useful in reducing inflammation for treatment or prophylactic purpose.
We thank the Flinders University librarians supporting Higher Degree by Research students for their assistance with this review.
Author contributions. All authors contributed to the conception and design of the review. M.S.M. and C.Y.H. screened and read titles and abstracts, and completed data evaluation and data extraction from selected articles. M.S.M. drafted the original article and made revisions to the article. C.Y.H., M.D.M., S.S., and C.L.D. provided critical revisions of the original and revised drafts, and provided final approval of the version to be published. All authors accept accountability for the work presented.
Funding. This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Declaration of interest. The authors have no relevant interests to declare.
The following Supporting Information is available through the online version of this article at the publisher’s website.
Appendix S1 Search strategies
Appendix S2 PRISMA checklist
