Impact of vitamin deficiency on microbiota composition and immunomodulation: relevance to autistic spectrum disorders.

OBJECTIVES: Inappropriate vitamin supply is a public health problem and is related to abnormalities in brain development, immune response and, more recently, in changes of gut microbial composition. It is known that low levels of vitamin in early life are linked to increased susceptibility to neurodevelopmental disorders, such as Autism Spectrum Disorders (ASD). Unfortunately, the possible peripheral influences of vitamin deficiency that leads to alterations in the gut microbiota-immune-brain axis, one important modulator of the ASD pathology, remain unclear. This narrative review discusses how the impact of vitamin deficiency results in changes in the immune regulation and in the gut microbiota composition, trying to understand how these changes may contribute for the development and severity of ASD. METHODS: The papers were selected using Pubmed and other databases. This review discusses the following topics: (1) vitamin deficiency in alterations of central nervous system in autism, (2) the impact of low levels of vitamins in immunomodulation and how it can favor imbalance in gut microbiota composition and gastrointestinal (GI) disturbances, (3) gut microbiota imbalance/inflammation associated with the ASD pathophysiology, and (4) possible evidences of the role of vitamin deficiency in dysfunctional gut microbiota-immune-brain axis in ASD. RESULTS: Studies indicate that hypovitaminosis A, B12, D, and K have been co-related with the ASD neuropathology. Furthermore, it was shown that low levels of these vitamins favor the Th1/Th17 environment in the gut, as well as the growth of enteropathogens linked to GI disorders. DISCUSSION: GI disorders and alterations in the gut microbiota-immune-brain axis seems to be linked with ASD severity. Although unclear, hypovitaminosis appears to regulate peripherally the ASD pathophysiology by modulating the gut microbiota-immune-brain axis, however, more research is still necessary to confirm this hypothesis.

The Role of the Status of Selected Micronutrients in Shaping the Immune Function.

OBJECTIVE: This narrative review gives an overview on the essential role of adequate nutrition to an optimally functioning immune defence. Micronutrients act as regulators of the immune response, with the focus of this review on the immunomodulatory effects of the trace elements iron, zinc and selenium, and the vitamins A, D, E, C, B6 and B12 and folic acid. RESULTS: Iron deficiency especially impairs the Th1 cell-borne cellular immunity. T lymphocytes are also most affected by a deficiency of zinc, needed for their maturation and the balance between the different T cell subpopulations and acting as a redox signal in the regulation of many enzymes. Selenium is also involved in redox reactions as the glutathione peroxidases and other redox enzymes are selenoproteins. Selenium status has shown special effects on cellular immunity and resistance to viral infections. Vitamin A in the form of retinoic acid induces a humoral Th2 cell response via antigen-presenting cells and is involved in maintaining intestinal immune defence and tolerance through its nuclear receptor RAR and via kinase signalling cascades. Immune tolerance is particularly promoted by vitamin D acting through dendritic cells to stimulate the differentiation of regulatory T cells. Vitamin E has antiinflammatory effects and stimulates naïve T cells especially in the elderly. Besides its antioxidative properties, vitamin C has effects on cell signalling and epigenetic regulation. The B vitamins are required for cytotoxic cellular immunity and modulate T cell responses. CONCLUSION: A diverse diet and regular exposure to sunlight are the best sources for a balanced nutrient supply to maintain an optimal immune defence.

[Effect of B-vitamin deficiency on biochemical, immunologic markers and trace element status of rats and mice of various lines].

Biochemical, vitamin, trace element and immunological changes were searched for the combined nutritional deficiency of vitamins B1, B2, B6 on in vivo models in rats and mice. Female rats of Wistar (W) strain and hybrids of the 1st generation of Dark Aguti and Wistar (DA x W) strains, female mice of BALB/c strain and DBCB tetrahybrids were used in experiment. Animals received for 35 days a balanced diet (control) according to AIN-93 or a similar diet with the exception of vitamins B1, B2, B6 (experimental groups). The content of vitamins B1, B2 in liver, riboflavin blood plasma level and urinary excretion of thiamine, riboflavin and 4-pyridoxic acid were determined, as well as in rats: blood and liver content of α-tocopherol and retinol, blood biochemical indices of lipid and nitrogen metabolism, activity of cytochrome P isoforms-450 (CYP) in liver; in mice: the circulating levels of pro- and anti-inflammatory cytokines of blood plasma, in animals of both species - the content of essential and toxic elements in the kidneys. DAxW rats compared to W and DBCB mice compared to BALB/c were more sensitive to the development of B-vitamin deficiency judging by the B-vitamin status indicators. In the rats of the experimental groups, there were signs of a deterioration in blood and liver levels of vitamin E, multidirectional shifts in vitamin A sufficiency, increased activity of the CYP3A isoform (6ß-TG), a decrease in triglycerides, total protein and albumin fraction levels with an increase in urea level. Manifestation degree of these effects depended on the choice of the animal's line. In mice, the B-vitamin deficiency was characterized by an increase in the levels of proinflammatory cytokines TNF-α, IL-10, IL-Ιß, IL-6 and a decrease in IFN-γ and IL-17A. The content of magnesium, copper, zinc, chromium and silver was lowered, of cesium - was increased in the kidneys of the rats of the experimental groups. In mice, B-vitamin deficiency resulted in diminishment of magnesium, copper, zinc, chromium, selenium, cadmium and lead content, excess accumulation of cobalt and cesium. Some of these biomarkers are supposed to be used in pre-clinical evaluation of the effectiveness of new vitamin complexes, specialized foods and dietary supplements, as well as studies of interactions of various vitamins.

Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes.

World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring.

Can vitamin a mediate immunity and inflammation?

Vitamins are natural components of foods and are organic compounds distinct from fat, carbohydrates and proteins. Vitamin A is the generic descriptor for compounds with the qualitative biological activity of retinol. Unlike beta-carotene, vitamin A is not an antioxidant and its benefit is related to possible boosting of immune reactions. The effect of vitamin A on immune function is wide-reaching and its deficiency appears to affect immunity in several ways. Innate and adaptive immune responses are affected in some way by lack of vitamin A. Retinoids seem to act on differentiation of lymphocytes, antibody production, phagocytosis of macrophages, NK, Treg, and T helper cell activity. In addition, in humans, signs of a vitamin A deficiency also include the dysregulation of cytokine/chemokine generation and release. However, excess of vitamin A has been demonstrated to have toxic effects in most species studied. Here we summarize some important effects of vitamin A in immunity and inflammation.

Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.

[The influence of dietary fibers on cell immunity under the adequate nutrition and in the presence of alimentary polyhypovitaminosis in rats].

The effect of wheat bran on cell immunity in rats adequately provided with vitamins or insufficiently supplied with vitamins has been investigated. 48 male Wistar rats (58.1 +/- 0.5 g) were divided into 6 group and fed with complete semi-synthetic diet, containing 100% or 20% of vitamin mixture (Vit) with or without supplement of insoluble dietary fiber (DF) in the dose corresponding to the upper allowable level of its consumption (5% wheat bran of diet mass) for 4 weeks. The animals of the 1 group received 100% of vitamin mixture (100% Vit); 2 group--100% Vit+DF; 3 group--20% of vitamin mixture (20% Vit); 4 group--20% of vitamin mixture and DF (20% Vit+DF). The next 5 days rats from vitamin-deficient groups were fed with diets supplemented with 80% of Vit: (5 group--20% Vit+80% Vit; 6 group--20% Vit+DF+80% Vit). The contents of lymphocytes, relative quantity of B-(CD45RA+) and T-lymphocytes (CD3+), subpopulations of T-lymphocytes: T-helper (CD3+CD4+) and cytotoxic T-lymphocytes (CD3+CD8+), NK-cells (CD161a+) in the peripheral blood of rats were determined by the method of flow cytometry using Beckman Coulter FC 500 (USA) cytometer. In rats fed complete semi-synthetic diet supplemented with DF (100% Vit+DF) the reduction of relative contents of T-lymphocytes and the increase of the fraction of cytotoxic T-lymphocytes in peripheral blood has been found. The analogous changes and more pronounced degree of immunosupression, that appeared in a lymphocytopenia, much smaller level of T-lymphocytes, T-helper and increase of cytotoxic T-lymphocytes content in rats fed a low vitamins diet (20% Vit) in comparison with these parameters of control group, have been detected. In rats received 20% Vit+DF the suppressed cell immunity was accompanied with decreased level of NK-cells. Normalization of vitamins content in the diets of rat deficient groups led to an almost complete recovery of cell immunity indicators to the level of the animals from the corresponding control groups. Inclusion in the diet of fiber requires its further enrichment with vitamins. Special studies of fiber diet influence on are needed to clarify the upper allowable level of insoluble dietary fiber in human nutrition.

Psychological stress and vitamins.

Conditions of stress and anxiety have complex interactions with insufficient vitamin intake and malnutrition. This study, based on literature research in Medline, analyzes the inter-relationship between vitamins and stress. This report concerns a number of vitamins that have been receiving much attention in earlier reviews of the literature, for their potential to protect against stress-related events, and focus is placed upon recent findings.

Interrelationship between vitamins and cytokines in immunity.

Cytokines are important proteins that modulate immunity and inflammation. Vitamins are also involved in immunity and inflammation. They are found to restore the ability of some cells to produce certain cytokines. Vitamin deficiency appears to affect the mechanism of immune cells, though the impact of reduced cytokine response in vitamin malnutrition is not clear. Vitamin D is involved in many medical conditions, such as infections and inflammation, and mediates innate immunity. Deficiency of vitamin D increases the risk of infectious and inflammatory diseases. In addition, this vitamin modulates Treg function and IL-10 production which is important for therapeutic treatment. Vitamin A increases inflammatory response and is involved in tissue damage; moreover, vitamin A is a key modulator of TGFbeta which can suppress several cytokines. Vitamin E, an anti-ageing compound, is associated with a defect of naive T cells and may inhibit some inflammatory compounds such as prostaglandin generation.

Vitamin-regulated cytokines and growth factors in the CNS and elsewhere.

There is a growing awareness that natural vitamins (with the only exception of pantothenic acid) positively or negatively modulate the synthesis of some cytokines and growth factors in the CNS, and various mammalian cells and organs. As natural vitamins are micronutrients in the human diet, studying their effects can be considered a part of nutritional genomics or nutrigenomics. A given vitamin selectively modifies the synthesis of only a few cytokines and/or growth factors, although the same cytokine and/or growth factor may be regulated by more than one vitamin. These effects seem to be independent of the effects of vitamins as coenzymes and/or reducing agents, and seem to occur mainly at genomic and/or epigenetic level, and/or by modulating NF-kappaB activity. Although most of the studies reviewed here have been based on cultured cell lines, but their findings have been confirmed by some key in vivo studies. The CNS seems to be particularly involved and is severely affected by most avitaminoses, especially in the case of vitamin B(12). However, the vitamin-induced changes in cytokine and growth factor synthesis may initiate a cascade of events that can affect the function, differentiation, and morphology of the cells and/or structures not only in the CNS, but also elsewhere because most natural vitamins, cytokines, and growth factors cross the blood-brain barrier. As cytokines are essential to CNS-immune and CNS-hormone system communications, natural vitamins also interact with these circuits. Further studies of such vitamin-mediated effects could lead to vitamins being used for the treatment of diseases which, although not true avitaminoses, involve an imbalance in cytokine and/or growth factor synthesis.

[Evaluation of dietary therapy efficiency, based on clinical and biochemical parameters in patients with cardiovascular disease and osteopenia].

Aim of investigation was to analysis of dietary intake in patients with cardiovascular diseases (CVD) and osteopenia. We studied 13 patients with CDV and osteopenia and 117 control subjects with CDV. Analysis of dietary intake in all patients showed high level consumption of fat, excessive consumption of phosphorus and deficiency in consumption of vitamins A, B1, B2. It was shown that diet-therapy has promoted the most positive changes of the clinical, biochemical and immunological parameters of patients had osteopenia less then control group.

Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses.

Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lactation, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to the body's natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body's natural defence system by enhancing all three levels of immunity.

Nutrition and immunity: laboratory and clinical aspects.

It is well known that inappropriate nutrient intake accounts for the maintenance of the immunological equilibrium, in humans and animals. Vitamins, elements, lipids, proteins and nucleic acids play an important role in the regulation of cellular and humoral immune responses since single or multiple deficits of these food components have been shown to cause immune abnormalities. For instance, in the course of protein-calorie malnutrition bacterial and/or viral infections represent the major cause of death. Ageing is characterized by a decline of many immune functions, and this process is called immunosenescence. Here, we report novel findings on the inability of superantigens to activate old CD8+, natural killer and B cells, as an expression of cell amnesia. In the elderly, this lack of activation could lead to lethal effects in the case of severe staphylococcal infections. Quite interestingly, recent findings outlined some similarities between human immune deficiency virus (HIV)-1 infection and ageing in terms of immune changes. The model of HIV-infection may be useful for the interpretation of ageing mechanisms and possible therapeutical interventions. Finally, the role of nutrition in different pathological conditions and the use of medical foods for correcting of immune deficits will be described.

Trace elements and vitamins in immunomodulation in infancy and childhood.

It has been established that there is a strict and cyclical relationship between infection, immune function and nutritional status with changes in one influencing the other two. Impairment of immune function can occur even in healthy subjects in apparently good nutritional status as a consequence of some nutrient deficiencies. The impact of trace elements and vitamins on immune function are briefly reviewed.