Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 14, Issue 4, 2014

In order to gain better insight into meaningful effects of nutrition on immune function, there is a need for guidance on the assessment and interpretation of immune markers. However, there is no consensus as to which markers best represent the various aspects of immunity, including acute, chronic or low-grade inflammation. International Life Sciences Institute European Branch has commissioned several expert groups comprising individuals from different backgrounds including academia, government and the food industry to prepare descriptive and guidance documents on this topic. Two of these considered the markers of the immune response mainly in the context of host defence against pathogens, two considered general markers of inflammation, and one focussed on chronic low-grade inflammation in relation to overweight and obesity. This article describes the background to these documents and will summarise the work, findings and recommendations of the expert groups.

Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The Mediterranean Diet (MedDiet) is a nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. This dietary pattern is characterized by the abundant consumption of olive oil, high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts and seeds); frequent and moderate intake of wine (mainly with meals); moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs; and low consumption of red meat, processed meat products and seeds. Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders. The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process. Thus, the aim of this review was to consider the current evidence about the effectiveness of the MedDiet in these chronic inflammatory diseases due to its antioxidant and anti-inflammatory properties, which may not only act on classical risk factors but also on inflammatory biomarkers such as adhesion molecules, cytokines or molecules related to the stability of atheromatic plaque.

The recent discovery that vitamin D regulates expression of the cathelicidin antimicrobial peptide gene has generated renewed interest in using vitamin D to fight infectious diseases. This review describes the historical use of vitamin D or its sources to treat infections, the mechanism of action through which vitamin D mediates its “antibiotic” effects, findings from epidemiological studies associating vitamin D deficiency with increased susceptibility to infection and clinical trials with vitamin D supplementation to treat or prevent infections. Furthermore studies examining an association between vitamin D levels and cathelicidin expression are discussed. The role of cathelcidin throughout the course of infection from the initial encounter of the pathogen to the resolution of tissue damage and inflammation indicates that individuals need to maintain adequate levels of vitamin D for an optimal immune response. In addition, for treating infections, carefully designed randomized, clinical trials that are appropriately powered to detect modest effects, target populations that are severely deficient in vitamin D,and optimized dose, dosing frequency and safety are needed.

In the early 1920s the antirachitic effect of food irradiated with ultraviolet light and cod liver oil has been recognized. The antirachitic substance was identified and called “vitamin D”. Since then the key role of vitamin D in calcium and bone homeostasis has been investigated. Moreover, it has been recognized that vitamin D is able to modulate a variety of processes and regulatory systems such as host defense, inflammation, immunity, and repair. According to recent studies, vitamin D deficiency is likely to be an important etiological factor in the pathogenesis of many chronic diseases, as well as it has been associated with higher mortality rate for respiratory disease. In this regard, either observational studies aimed to verify an association between low vitamin D level and the incidence of respiratory tract infections (RTIs) or clinical trials on the effect of vitamin D as a supplementary treatment in RTIs patients have been presented in the emerging clinical literature. Conflicting results have been demonstrated in several randomized, doubleblind, placebo controlled trials concerning the vitamin D treatment in tuberculosis. Some studies suggest a beneficial effect by vitamin D but it could not be reproduced in larger studies so far. In conclusion, although basic science research suggests that vitamin D may play an important role in modulating immune functions, no strong evidence exists whether correction of vitamin D depletion may be useful in the prevention or treatment of infections. Further and larger studies may clarify the role of vitamin D in infection.

Immune decline with ageing accounts for the increased risk of infections, inflammatory chronic disease, autoimmunity and cancer in humans. Both innate and adaptive immune functions are compromised in aged people and, therefore, attempts to correct these dysfunctions represent a major goal of modern medicine. In this review, special emphasis will be placed on the aged innate immunity with special reference to polymorphonuclear cell, monocyte/ macrophage, dendritic cell and natural killer cell functions. As potential modifiers of the impaired innate immunity, some principal nutraceuticals will be illustrated, such as micronutrients, pre-probiotics and polyphenols. In elderly, clinical trials with the above products are scanty, however, some encouraging effects on the recovery of innate immune cells have been reported. In addition, our own results obtained with symbiotics and polyphenols extracted from red wine or fermented grape marc suggest the potential ability of these substances to modulate the innate immune response in ageing, thus reducing the inflammaging which characterizes immune senescence.

Numerous studies have provided evidence suggesting that aging is associated with significant adverse changes in the immune system, a phenomenon often called immunosenescence, which may be responsible for an observed increase in morbidity and mortality from infectious disease and cancer in the elderly. While a variety of immune cells are known to be affected by aging, declined T cell function is the most striking and best characterized feature of immunosenescence. Both intrinsic changes in T cells and alteration in extrinsic factors are involved. Nutritional intervention has been promoted as a promising approach to delaying/reversing immunosenescence, and vitamin E is one of the best studied candidates in this regard. While vitamin E deficiency is rarely seen, both animal and human studies suggest that intake above currently recommended levels may help restore T cell function which becomes impaired with aging. This effect of vitamin E can be accomplished by directly impacting T cells as well as indirectly, by inhibiting production of prostaglandin E2, a T cell-suppressing lipid mediator known to increase with aging. Vitamin E-induced enhancements of immune functions may have significant clinical implications since vitamin E supplementation has been shown to be associated with both enhanced resistance to influenza infection in aged mice and reduced risk of acquiring upper respiratory infections in elderly human subjects. With a focus on our own work, this paper provides an overview on the beneficial effects of increased vitamin E intake on age-related decline in T cell function, the underlying mechanisms, and its clinical application in reducing the risk of infection.

Over the last decade our understanding of human gut microbiology underwent a tremendous transformation. The limitations of culture-based methods have given way to Next Generation Sequencing techniques, allowing us to understand the microbial gut community in greater depth. The human GI-tract harbours one of the most complex and abundant ecosystems colonized by more than 100 trillion microorganisms, among which Firmicutes and Bacteroidetes are the major phyla. Although stable over long periods, the composition and functions of the microbiome may be influenced by a number of factors including genetics, mode of delivery, age, diet, geographic location and medical treatments. Dysbiosis, changes in microbiome structure, has been linked to inflammatory, functional and metabolic disorders such as IBD, IBS and obesity. However, it is still not clear whether these changes are a contributing factor or a result of the disease. This synopsis provides a chronological overview of the techniques used to study the gut microbiota and the current knowledge with respect to the stability and variability of microbiome composition and functions.

The beneficial effects of the Mediterranean diet (MD) had been first observed about 50 years ago. Consumption of fresh vegetables and fruits, cereals, red wine, nuts, legumes, etc. has been regarded as the primary factor for protection from many human pathologies by the Mediterranean diet. Subsequently, this was attributed to the presence of polyphenols and their derivatives that, by exerting an anti-inflammatory and anti-oxidative effect, can be involved in the prevention of many diseases. Clinical trials, observational studies and meta-analysis have demonstrated an antiageing effect of MD accompanied by a reduced risk of age-related pathologies, such as cardiovascular, metabolic and neurodegenerative diseases, as well as cancer. The scientific explanation of such beneficial effects was limited to the reduction of the oxidative stress by compounds present in the MD. However, recently, this view is changing thanks to new studies aimed to uncover the molecular mechanism(s) activated by components of this diet. In particular, a new class of proteins called sirtuins have gained the attention of the scientific community because of their antiageing effects, their ability to protect from cardiovascular, metabolic, neurodegenerative diseases, cancer and to extend lifespan in lower organisms as well as in mammals. Interestingly, resveratrol a polyphenol present in grapes, nuts and berries has been shown to activate sirtuins and such activation is able to explain most of the beneficial effects of the MD. In this review, we will highlight the importance of MD with particular attention to the possible molecular pathways that have been shown to be influenced by it. We will describe the state of the art leading to demonstrate the important role of sirtuins as principal intracellular mediators of the beneficial effects of the MD. Finally, we will also introduce how Mediterranean diet may influence microbioma composition and stem cells function.

Malnutrition is a complex syndrome caused by an inadequate intake of energy, protein, minerals and vitamins which affects the immune system. Nutritional imbalances, present in children with energy-protein malnutrition and infections, make defining the specific effects of each of them on the thymus difficult. For this reason, it is necessary to design an experimental model in animals that could define a single variable. As the thymus atrophy described in humans is similar to that observed in murines, a rat experimental model makes the extrapolation to man possible. Some authors suggest that the activity of Adenosine Deaminase (ADA) and Purine Nucleoside Phosphorylase (PNP) - involved in purine metabolism - have an influence on T lymphocyte development and the immune system, due to intracellular accumulation of toxic levels of deoxynucleotides. Studies in our group, performed in an experimental model on Wistar growing rats, have demonstrated that protein deficiency or imbalance in the profile of essential amino acids in the diet, produce loss of thymus weight, reduction in the number of thymocytes, a diminished proportion of T cells presenting the W3/13 antigenic determinant and DNA content with concomitant increase in cell size, and the proportion of immature T cells and activity of ADA and PNP, without modifying the activity of 5´Nucleotidase in the thymus. It is important to point out that there were neither differences in energy intake between experimental groups and their controls, nor clinical symptoms of deficiency of other nutrients. The increase in these thymic enzyme activities was an alternative mechanism to avoid the accumulation of high levels of deoxynucleotides, which would be toxic for T lymphocytes. On the other hand, the administration of a recovery diet, with a high amount of high quality protein, was able to reverse the mentioned effects. The quick reply of Adenosine Deaminase to nutritional disorders and the following nutritional recovery, points out to this determination as a potential functional marker of nutritional status. Some authors have demonstrated an increase in ADA activity, in serum and other biological fluids in patients with various diseases involving defense mechanisms. According to these findings, it could be inferred that ADA activity in serum would follow the same behavior as observed in a rat thymus. So, we have analyzed if its determination could be considered a functional biochemical parameter in populations at nutritional risk. We analyzed the serum ADA activity in groups of individuals with altered nutritional status evaluated through different markers - young adult patients with Nervous Anorexia, overweight or obese school children, children suffering cystic fibrosis. The results show a statistically significant increase in the ADA activity in all groups, with respect to their healthy controls - same age range and socio economic status. The results obtained to date suggest the importance of including the determination of serum Adenosine Deaminase activity in the biochemical evaluation of the nutritional status, as a functional marker related to defense mechanisms.

Objectives: Obesity is a worldwide problem, leading to cardiomyopathy. Oxidative stress and inflammation have been reported to play significant roles in developing obesity cardiomyopathy. N-acetylcysteine is a glutathione prodrug that preserves liver against steatosis via constraining the production of reactive oxygen species. Etodolac is a nonsteroidal anti-inflammatory drug which has been demonstrated to protect liver against fibrosis. The aim of the present study was to evaluate and compare the effects of N-acetylcysteine and etodolac on impaired cardiac functions due to highfat- diet (HFD) induced myocardial steatosis in rats. Material and Methods: Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Control group was maintained on standard-rat-basic-diet (SD) for 20 weeks, while HFD was given to three study groups for 20 weeks. Then N-acetylcysteine was given to one of the study groups (HFD+NAC), and etodolac to another group (HFD+ETD) as a supplement for 4 weeks while all groups were continued on SD. At the end of the study periods, hearts were examined by Langendorff technique and rat livers were evaluated histologically. Results: HFD and HFD+ETD groups presented with significantly higher steatosis and fibrosis in liver compared to other groups. HFD+NAC preserved diastolic functions. Also HFD+NAC and HFD+ETD groups had significantly better systolic funtions than HFD group. Conclusions: Obesity is associated with diastolic dysfunction rather than systolic dysfunction. NAC may protect the heart against diastolic dysfunction due to obesity. NAC and etodolac treatment improve systolic function, even in the absence of systolic dysfunction.