5  Mediterranean diet and the impact on inflammation
The Mediterranean diet (MD) is based on the dietary pattern found in the Mediterranean basin (Greece, southern regions of Italy and Spain), and includes high amounts of fresh vegetables and fruits, seeds, nuts, along with olive oil and whole grain cereals. Milk, cheese, yogurt, eggs, fish and poultry are consumed in moderate amounts, as is wine (especially red), with low amounts of red meat and sugary deserts (Martinez-Gonzalez et al., 2014; Tosti et al., 2018). This diet is abundant in minerals and vitamins, antioxidants and phytochemicals (Tosti et al., 2018). Although several of its components exerted beneficial actions, most likely their combined synergistic effects contribute to reducing the systemic inflammatory burden (Tosti et al., 2018). Some authors posit that MD exerts a hormetic effect, similar to caloric restriction, highlighting the Nrf2 pathway, regulating the pro-/anti-inflammatory processes equilibrium (Martucci et al., 2017). Epigenetic regulation was also hypothesized, especially due to components found in nuts and extra virgin olive oil, which were reported to alter the methylation of some genes related to inflammation, metabolism and signal transduction (Arpon et al., 2016, 2017).
In healthy subjects, even one MD-style meal was shown to reduce the expression of pro-inflammatory molecules (De Lorenzo et al., 2017), with no differences between sexes regarding effects on systemic inflammatory status (Bedard et al., 2015). In elderly individuals, a MD intervention lead to lower glycoxidative impairment (Lopez-Moreno et al., 2018) and inflammatory response (Camargo et al., 2012; Yubero-Serrano et al., 2012), paralleled to a diet based on saturated fatty acids (Fig. 2 ).
Fig. 2 Diets rich in proteins, lipids and carbohydrates induce the production of pro-inflammatory molecules that lead to the activation of several inflammatory pathways including JAK/STAT pathway, NF-Kβ pathway and MAPK kinase cascade. These pathways lead to oxidative stress, as wells as, COX-2, TNF-α, and interleukins production via transcriptional regulation ultimately leading to chronic inflammation. Oxidative stress either directly or via metabolic dysfunctions causing e.g insulin resistance, as well as the rest of the inflammatory molecules as a result of unhealthy diet promote the onset of several chronic diseases including CVD, neurodegenerative diseases, autoimmunity, pulmonary diseases and are-related frailty; (NF-kβ – nuclear factor kappa-light-chain-enhancer of activated B cells heterodimer, consisting of p50, p65 and IkBα proteins; STAT3 – Signal transducer and activator of transcription 3; ERK/MAPK – mitogen-activated protein kinases; JNK – c-Jun N-terminal kinases; COX-2 – cyclooxygenase 2; TNF-α – Tumour necrosis factor alpha; IL-1/6/8 – interleukin 1/6/8).
A marked reduction of inflammatory molecules (C reactive protein – CRP, E-selectin, P-selectin, TNF-α, IL-1β, IL-6) and of mRNAs of pro-inflammatory genes was reported in overweight and obese individuals which adhered a classic or modified MD (Bekkouche et al., 2014; Marques-Rocha et al., 2016; Paoli et al., 2015; Rallidis et al., 2017; Tripp et al., 2019). Furthermore, in diabetics and patients with high cardiovascular risk, MD determined a significant reduction of serum levels of CRP, interleukins and adhesion molecules (Casas et al., 2014; Ceriello et al., 2014; Maiorino et al., 2016; Mayr et al., 2018). In a group of asthmatic children, MD supplemented with 150g cooked fish twice a week resulted in significantly improved pulmonary function and markedly increased docosahexaenoic acid (DHA) levels and improved omega-6 to omega-3 ratio (Papamichael et al., 2019). The recent clinical trials addressing the relationship between MD and inflammation are summarized in Table 4 .
Table 4 Recent reports concerning Mediterranean diet and inflammation.
Design Population Intervention Effects Reference
Feeding study 25 subjects One-meal intervention:➢ Tocopherol-enriched Mediterranean meal
➢ Western high-fat meal ↓ expression of inflammation-related genes De Lorenzo et al. (2017)
Controlled feeding study 35 men and 27 women ➢ 4-week MD intervention MD induced the same type of response regarding hs-CRP both in males and females Bedard et al. (2015)
Randomized Controlled Trial 1142 subjects 12-month diet intervention:➢ MD-like NU-AGE diet + vitamin D3 (10 μg/day)
➢ Control group Slowed the decline of bone mineral density only in the femoral neck in subjects with osteoporosis Jennings et al. (2018)
Randomized Controlled Trial 20 elderly subjects 4-week diet intervention:➢ MD + coenzyme Q10 (MD-Q10)
➢ MD
Diet rich in saturated fatty acids (SFAD) MD, MD-Q10: ↓ expression of p65, IKK-b, MMP-9, IL-1b (versus SFAD)MD-Q: marked decrease of P65 and IKK-b (versus the other diets) Yubero-Serrano et al. (2012)
Randomized Controlled Trial 20 elderly people 4-week diet intervention:➢ MD + olive oil (MD-O)
➢ diet rich in saturated fatty acids (SFAD) low-fat, high-carbohydrate diet enriched in n-3 PUFA (LFHC-PUFA) MD-O: ↓ expression of inflammation-related genes (versus SFAD: p65, MCP-1; versus LFHC-PUFA: p65, TNF-α) Camargo et al. (2012)
Randomized Controlled Crossover Trial 20 elderly subjects isocaloric diets for successive periods of 4 weeks in a crossover design: MD, MD + CoQ, Western diet ↓ AGE, RAGE Lopez-Moreno et al. (2018)
Randomized Controlled Trial 34 male overweight subjects 4-week diet intervention:➢ Ketogenic MD (KMD)
KMD + omega-3 (KMD-O3) KMD: ↓ TNF-αKMD-O3: ↓ IL-1β, IL-6, TNF-α, ↑ adiponectin Paoli et al. (2015)



Controlled feeding study 50 overweight and obese subjects 13-week diet intervention: Caloric restriction, MD + dietary supplementation ↓ CRP (versus baseline) Tripp et al. (2019)
Clinical Trial 90 subjects with abdominal obesity 2-month diet intervention:➢ MD, using olive oil
Control group MD: ↓ CRP, P-selectin, E-selectin (versus baseline) Rallidis et al. (2017)
Clinical Trial 40 subjects with metabolic syndrome 8-week diet hypocaloric MD intervention ↓ mRNA associated with the regulation of inflammatory genes Marques-Rocha et al. (2016)
Randomized Controlled Trial 36 subjects with metabolic syndrome 3-month MD intervention ↓ CRP, insulin Bekkouche et al. (2014)
Randomized Controlled Trial 24 T2DM patients 3-month diet intervention:➢ MD, using olive oil
Low fat diet (LFD) MD: ↓ IL-6, ICAM-1, ↑ GLP-1 stimulated insulin secretion Ceriello et al. (2014)
Randomized Controlled Trial 215 T2DM (newly diagnosed) 12-month diet intervention:➢ MD
Low fat diet (LFD) MD: ↓ CRP (37%), ↑ adiponectin (43%) Maiorino et al. (2016)
Randomized Controlled Trial 56 coronary heart disease patients 6-month diet intervention:➢ MD
Low fat diet (LFD) ↓ dietary inflammatory index (including IL-1b, IL-4, IL-6, IL-10, TNF-α, CRP) Mayr et al. (2018)
Randomized Controlled Trial 164 subjects with high cardiovascular risk 12-month diet intervention:➢ MD + 50 mL extra virgin olive oil (MD-O)
➢ MD + 30 g nuts (MD-N)
Low fat diet (LFD) MD-O: ↓ CRP (45%), IL-6 (35%), sICAM-1 (50%), P-selectin (27%)MD-N: ↓ CRP (45%), IL-6 (35%)(versus LFD) Casas et al. (2014)
In recent years, the effects of a diet similar to MD started to be investigated: the Nordic diet (ND). Similarly, ND is based on fruits, especially berries, and vegetables, fish, whole grains, and includes low amounts of processed red meat and is almost lacking saturated fats. As olive oil is specific for the Mediterranean basin, the ND includes canola oil (Lankinen et al., 2019; Magnusdottir et al., 2017). Literature reports are reviewed elsewhere (Lankinen et al., 2019) and although scarce, they indicated that ND exerted anti-inflammatory effects, as it was able to reduce the serum levels of CRP (de Mello et al., 2011; Lankinen et al., 2019).
Dietary interventions based on Mediterranean/Nordic style induce positive effects on both inflammation and redox stress, both in healthy patients and in those with metabolic impairments (diabetes mellitus, obesity, metabolic syndrome). The hormetic effects induced at the level of the immune system is pointed out by the positive results induced by MD on people with inflammatory phenomena impacting the respiratory system, including children with asthma.