Associations of Dietary Intake on Biological Markers of Inflammation in Children and Adolescents: A Systematic Review

Background: In children and adolescents, chronic low-grade inflammation has been implicated in the pathogenesis of co- and multi-morbid conditions to mental health disorders. Diet quality is a potential mechanism of action that can exacerbate or ameliorate low-grade inflammation; however, the exact way dietary intake can regulate the immune response in children and adolescents is still to be fully understood. Methods: Studies that measured dietary intake (patterns of diet, indices, food groups, nutrients) and any inflammatory biomarkers in children and adolescents aged 2 to19 years and published until November 2020 were included in this systematic review, and were selected in line with PRISMA guidelines through the following databases: Academic Search Complete, CINAHL, Global Health, Medline COMPLETE and Web of Science–Core Collection. A total of 53 articles were identified. Results: Results show that adequate adherence to healthful dietary patterns such as the Mediterranean diet, or food groups such as vegetables and fruit, or macro/micro nutrients such as fibre or vitamin C and E, are associated with decreased levels of pro-inflammatory biomarkers, mainly c-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), whereas adherence to a Western dietary pattern, as well as intake of food groups such as added sugars, macro-nutrients such as saturated fatty acids or ultra-processed foods, is associated with higher levels of the same pro-inflammatory biomarkers. Conclusions: This is the first systematic review examining dietary intake and biological markers of inflammation in both children and adolescents. A good quality diet, high in vegetable and fruit intake, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a promising therapeutic approach, as well as an important element for disease prevention in both children and adolescents.


Introduction
Inflammation is a physiological response to cellular and tissue damage. It is designed to protect the host from bacteria, viruses and infections by eliminating pathogens, promoting cellular repair and restoring homeostatic conditions [1]. However, a prolonged inflammatory state through chronic low-grade inflammation has deleterious effects, including irreparable damage to tissues and organs, and increased risk of disease status [2]. children and adolescents aged 2-19 years, describing associations between inflammation and/or: (a) patterns or indices of dietary intake, such as the Mediterranean Diet, the Western Dietary pattern, and the Healthy Eating Index, (b) food groups such as fruit and vegetables, whole and refined grains and dairy, (c) macronutrients, such as fat and fibre, and (d) micronutrients, such as vitamins A and C. Whereas, exclusion criteria included: non-peer reviewed article publications, studies in a language other than English, animal studies, studies in pregnant women that only examined maternal diet, and supplementation interventions or dietary rehabilitation interventions for malnutrition. The search included studies published until December 2020. Overall, a total of 53 studies met the inclusion criteria for our review (see Figure 1) and were assessed for risk of bias following the Cochrane risk-of-bias (RoB 2.0) for intervention studies, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for observational studies [35,36], see Supplement S1. The majority of the studies included in this review had a low risk of bias.

Results
The 53 studies included in this review have been categorized into: (1) dietary patterns and indices (see Table 1), (2) food groups and (3) macronutrients and micronutrients (see Table 2). In particular, 26 studies examined dietary patterns and indices, 15 studies examined food groups, 19 studies examined macronutrients and 7 studies examined micronutrients, while some studies examine more than one category. In total, there were 8 interventional studies, and 45 observational studies, of which 2 were longitudinal [37,38], while the remaining 43 studies were cross-sectional.

Results
The 53 studies included in this review have been categorized into: (1) dietary patterns and indices (see Table 1), (2) food groups and (3) macronutrients and micronutrients (see Table 2). In particular, 26 studies examined dietary patterns and indices, 15 studies examined food groups, 19 studies examined macronutrients and 7 studies examined micronutrients, while some studies examine more than one category. In total, there were 8 interventional studies, and 45 observational studies, of which 2 were longitudinal [37,38], while the remaining 43 studies were cross-sectional.

Dietary Patterns
Out of the 53 studies, 17 examined a priori dietary patterns which are based on countries dietary guidelines [9]. The examined dietary patterns included the Dietary Nutrients 2021, 13, 356 4 of 29 Approaches to Stop Hypertension (DASH) dietary pattern, low and high glycaemic index dietary patterns, the Mediterranean dietary pattern and the Western dietary pattern. Two studies examined more than one dietary pattern [39,40].

DASH Dietary Pattern
The DASH dietary pattern was examined in one intervention study [41] and one observational study [40]. The first study found adherence to a DASH diet and lower levels of CRP, in a female cohort of patients with metabolic syndrome [41]. In contrast, the second study did not find an association between adherence to a DASH diet and CRP in a cohort of males and females with type-1 diabetes [40].

Low and High Glycaemic Index Dietary Pattern
Low and high glycaemic index diet patterns were examined in four interventional studies [42][43][44][45]. These studies found that adherence to a low glycaemic index diet pattern or to a hypocaloric high glycaemic index diet pattern was associated with lower levels of CRP, both in males and females with obesity.
In particular, the first study found an association between adherence to a low glycaemic index diet and lower levels of CRP and IL-6 in females with obesity or overweight [45]. Another two studies found an association between adherence to both a hypocaloric low and a hypocaloric high glycaemic index diet and lower levels of high sensitivity c-reactive protein (hs-CRP) in males and females with obesity [43,44]. In contrast, a fourth study did not find any associations between low and high glycaemic index diet patterns and inflammatory outcomes in a healthy cohort of male and female participants [42].

Mediterranean Dietary Pattern
The Mediterranean dietary pattern was examined in 10 observational studies [39,40,[46][47][48][49][50][51][52][53], one of which was also discussed in Section 3.1.1 [40]. These studies found that adherence to a Mediterranean dietary pattern was associated with lower levels of CRP, IL-6, and TNF-α in healthy males and females, whereas the majority of studies conducted in cohorts with underlying pathologies, including type-1 diabetes and obesity, found no associations with inflammatory biomarkers.
Two studies, in particular, found an association between a Mediterranean diet pattern and lower levels of hs-CRP in females only [52], or both in males and females [46], whereas another study found an inverse association between a Mediterranean diet and IL-1, IL2, IL-6 and TNF-α both in males and females [48], all studies were conducted in cohorts of healthy participants. In contrast, one study found a positive association between a Mediterranean diet pattern, and CRP and transforming growth factor beta 1 (TGFβ-1) in males only, but an inverse association with soluble vascular cell adhesion molecule-1 (sVCAM-1) in male and females [47], again the study was conducted in a cohort of healthy participants. Another study found an association between a Mediterranean diet pattern and lower levels of IL-4 and IL-17, but higher levels of IL-33, in both males and females with asthma [49]. In contrast, one study in a type-1 diabetic cohort [40], three studies in obese cohorts [50,51,53], and one study in a healthy cohort [39] did not find any associations.

Western Dietary Pattern (WDP)
The WDP was examined in three observational studies [37,39,54]; one study was aforementioned in Section 3.1.3 [39]. These studies found that adherence to a WDP was associated with higher levels of CRP in a cohort of healthy males and females.
The first study was longitudinal and found an association between WDP adherence at 14-years and higher levels of hs-CRP at 17-years both in healthy males and females [37]. The remaining two studies found an association between WDP adherence, and higher levels of CRP and IL-6 in this case in female cohorts of healthy participants [39,54].

Indices
Out of the 53 studies, 11 examined dietary indices, including the dietary inflammatory index, healthy eating index and the diet quality index. One study examined both a pattern and an index [51], while another study examined two patterns and one index [40].

Dietary Inflammatory Index (DII)
The DII, a tool that assesses the inflammatory potential of a diet [32], was examined in 6 observational studies [38,51,[55][56][57][58], one of which was also discussed in Section 3.1.3 [51]. These studies found that adherence to a pro-inflammatory diet (indicated by a higher score in the DII) was associated with higher levels of hs-CRP, IL-6 and TNF-α in healthy males and females.
In particular, four studies found a positive association between adherence to a proinflammatory diet (indicated by a higher score in the DII) and IL-6 [55,57], IL-1, IL-2, interferon gammon and sVCAM-1 in healthy males and females [58], but also a positive association between DII and CRP in males and females with obesity [51]. However, two studies did not find any associations between the DII and CRP [38], or IL-6, MCP-1 or TNF-α [56] in neither healthy males or females.

Healthy Eating Index (HEI)
The HEI, a tool that assesses adherence to the Dietary Guidelines of Americans in any given year, was examined in three observational studies [40,59,60]. One of which was also discussed in Sections 3.1.1 and 3.1.3 [40]. The first study found that a higher score in the HEI (healthy diet) was associated with lower levels of CRP in females, but not males from a healthy cohort [59]. In contrast, two studies found that moderate HEI scores (moderately healthy diet) were not associated with CRP or IL-6 in males or females in cohorts of patients with type-1 diabetes [40,60].

Diet Quality Index (DQI)
The DQI, a composite individual-level diet quality indicator that enables cross-cultural diet quality comparisons was examined in two observational studies [61,62]. Neither of the studies found an association between the DQI and CRP [61,62] or IL-1, IL-6, IFN-y and TNF-α [62]. This suggests a lack of sensitivity associated with the DQI as a measure of inflammatory status.

Vegetables and Fruits
Vegetable and/or fruit intake was examined in nine observational studies [47,59,60,[63][64][65][66][67][68], two of which were also discussed in Section 3.2.2 [59,60]. These studies found that high dietary intake of vegetables and/or fruits was associated with lower levels of CRP and IL-6 (both in healthy males and females), TNF-α (only in healthy females), and IL-17F (both male and female patients with asthma).
In particular, three studies found an association between vegetable and fruit intake and lower levels of CRP [63][64][65], and IL-6 and TNF-α [66], both in healthy males and females, as well as in males and females with obesity [69]. In contrast, one study found an association between vegetable and fruit intake and lower levels of hs-CRP in healthy females, but not in males [59]. While another found an association between vegetable and fruit intake and higher levels of CRP in males, but not in females, lower levels of IL-4 in males and females, and lower levels of TNF-α in females, but not in males, and higher levels of IL-10 in males and females, in a cohort of healthy participants [47]. While one study found an association between fruit and vegetable intake and lower levels of IL-17F in males and females from a cohort of patients with asthma [67], another study found no associations between vegetable and fruit intake and CRP in a cohort of male and female patients with type-1 diabetes [60].

Dairy
Dairy was examined in seven observational studies [47,60,63,64,[67][68][69], six of which were also discussed in Section 3.3.1 [47,60,63,64,67,69], and one in Section 3.1.3 [47]. One study found an association between dairy intake and higher levels of IL-17F in males and females, from a cohort of patients with asthma. However, the majority of studies did not find an association between dairy intake and CRP or IL-6 in males or females from healthy cohorts.
One study found an association between dairy intake and higher levels of IL-17F in males and females from a cohort of patients with asthma [67] while a second study found an association between dairy intake and higher levels of IL-6, Il-10 and TGFβ-1 in females, but not in males, and IL-1 in both males and females, and IL-5 in males but not in females in a healthy cohort [47]. The remaining five studies did not find any associations between dairy intake and CRP and IL-6 in males and females from healthy cohorts [60,63,64,68,69].

Meat, Seafood and Eggs
Meat, seafood and eggs were examined in seven observational studies [47,60,63,64,67,69,70], six of which were also discussed in Sections 3.3.1 and 3.3.2 [47,60,63,64,67,69], and one in Section 3.1.3 [47]. The majority of studies did not find an association between dietary intake of meat, seafood and eggs and CRP, IL-6 and TNF-α in males and females from healthy cohorts.
Two studies, in healthy populations found an association between meat intake and higher levels of IL-2, IL-10 [47] and IL-6 [70] in healthy males and females, however the remaining five studies did not find any associations between meat, seafood or eggs intake and CRP, IL-6 and TNF-α [60,63,64,67,69].

Whole and Refined Grains
Whole and refined grains were examined in one intervention [71] and six observational [47,63,64,67,69,72] studies, six of which were also discussed in Sections 3.3.1-3.3.3 [47,63,64,67,69], and one in Section 3.1.3 [47]. These studies found that wholegrain dietary intake was associated with lower levels of CRP and IL-17F in males and females from cohorts with and without underlying pathologies. In contrast, results on the association between refined grain intake and inflammatory markers remain inconclusive.
In particular, the first study found an association between wholegrain intake and lower levels of CRP in a female only cohort of participants with obesity [71]. The second study found an association between wholegrain intake and lower levels of IL-17F in males and females from a cohort of patients with asthma [67]. A third study found an association between wholegrain intake and lower levels of CRP, in males and females from a healthy cohort [72].
The remaining studies examined refined grains in healthy populations. One study reported an association between refined grain intake and lower levels of hs-CRP in males and females [64], while another study found an association with higher levels of CRP, only in females but not in males [63]. A third study found refined grains were associated with lower levels of IL-6 and IL-10 in males and females [47]. Lastly, one study found no association between refined grain intake and CRP in males and females [69].

Added Sugar and Sugar Sweetened Beverages (SSB)
Added sugars (snacks-candy, jams, spreads, sugar sweetened beverages, fruit juice) were examined in one interventional [73] and eight observational [50,60,63,[65][66][67]69,74] studies, two of which were also discussed in Sections 3.2.1-3.2.3 [67,69]. The majority of studies did not find an association between added sugar intake and CRP, for males or females from cohorts with healthy participants, as well as for patients with inflammatory bowel disease, Type-1 diabetes and obesity.
In particular, the first study found glucose intake decreased levels of hs-CRP, compared with fructose in a cohort of male and female patients with non-alcohol fatty liver disease [73]. Another study found an association between higher SSB intake and higher levels of CRP in males and females from a cohort of healthy participants [74]. Another two studies found an association between SSB intake and higher levels of CRP in females, but not in males in a cohort of healthy participants [63], and IL-17F in both males and females from a cohort of patients with asthma [67]. Five studies found no association between added sugar intake and CRP, IL-6 and TNF-α from cohorts of healthy participants [66,69], patients with inflammatory bowel disease, Type-1 diabetes [60] and obesity [50].

Macronutrients
A total of 19 studies examined macronutrients, including (1) fats and (2) [60,64], and Section 3.3.5 [50,60]. The studies found that saturated fatty acids (SFAs) intake was associated with higher levels of CRP, IL-6, Transforming growth factor-beta and sVCAM-1, while monounsaturated fatty acid (MUFA) intake was associated with lower levels of IL-6, and omega-3 PUFA intake was associated with lower levels of plasminogen activator inhibitor-1, in males and females from cohorts of healthy participants.
These studies found an association between SFAs and higher levels of CRP in females, but not in males from a cohort of healthy participants [59], as well as in male and female obese participants [70]. In contrast, one study found a positive association between SFA intake and CRP in males, but not in females from a cohort of healthy participants [67]. Another study found an inverse association between dietary intake of MUFA and IL-6, as well as between omega-3 PUFAs and plasminogen activator inhibitor-1, in a female cohort of healthy participants [39]. Another study found a positive association between MUFA:SFA ratio and IL-6 in males and females, TGFβ-1 in females but not in males, and sVCAM-1 in males but not in females, from a cohort of healthy participants [47]. The same study also found an inverse association between SFA and sVCAM-1 in females but not in males [47]. Lastly, seven studies found no associations between SFA and CRP [60,76] and total fat and CRP [50,64,75,79,80] or IL-6 [80].
The first study found an association between dietary fibre intake and higher levels of TNF-α in males and females from a cohort of healthy participants [81]. Another two studies in healthy participants found an association between dietary fibre intake and lower levels of CRP in females, but not in males [59], or both in males and females [85]. A fourth study found that total fibre intake was inversely associated with plasminogen activator inhibitor-1, while insoluble fibre was inversely associated with plasminogen activator inhibitor-1 and monocyte chemoattractant protein-1, in males and females from a cohort of overweight participants [86]. Lastly, six studies found no associations between fibre intake and CRP in males or females from cohorts of healthy participants [64,78,[82][83][84], or in obese participants [50].

Micronutrients
A total of seven observational studies examined various micronutrients [39,59,66,79,[87][88][89]. Three of the studies were also discussed in Section 3.2.2 [59], Section 3.3.1 [59,66] and Section 3.4.1 [59,79]. These studies found an association between dietary intakes of vitamins and lower levels of CRP and IL-6, while sodium was associated with higher levels of TNF-α, in males and females from a cohort of healthy participants [87].
Vitamin C intake was associated with lower levels of hs-CRP and IL-6 in males and females from a cohort of healthy participants. [66]. Dietary intake of beta-carotene was associated with lower levels of IL-6 and TNF-α [66], while vitamins A and E were inversely associated with hs-CRP, in males and females from cohorts of healthy participants [59]. Magnesium was inversely associated with hs-CRP in healthy male and female participants [88] and positively associated with IL-6 in healthy females [39]. One study examined sodium intake and found a positive association with TNF-α in healthy males and females [87]. However, two studies found no associations between micronutrient intake and CRP in males and females from healthy populations [79,89].

Table 1. Summary of studies investigating the associations between dietary patterns/scores/indices and biological markers of inflammation in children and adolescents.
Author and Country (* also in Table 2 LGI intake: IL-6 and CRP ↓, HND intake: Il-6 ↓ All other ↔

Discussion
This review provides the first evidence for the association between dietary intake (dietary patterns, food groups, macronutrients and micronutrients) and biological markers of inflammation in children and adolescents. The main results (Tables 1 and 2, Figure 2) indicate that adequate adherence to healthful dietary patterns, such as the DASH diet, low glycaemic index diets and the Mediterranean diet are associated with decreased levels of biomarkers, including CRP, IL-6 and TNF-α. Among the individual constituents of these diets, vegetable and fruit intake and wholegrains, as well as healthy fats were associated with a favourable inflammatory response. In contrast, a Western dietary pattern, as well as its separate constituents including saturated fatty acid, elicited a pro-inflammatory response increasing levels of pro-inflammatory biomarkers, such as CRP, IL-6, TNF-α and sVCAM-1. Associations across the studies included in this review were attenuated by gender, as well as the presence of underlying pathologies, independent of dietary intake.

Discussion
This review provides the first evidence for the association between dietary intake (dietary patterns, food groups, macronutrients and micronutrients) and biological markers of inflammation in children and adolescents. The main results (Tables 1 and 2, Figure 2) indicate that adequate adherence to healthful dietary patterns, such as the DASH diet, low glycaemic index diets and the Mediterranean diet are associated with decreased levels of biomarkers, including CRP, IL-6 and TNF-α. Among the individual constituents of these diets, vegetable and fruit intake and wholegrains, as well as healthy fats were associated with a favourable inflammatory response. In contrast, a Western dietary pattern, as well as its separate constituents including saturated fatty acid, elicited a proinflammatory response increasing levels of pro-inflammatory biomarkers, such as CRP, IL-6, TNF-α and sVCAM-1. Associations across the studies included in this review were attenuated by gender, as well as the presence of underlying pathologies, independent of dietary intake. Traditionally diet-disease relationships have been examined by focusing on nutrients or food groups, which can be limiting. Foods are typically eaten in combination, and nutrients have both synergistic and antagonistic biochemical interactions [90]. More recently, dietary patterns that capture the whole diet, involving the combination of foods and nutrients have been examined [91]. Traditionally diet-disease relationships have been examined by focusing on nutrients or food groups, which can be limiting. Foods are typically eaten in combination, and nutrients have both synergistic and antagonistic biochemical interactions [90]. More recently, dietary patterns that capture the whole diet, involving the combination of foods and nutrients have been examined [91]. The most examined dietary pattern in this review was the Mediterranean diet and in observational studies conducted in healthy populations adequate to high adherence resulted in decreased levels of pro-inflammatory biomarkers [46,48,52]. Similar results were found for studies examining low glycaemic index diets in obese populations [43][44][45] and one intervention study in females with metabolic syndrome which examined the DASH diet [41].
The mechanisms by which these healthful dietary patterns affect the inflammatory process are largely underexplored [18]. It has been hypothesised that the protective effect of these patterns may be derived from the anti-inflammatory properties of their constituents [92]. The Mediterranean diet is characterized by high intakes of vegetables, fruit, wholegrains, legumes, nuts, fish and low-fat dairy, and low intakes of red meat and adequate intakes of healthy fats [93]. As such, the diet is rich in antioxidants, folate, and flavonoids which are anti-inflammatory. The high dietary fibre content supports gut health and the growth of microbial species which potentially regulate the inhibition or production of pro-inflammatory chemokines and cytokines [94]. Omega-3 PUFAs, found in high concentration in oily fish such as salmon, have been shown to regulate the immune response by inhibiting the activation of pro-inflammatory pathways and reducing cytokine expression [3]. High-dose eicosapentaenoic acid has been shown to improve cognitive symptoms in Attention deficit hyperactivity disorder (ADHD) youth with low baseline levels [95,96], while research in animal models has demonstrated inflammation-induced reductions in neurogenesis can be prevented through omega-3 PUFAs intake [97]. Lastly, sodium intake has been implicated in the regulation of the immune response [98]. The DASH diet, which is similar to the Mediterranean diet, with a greater focus on minimal red meat and processed foods, also restricts sodium intake [99]. Similar to sodium, the studies included in this review also examined other dietary components with strong antiinflammatory properties. For example, studies showed that high intakes of vegetables and fruit [59,[63][64][65][66][67]69], and whole-grains [67,72] resulted in lower levels of inflammatory biomarkers, such as CRP, IL-6 and TNF-α. The same was for various micronutrients such as beta-carotene [66] and vitamins C and E [39] all of which are considered to have anti-inflammatory properties [100].
In contrast to healthful dietary patterns, studies that examined the Western dietary pattern, characterised by high amounts of refined grains, red meat, high fat dairy, ultraprocessed food intake and trans fatty acids while being low in omega-3 PUFAs [101,102] showed positive associations with pro-inflammatory markers [37,54]. Similarly, in the studies that examined the DII, diets with high inflammatory potential, inducing a higher inflammatory response were positively associated with pro-inflammatory biomarkers in males and females [51,55,57,58]. In terms of separate components comprising these diets, saturated fatty acid intake is known to be a significant pro-inflammatory contributor that stimulates IL-6 secretion, while in contrast high intakes of healthier fats, such as omega-3 PUFAs found in oily fish can inhibit the inflammatory response [103]. Across the studies that examined saturated fatty acids in this review there was evidence for a positive association between saturated fatty acid and CRP, as well as various cytokines, IL-6, sVCAM and sICAM [59].
As demonstrated in this review, the relationship between diet and inflammation is attenuated by a number of different factors [1,104,105]. For example, gender differences were evident across the studies included in this review, however, they were not specific to one particular diet, food group, macro-or micronutrient. Nor where they specific to any inflammatory biomarker. We hypothesize the gender difference is potentially attributable to the influence of hormones. Sex hormones affect immune function, whereby estrogens stimulate auto-immunity and androgens exhibit protective properties [106][107][108][109]. Other evidence indicates genetic, epigenetic and environmental factors may also contribute to gender differences; however, no included studies explored these potential associations [109,110]. Furthermore, we acknowledge the heterogeneity in the cohorts of the studies included in this review, and as such some associations could have been confounded by the sample population. A number of studies examined cohorts with underlying pathologies, with overweight/obesity [42][43][44][45]50,51,53,70,71,75,81,86], and type-1 diabetes [40,60,82] being the most studied. In overweight and obese populations excess adipose tissue has been linked to an increase in sub-chronic levels of key pro-inflammatory cytokines, mainly CRP, IL-6 and TNF-α [111], and this may prevent or attenuate any potential therapeutic effect exerted by a healthful diet [112]. Taken together, physiologic mechanisms specific to disease state or population may inhibit any beneficial influence of a healthy dietary pattern, potentially explaining the lack of significant associations in the studies discussed in our review [82].
With regards to methodology, it is widely accepted that nutrition epidemiology studies are affected by reporting bias. Imprecision in the measurement of dietary intake is often observed, particularly in children and adolescents, which can cause the over-or underestimation of the impact of exposure [113][114][115]. Moreover, the measurement tools themselves are often flawed, for example the KidMed questionnaire, used to evaluate the level of adherence to the Mediterranean diet, has a strong bias toward healthy foods and as such may not adequately capture hidden constituents such as sodium [116]. These methods also do not consider the biological effect of food (intake versus absorption) [117]. More recently, several studies have examined associations between biological markers of dietary intake and pro-inflammatory biomarkers. Using these methods, an inverse association between fatty acid composition in erythrocytes and pro-inflammatory biomarkers (IL-1β and IL-6) has been observed in children and adolescents [118], and higher omega-6/omega-3 PUFAs ratio has been associated with higher levels of inflammation [119] and subsequent adverse mental health effects [120]. These biological, rather than self-reported, dietary measures are a more accurate and reliable way of investigating dietary intake, which should be more often used in future research studies [121].
Lastly, there is currently no consensus regarding the inflammatory biomarkers best used to represent chronic low-grade inflammation in children and adolescents, and biomarker measurement error such as sampling, storage and laboratory errors also cannot be excluded [122]. The majority of the studies in this review used a single static measurement of inflammation, however, inflammatory markers owing to their role in homeostasis and immune response are by nature not static and when measured in the fasting state are recognised as being insensitive, and producing highly variable results [2]. Multiple, non-fasting state measures would provide for more accurate and meaningful outcomes.

Conclusions
In conclusion, our review shows that healthful dietary patterns such as the Mediterranean diet, high in vegetables, fruit, wholegrains, legumes, nuts, fish and low-fat dairy, alongside moderate to low consumption of meat and healthy fats, have an inverse association with pro-inflammatory biomarkers, particularly CRP, IL-6 and TNF-α, in children and adolescents. Components of healthful diets that were examined separately, including food groups such as vegetables and fruit, or macronutrients such as fibre, or micronutrients such as Vitamins A, C and E also have inverse associations with pro-inflammatory biomarkers. In contrast, the Western dietary pattern, as well as its individual components including macronutrients such as saturated fatty acids, micronutrients such as sodium and ultra-processed foods, increases levels of the same pro-inflammatory biomarkers. Further interventional research is needed to establish the strength of associations between dietary intake and inflammatory biomarkers, and ultimately to develop a better understanding of the biological mechanisms underlying such associations.
Author Contributions: All authors contributed to the manuscript. All authors have read and agreed to the published version of the manuscript. paper is independent from this funding. In addition, C.M.P. is funded by the Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA) Consortium (104025), which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer, but, again, this paper is independent from this funding.
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable because it is a systematic review. All data is available in primary studies.

Conflicts of Interest:
Authors declare no conflict of interest.