JO VOL. 12 N. 2, JULY-DEC, 2020
Fibromyalgia and nutrition
Alì Younes1*, Fabiola Turco2, Rhiannon Ross3, Vittorio Calvisi4 and Pio Conti5
1Medical Center “Mai più Dolore”, Pescara, Italy
2Private Division of Dentistry, Pescara, Italy
3University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
4Orthopedics Division, University of L’Aquila, Italy
5Postgraduate Medical School, University of Chieti, Italy
Fibromyalgia syndrome (FMS) is a chronic pathological condition characterized by widespread musculoskeletal pain, tissue hypersensitivity, pain, sleep dysfunction, rigidity, fatigue and cognitive dysfunction (1). FMS is estimated to affect 2–8% of the adult population and is considered to be the most common cause of musculoskeletal pain in women aged 20 to 60 (2). Diagnostic criteria for FMS have been developed over the past decade and research on the etiology of FMS has recently focused on neuroinflammation, allergens, infectious agents, irritants, exposure to chemicals and stress. Inflammatory mediators include neuropeptides, cytokines, growth factors and neurotransmitters. Mast cells are involved in allergic conditions but can also be mediators of systemic inflammation (3). Mast cells (MCs) have been shown to be involved in FMS where they are increased in the dermis, albeit inconsistently. MCs are found perivascularly near neurons, in the skin and in the diencephalon and when activated they secrete numerous vasoactive, neurosensitizing and proinflammatory cytokines (3). Previously, we published that MCs are not only involved in allergic diseases, asthma and mastocytosis, but they also mediate many other acute and chronic diseases, including fibromyalgia and chronic fatigue syndrome (4).
Stress and inflammation are the main pathogenetic factors in multiple diseases that often present comorbidities such as allergy, asthma, eczema, psoriasis, irritable bowel syndrome, myalgic encephalomyelitis, chronic fatigue and fibromyalgia (5). Fibromyalgia therapy is currently obscure as there are no specific effective drugs for the treatment of this pathology. The cross-talk between mast cells and microglia in the hypothalamus and amygdala could explain stress-induced inflammation, but these data are still to be confirmed (6). Recently, in an article published in an international journal, we demonstrate that the use of polyphenols could be of considerable benefit in fibromyalgia patients. Polyphenols (flavonoids, phenolic acids, and others) are contained in large quantities in plants and can have an effect on capillary fragility and on the protection of the nervous system (7). To date, we can count more than 800 flavonoids that can be synthesized above all by food, playing a pharmacological rather than nutritional role. Flavonoids exert antioxidant properties and exhibit pleiotropic biological activities such as the protection of tissues, and the ability to chelate divalent metallic cations (eg Cu ++, Fe ++). Luteolin (3,4,5,7-tetrahydroxy flavone) belongs to the flavonic polyphenol family originally synthesized from some vegetables and olive oil. In clinical studies, flavonoids, and in particular luteolin, exerts an antidepressant role on the central nervous system by increasing serotonin, norepinephrine, glucocorticoid receptors and the neurotrophic factor of the brain with a modulating effect on the hypothalamic-pituitary-adrenal axis (7). Luteolin with its antioxidant properties, counteracts the proliferation of cancer cells and regulates mast cell activity in immune and inflammatory diseases by inhibiting the gene and protein expression of the cytokine IL-1, a highly pro-inflammatory and pain-inducing agent, through stimulation of PGE2.
Omega-3, contained in food such as fish, is anti-inflammatory and can certainly help fibromyalgia patients. In contrast, high cholesterol foods are harmful to this disease. Cholesterol is essential for maintaining the fluidity of cell membranes, and its derivatives are implicated in regulating the immune system both physiologically and in disease (8). In addition, cholesterol is an essential substrate for the synthesis of different classes of compounds such as steroid hormones and bile acids. Once synthesized, cholesterol can be complexed with lipoproteins and transported through the bloodstream. There are five different categories of lipoproteins: high density (HDL), intermediate density (IDL), low density (LDL), very low density (VLDL) and ultra low density (ULDL, also known as chylomicrons). There are two main ways through which cholesterol is catabolized (9). The classical way of synthesis of bile acids is the predominant way (10-11). Lipid molecules play an important role in the atherosclerotic process as they have immunogenic and inflammatory effects. Inflammation is a physiological response that contributes to defense mechanisms in living organisms. Increased release of inflammatory cytokines, such as interleukin-6 or tumor necrosis factor (TNF), can suppress appetite, cause muscle proteolysis and hypoalbuminemia and may be involved in arteriosclerosis and reduced kidney function (12). An increase in serum IL-6 levels has been reported to be associated with an increase in mortality. Hence, if the inflammation is prolonged, it can lead to adverse and consequential effects such as loss of appetite, an increase in the rate of protein and skeletal muscle depletion, loss of fat (hypercatabolism), vascular endothelial damage and atherosclerosis.
Atherosclerosis is accelerated by diet, cigarette smoking, genetic predisposition and hypertension. Atherosclerotic plaques can form on any artery in the body, the most prone to rupture being formed at the bifurcation sites of the arteries. Atherosclerosis has been shown to begin as an inflammatory response from the subendothelial cell layer of the arterial wall due to the accumulation of LDL and OxLDL. Various recruiters such as M-CSF attract circulating monocytes, which bind to V-CAM, P-selectin and ICAM-1 on the endothelium and infiltrate the intima, phagocyte the lipids forming pro-inflammatory foamy cells. Further progression of the lesion involves the migration of smooth muscle cells (SMC) into the intima where they proliferate, with consequent plaque formation. The development of plaque leads to infiltrated cells with the release of extracellular lipids and cellular debris. At this point, other macrophages come to protect and engulf the whole, producing pro-inflammatory substances and increasing the plaque which leads to fatal thrombus. Macrophages are innate immune cells with phagocytic and inflammatory properties, along with neutrophils and dendritic cells. Macrophages can be found in many tissues, where they respond to metabolic signals and cholesterol by producing inflammatory proteins (cytokines). Macrophages participate in atherosclerosis and are associated with the accumulation of lipids including cholesterol which determines the formation and progression of plaque which can subsequently lead to myocardial infarction and ischemic stroke. In the inflammatory state, there is an increased circulating level of C-reactive protein (CRP), the inflammatory marker most used in the clinical setting, which represents a risk factor for cardiovascular diseases. Also the serum amyloid A (SAA), which is mainly transported by HDL, participate in this event. The serum levels of this protein increase significantly during inflammation. Rising SAA levels predict the risk of cardiovascular disease in humans. Fish and fish products, such as fish oil, are important from a nutritional point of view due to the presence of proteins with a high biological value and the high content of polyunsaturated fatty acids, in particular those of the omega-3 series, and especially eicosapentaenoic acid and acid docosahexaenoic. Clinical studies suggest that fish oil not only prevents the incidence of harmful cardiovascular events, but also reduces the cardiovascular mortality rate. Fish oil can regulate blood pressure and improve vascular integrity and compliance. In addition, omega-3s have the ability to protect vascular endothelial cells by decreasing oxidative stress, arresting atherosclerotic events, and preventing inflammatory cascades and vascular adhesion.
However, the fatty acids and cholesterol present in fish are not stable (13). Instability is influenced by its chemical structure, by the presence of metal ions, oxygen, light, processing techniques and more. Hence, temperature, time required for preparation and shipping as well as storage conditions are factors that can contribute to the oxidation and degradation of cholesterol. The influence of cholesterol oxides on human health deserves to be emphasized because oxidation can cause harmful physiological changes. Cholesterol degradation contributes significantly to complex cellular and molecular events, leading to the formation of pro-inflammatory products with the generation of fibrous and atherosclerotic plaques (13). Aerobic exercise significantly improves the risk of developing cardiovascular and rheumatic diseases, including fibromyalgia (14). Physical activity improves the mass and anointing of the beta cells of the pancreas by increasing the insulin content in the beta cells that acquire a greater ability to secrete insulin in response to glucose. These benefits have been seen after workouts and gymnastic exercises.
Our future studies aim to analyze the effects of natural anti-inflammatory compounds such as flavonoids, and in particular of luteolin, on fibromyalgia patients, evaluating both clinical and experimental aspects with dosage of pro and anti-inflammatory cytokines in cell cultures.
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