Dietary supplementation with Lactobacilli improves emergency granulopoiesis in protein-malnourished mice and enhances respiratory innate immune response.

This work studied the effect of protein malnutrition on the hemato-immune response to the respiratory challenge with Streptococcus pneumoniae and evaluated whether the dietary recovery with a probiotic strain has a beneficial effect in that response. Three important conclusions can be inferred from the results presented in this work: a) protein-malnutrition significantly impairs the emergency myelopoiesis induced by the generation of the innate immune response against pneumococcal infection; b) repletion of malnourished mice with treatments including nasally or orally administered Lactobacillus rhamnosus CRL1505 are able to significantly accelerate the recovery of granulopoiesis and improve innate immunity and; c) the immunological mechanisms involved in the protective effect of immunobiotics vary according to the route of administration. The study demonstrated that dietary recovery of malnourished mice with oral or nasal administration of L. rhamnosus CRL1505 improves emergency granulopoiesis and that CXCR4/CXCR12 signaling would be involved in this effect. Then, the results summarized here are a starting point for future research and open up broad prospects for future applications of probiotics in the recovery of immunocompromised malnourished hosts.

Effect of a probiotic fermented milk on the thymus in Balb/c mice under non-severe protein-energy malnutrition.

Protein­energy malnutrition (PEM) causes a significant impairment of the immune system, the thymus being one of the most affected organs. It has been demonstrated that the administration of probiotic fermented milk (PFM) recovered the intestinal barrier, histological alterations and mucosal and systemic immune functions in a non-severe malnutrition model using BALB/c mice. The aim of the present study was to evaluate, in the same model of malnutrition, the effect of a PFM added to a re-nutrition diet on the recovery of the thymus, analysing histological and functional alterations caused by malnutrition. Mice were undernourished and divided into three groups according to the dietary supplement received during re-nutrition: milk, PFM or its bacterial-free supernatant (BFS). They were compared with well-nourished and malnourished mice. PFM was the most effective re-nutrition supplement to improve the histology of the thymus, decreasing cellular apoptosis in this organ and recovering the percentage of CD4þ/CD82 single-positive thymocytes. Immature doublepositive thymocytes were increased in the malnourished control (MC). The production of different cytokines in the thymus was increased in mice given PFM, compared with the mice that received other dietary supplements and MC. Mice given the BFS presented an improvement in the thymus similar to those that received milk. We demonstrated the importance of the whole PFM supplementation on the histological and functional recovery of the thymus in a non-severe PEM model.

Modulation of the nuclear factor-kappa B (NF-κB) signalling pathway by glutamine in peritoneal macrophages of a murine model of protein malnutrition.

BACKGROUND AND AIMS: Protein malnutrition affects resistance to infection by impairing the inflammatory response, modifying the function of effector cells, such as macrophages. Recent studies have revealed that glutamine-a non-essential amino acid, which could become conditionally essential in some situations like trauma, infection, post-surgery and sepsis-is able to modulate the synthesis of cytokines. The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappa B (NF-κB) signalling pathway of peritoneal macrophages from malnourished mice. METHODS: Two-month-old male Balb/c mice were submitted to protein-energy malnutrition (n = 10) with a low-protein diet containing 2 % protein, whereas control mice (n = 10) were fed a 12 % protein-containing diet. The haemogram and analysis of plasma glutamine and corticosterone were evaluated. Peritoneal macrophages were pre-treated in vitro with glutamine (0, 0.6, 2 and 10 mmol/L) for 24 h and then stimulated with 1.25 µg LPS for 30 min, and the synthesis of TNF-α and IL-1α and the expression of proteins related to the NF-κB pathway were evaluated. RESULTS: Malnourished animals had anaemia, leucopoenia, lower plasma glutamine and increased corticosterone levels. TNF-α production of macrophages stimulated with LPS was significantly lower in cells from malnourished animals when cultivated in supraphysiological (2 and 10 mmol/L) concentrations of glutamine. Further, glutamine has a dose-dependent effect on the activation of macrophages, in both groups, when stimulated with LPS, inducing a decrease in TNF-α and IL-1α production and negatively modulating the NF-κB signalling pathway. CONCLUSIONS: These data lead us to infer that the protein malnutrition state interferes with the activation of macrophages and that higher glutamine concentrations, in vitro, have the capacity to act negatively in the NF-κB signalling pathway.

Interaction of nutrition and infections globally: an overview.

The interaction of nutrition and infections is known by experience by generations of medical doctors. Before the era of antibiotics, diet was an integral part of the management of infections. Now, it is necessary to take a fresh look at this interaction as the understanding of immune response has expanded considerably. Comparatively little research has addressed the impact of nutrition interventions on the management of infectious diseases. Most observations of the interaction between nutrition and infections are epidemiological in character. This holds especially true for measles as well as for tuberculosis. In AIDS, the deterioration of the nutritional status is an indicator of disease progression. Infections in undernourished children are a common cause of death, and taking this finding into account helps to reduce the case fatality rate in severely malnourished patients. Regarding the immune response, cellular as well as soluble components are affected by deficiencies of single nutrients or general undernutrition. The immunosuppressive effect of undernutrition starts during intrauterine life already: maternal nutrition status has been shown to impact on immune function in adult animals. Recent research suggests that not only undernutrition but also caloric overnutrition impacts on immune response to infections and immunization. This is partly due to the chronic inflammatory activity of the adipose tissue and partly due to neuroendocrine alterations. Infectious diseases also impact on the nutritional status, either specifically or through unspecific mechanisms, such as anorexia, tachypnea, and vomiting.

Effect of honey on 50% complement hemolytic activity in infants with protein energy malnutrition: a randomized controlled pilot study.

Protein energy malnutrition (PEM) is associated with a significant impairment of cell-mediated immunity and complement system, which may be responsible for the high incidence of infections among these patients. This study was designed to examine the effect of honey, as a natural substance, on the 50% complement hemolytic activity (CH50) in patients with PEM. Thirty patients with PEM and 20 healthy infants serving as controls participated in this study. The patients were randomized to receive either honey (group 1) or placebo (group 2), in addition to conventional nutritional rehabilitation therapy. Measurements of weight, midarm circumference, skin fold thickness, serum albumin, and CH50 were done for all patients before and after 2 weeks of rehabilitation. Before nutritional rehabilitation, the CH50 was significantly lower in the PEM groups compared with the control. However, after rehabilitation, the CH50 increased significantly in both PEM groups, compared with the pre-interventional state and with the controls. Moreover, the rise of CH50 was significantly more in the honey group compared with the placebo. On the other hand, the improvement in the anthropometric measures and serum albumin did not differ significantly between the honey and placebo groups after rehabilitation. Thus honey supplementation in patients with PEM increased the level of CH50. Whether this would have an effect on the frequency and severity of infections in patients with PEM needs further studies.

Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses.

The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+ cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+ thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.

Landscape analysis of interactions between nutrition and vaccine responses in children.

The world's poorest children are likely to be malnourished when receiving their childhood vaccines. It is uncertain whether this affects vaccine efficacy and whether the coadministration of nutrient supplements with vaccines has beneficial or detrimental effects. More recently, a detrimental interaction between vitamin A (VA) supplementation (VAS) and the killed diphtheria-tetanus-pertussis vaccine given in early childhood has been suggested. This report provides a critical review of the published interactions between nutritional status and/or supplementation and vaccine responses in children. Due to an absence of evidence for most nutrients, this analysis focused on protein-energy, vitamins A and D, and iron and zinc. All vaccines were considered. Both observational studies and clinical trials that led to peer-reviewed publications in English or French were included. These criteria led to a pool of 58 studies for protein-energy malnutrition, 43 for VA, 4 for vitamin D, 10 for iron, and 22 for zinc. Our analysis indicates that malnutrition has surprisingly little or no effect on vaccine responses. Evidence for definitive adjunctive effects of micronutrient supplementation at the time of vaccination is also weak. Overall, the paucity, poor quality, and heterogeneity of data make it difficult to draw firm conclusions. The use of simple endpoints that may not correlate strongly with disease protection adds uncertainty. A detailed examination of the immunological mechanisms involved in potential interactions, employing modern methodologies, is therefore required. This would also help us understand the proposed, but still unproven, negative interactions between VAS and vaccine safety, a resolution of which is urgently required.

Cytokine response to dietary rehabilitation with curd (Indian dahi) & leaf protein concentrate in malnourished children.

BACKGROUND & OBJECTIVE: Protein energy malnutrition (PEM), an important cause of secondary immune deficiency, is associated with several abnormalities in the immune system including cytokine production. In the present study cytokine levels (both pro- and anti-inflammatory) were evaluated in protein energy malnourished children following nutritional rehabilitation with curd (Indian dahi) and leaf protein concentrate (LPC). METHODS: Eighty moderately and severely malnourished children, 1-5 yr of age, received the WHO recommended diet for severe malnutrition, modified according to local dietary habits, containing in addition either curd or micronutrient-rich leaf protein concentrate, for a period of 15 days. Cytokine levels [tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin-10 (IL-10), interleukin-4 (IL-4)] were measured before and after dietary rehabilitation. RESULTS: The baseline cytokine levels (TNFalpha, IFNgamma, IL-10 and IL-4) were high in malnourished children. Both the diets caused an increase in serum pro-inflammatory (TNFalpha, IFNgamma), and anti-inflammatory (IL-10) cytokine levels after nutritional rehabilitation. The increase in IL-10 was significant in children receiving curd. There was an insignificant fall in IL-4 levels with both the diets. The cytokine response was comparable in children with moderate and severe malnutrition, as also in children < 2 yr to those between 2-5 yr. INTERPRETATION & CONCLUSION: The study suggests that cytokines (TNFalpha, IFNgamma, IL-10 and IL-4) may serve as biological markers to assess the effect of functional foods like curd or LPC on immunity in malnutrition. Curd may help to maintain the balance in cytokine production by increasing the production of IL-10, and may be considered in place of milk in the nutritional rehabilitation of malnourished children.

Protein-energy malnutrition decreases immune response to Leishmania chagasi vaccine in BALB/c mice.

Protein-energy malnutrition and visceral leishmaniasis are important problems of public health affecting millions of people worldwide. Vaccine efficacy depends on the ability of individuals to mount an appropriate immune response and may be inadequate in malnourished persons. In this study, we used a mouse model to verify the effect of combined protein, iron and zinc deficiency in the response to Leishmania chagasi antigen vaccine. BALB/c mice were fed with a low-protein (3% casein), iron- and zinc-deficient diet or control diet (14% casein and sufficient in zinc and iron). After malnutrition establishment, mice were vaccinated subcutaneously with L. chagasi Ag plus saponin. After vaccination, mice were nutritionally repleted and then all mice were challenged with L. chagasi promastigotes. Four weeks later, liver and spleen parasite load was evaluated. Our data show that vaccine caused a significant reduction in parasite load in spleen and liver from mice fed with control diet. However, splenic parasitism was increased in mice fed with deficient diet and this diet caused a reduction in splenocyte IFN-gamma production in response to the vaccine in repleted mice. These data suggest that malnutrition may alter immune response to L. chagasi vaccine in BALB/c model of infection, even after nutritional repletion.

A pilot study on the effects of curd (dahi) & leaf protein concentrate in children with protein energy malnutrition (PEM).

BACKGROUND & OBJECTIVE: In protein-energy malnutrition (PEM) there is a significant impairment of immunity, both cell-mediated and humoral, which may be reversed with nutritional rehabilitation. With the use of probiotics like curd (dahi) and micronutrient-rich leaf protein concentrate (LPC), this immune recovery may be hastened. This study was conducted to assess the impact of supplementation of curd and LPC on nutritional status, and immunity as assessed by anthropometry, haemoglobin, ferritin levels, T- cell subpopulation and C-reactive protein (CRP), in children suffering from PEM. METHODS: Eighty moderate to severely malnourished children (1-5 yr) were randomized to receive either curd or LPC in addition to WHO recommended two-step diet over 15 days. Nutritional, immunological and haematological parameters were measured before and after supplementation and compared within the groups. RESULTS: The change in weight, haemoglobin level and CD4:CD8 T-cell subpopulation was significant in both the groups after supplementation. Response of CRP was blunted in PEM. Serum ferritin decreased significantly after supplementation in both groups. INTERPRETATION & CONCLUSION: Curd and LPC when added to diet of malnourished children, may have therapeutic value by accelerating immune recovery. More studies need to be done on a larger sample to confirm these findings.

N-acetyl-L-glutamine, a liquid-stable source of glutamine, partially prevents changes in body weight and on intestinal immunity induced by protein energy malnutrition in pigs.

The goal of this study was to evaluate the preventive effect of free glutamine versus N-acetyl-L-glutamine, a liquid-stable source of glutamine, on gut damage induced by protein energy malnutrition in pigs. Healthy pigs (n = 6) were fed a liquid formula for 30 days. Three subgroups of malnourished pigs (n = 6) received daily 20% of the food intake recorded in control group, supplemented with calcium caseinate, glutamine, or N-acetyl-L-glutamine. Body weight was recorded, and small intestinal samples were evaluated for biochemical and immunologic parameters. Suppression in body weight gain was significantly lower in pigs fed with N-acetyl-L-glutamine than in the rest of malnourished pigs. Total number of lymphocytes, CD21+ B cells and CD4+ T cells in ileal Peyer patches were not significantly different in malnourished pigs fed with N-acetyl-L-glutamine and in healthy pigs. In conclusion, N-acetyl-L-glutamine has a moderate protective effect, partially preventing changes induced by protein energy malnutrition.

Insect psychoneuroimmunology: immune response reduces learning in protein starved bumblebees (Bombus terrestris).

It is well established in vertebrates that there are many intricate interactions between the immune system and the nervous system. Here, we present behavioural evidence indicating a link between the immune system and the nervous system in insects. We show that otherwise non-infected bumblebees whose immune systems were challenged by a non-pathogenic immunogenic elicitor (lipopolysaccharide) have reduced abilities to learn or recall a memory in a classical conditioning paradigm. There is evidence that protein is intricately involved as this immune induced reduction in memory only becomes apparent after the bees are deprived of pollen (their only protein sources).

Nutrients as modulators of anergy in acquired immune deficiency syndrome.

Malnutrition induces a spectrum of immune abnormalities including a state of anergy in the host. This state is due to a decrease in CD4 + helper cells, diminished cytotoxic cell activity and reduction in production of lymphokines required for signal transduction. Human immunodeficiency virus (HIV), the retrovirus known to cause acquired immune deficiency syndrome (AIDS), leads to a state of anergy by causing similar immunological changes. Micronutrient abnormalities, concomitant infections and genetic factors, etc., are some of the compounding co-factors which further contribute to the deterioration of the immune functions in AIDS patients. Reversal of these immune abnormalities would improve the quality of life of HIV-infected individuals.

Immune recovery of malnourished children takes longer than nutritional recovery: implications for treatment and discharge.

Protein-energy malnutrition decreases cellular immunity yet immune recovery has rarely been investigated during nutritional rehabilitation. Malnourished children from low income families of Cochabamba (Bolivia) were hospitalized for 2 months in the Center for Immune and Nutritional Rehabilitation (CRIN), of the German Urquidi Materno-Infantil Hospital. They received a special four-step diet. Nutritional status was determined by a daily clinical examination and weekly anthropometric measurements. Immune status was assessed by weekly ultrasonography of the thymus. The classical criterion for discharge (90 per cent of median reference weight for height) was reached after the first month, whereas a 2-month period was required for complete immunologic recovery. The children belonged to disadvantaged population groups with high exposure to disease. In such an environment, discharge based only on nutritional status after 1 month of treatment could explain frequent relapses because the children were still immunodepressed.

Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial.

BACKGROUND: Increased acute lower respiratory infection incidence, severity, and mortality are associated with malnutrition, and reduced immunological competence may be a mechanism for this association. Because zinc deficiency results in impaired immunocompetence and zinc supplementation improves immune status, we hypothesized that zinc deficiency is associated with increased incidence and severity of acute lower respiratory infection. METHODS: We evaluated the effect of daily supplementation with 10 mg of elemental zinc on the incidence and prevalence of acute lower respiratory infection in a double-blind, randomized, controlled trial in 609 children (zinc, n = 298; control, n = 311) 6 to 35 months of age. Supplementation and morbidity surveillance were done for 6 months. RESULTS: After 120 days of supplementation, the percentage of children with plasma zinc concentrations <60 microg/dL decreased from 35.6% to 11.6% in the zinc group, whereas in the control group it increased from 36.8% to 43.6%. Zinc-supplemented children had 0.19 acute lower respiratory infection episodes/child/year compared with 0.35 episodes/child/year in the control children. After correction for correlation of data using generalized estimating equation regression methods, there was a reduction of 45% (95% confidence interval, 10% to 67%) in the incidence of acute lower respiratory infections in zinc-supplemented children. CONCLUSIONS: A dietary zinc supplement resulted in a significant reduction in respiratory morbidity in preschool children. These findings suggest that interventions to improve zinc intake will improve the health and survival of children in developing countries.

Immunological aspects of aging and malnutrition: consequences and intervention with nutritional immunomodulators.

As knowledge of molecular and cellular mechanisms of development and aging is elucidated, the need to understand the relationships among tissues, organ systems, health habits, nutrition, physical activity, and environmental factors on successful aging becomes more explicit. Progress in our understanding of how the immune system functions and responds with other factors, such as aging and nutrition, is spawning significant inroads to achieving a successful old age.

Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments.

Nutrition has a strong influence on the immune system of the elderly. Aging induces dysregulation of the immune system, mainly as a result of changes in cell-mediated immunity. Aging is associated with changes to the equilibrium of peripheral T and B lymphocyte subsets, such as decreases in the ratios of mature to immature, naive to memory, T helper 1 subset (TH1) to TH2, and CD5- to CD5+ cells. As a consequence, cell-mediated immune responses are weaker and neither cell-mediated nor humoral responses are as well adapted to the antigen stimulus. Undernutrition, common in aged populations, also induces lower immune responses, particularly in cell-mediated immunity. Protein-energy malnutrition is associated with decreased lymphocyte proliferation, reduced cytokine release, and lower antibody response to vaccines. Micronutrient deficits, namely of zinc, selenium, and vitamin B-6, all of which are prevalent in aged populations, have the same influence on immune responses. Because aging and malnutrition exert cumulative influences on immune responses, many elderly people have poor cell-mediated immune responses and are therefore at a high risk of infection. Nutritional therapy may improve immune responses of elderly patients with protein-energy malnutrition. Supplementation with high pharmacologic doses of a single nutrient (zinc or vitamin E) may be useful for improving immune responses of self-sufficient elderly people living at home. Therefore, nutritional deficiency must be treated in the elderly to reduce infectious risk and possibly slow the aging process.

Nutritional health: prevention and treatment of HIV-associated malnutrition. A case manager's guide.

AIDS: Nutritional health in HIV-infected patients is critical because it optimizes existing immune system function, can help reduce the incidence of complications of HIV disease, reduces the overall cost of medical care, helps achieve maximum benefit from drug therapies, and improves the patient's quality of life. The following areas of nutrition relative to HIV disease are discussed: nutrition and the immune system; malnutrition and cost of medical care; the immune system; nutritional status and immune function; the effects of HIV disease on nutritional status; and the nutritional management of HIV disease. It is advised that, in order to be most cost-effective and have the greatest benefits, nutritional intervention should begin at the time of HIV disease diagnosis and continue throughout the disease process. Nutritional therapeutic options include nutrition education and counseling, oral supplements and, when necessary, appetite stimulants, anabolic agents and enteral or parenteral nutrition.^ieng