The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial).

INTRODUCTION: Cancer, malnutrition, and surgery negatively impact patient's immune system. Despite standardized surgical technique and the development of new perioperative care protocols, morbidity after cystectomy remains a serious challenge for urologists. Most common postoperative complications, such as infections and ileus, often lead to longer length of stay and worse survival. The immune system and its interaction with the gut microbiota play a pivotal role in cancer immunosurveillance and in patient's response to surgical stress. Malnutrition has been identified as an independent and modifiable risk factor for both mortality and morbidity. Immunonutrition (IN) may improve the nutritional status, immunological function, and clinical outcome of surgical patients. Aims of the study are (1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy and (2) to determine immune and microbiota signature that would predict IN effect. METHODS: This is a randomized, multicentric, controlled, pragmatic, parallel-group comparative study, supported by the Swiss National Science Foundation. A total of 232 patients is planned to be enrolled between April 2023 and June 2026. Three participating centers (Lausanne, Bern, and Riviera-Chablais) have been selected. All patients undergoing elective radical and simple cystectomy will be randomly assigned to receive 7 days of preoperative IN (Oral Impact®, Nestlé, Switzerland) versus standard of care (control group) and followed for 90 days after surgery. For the exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at Lausanne. In order to determine the impact of IN on immune fitness, patients enrolled at Lausanne will be vaccinated against influenza and the establishment of the vaccine-specific immune response will be followed. Analysis of the microbiota and expression of argininosuccinate synthetase 1 as potential biomarker will also be performed. DISCUSSION AND CONCLUSION: Strengths of the INCyst study include the randomized, multicenter, prospective design, the large number of patients studied, and the translational investigation. This study will challenge the added value of preoperative IN in patients undergoing cystectomy, assessing the clinical effect of IN on the onset of postoperative morbidity and mortality after cystectomy. Furthermore, it will provide invaluable data on the host immune response and microbiota composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT05726786. Registered on March 9, 2023.

Maternal Undernutrition Affects Fetal Thymus DNA Methylation, Gene Expression, and, Thereby, Metabolism and Immunopoiesis in Wagyu (Japanese Black) Cattle.

We aimed to determine the effects of maternal nutrient restriction (MNR) on the DNA methylation and gene expression patterns associated with metabolism and immunopoiesis in the thymuses of fetal Wagyu cattle. Pregnant cows were allocated to two groups: a low-nutrition (LN; 60% nutritional requirement; n = 5) and a high-nutrition (HN; 120% nutritional requirement, n = 6) group, until 8.5 months of gestation. Whole-genome bisulfite sequencing (WGBS) and RNA sequencing were used to analyze DNA methylation and gene expression, while capillary electrophoresis-Fourier transform mass spectrometry assessed the metabolome. WGBS identified 4566 hypomethylated and 4303 hypermethylated genes in the LN group, with the intergenic regions most frequently being methylated. Pathway analysis linked hypoDMGs to Ras signaling, while hyperDMGs were associated with Hippo signaling. RNA sequencing found 94 differentially expressed genes (66 upregulated, 28 downregulated) in the LN group. The upregulated genes were tied to metabolic pathways and oxidative phosphorylation; the downregulated genes were linked to natural killer cell cytotoxicity. Key overlapping genes (GRIA1, CACNA1D, SCL25A4) were involved in cAMP signaling. The metabolomic analysis indicated an altered amino acid metabolism in the MNR fetuses. These findings suggest that MNR affects DNA methylation, gene expression, and the amino acid metabolism, impacting immune system regulation during fetal thymus development in Wagyu cattle.

Protection from environmental enteric dysfunction and growth improvement in malnourished newborns by amplification of secretory IgA.

Environmental enteric dysfunction (EED) is a condition associated with malnutrition that can progress to malabsorption and villous atrophy. Severe EED results in linear growth stunting, slowed neurocognitive development, and unresponsiveness to oral vaccines. Prenatal exposure to malnutrition and breast feeding by malnourished mothers replicates EED. Pups are characterized by deprivation of secretory IgA (SIgA) and altered development of the gut immune system and microbiota. Extracellular ATP (eATP) released by microbiota limits T follicular helper (Tfh) cell activity and SIgA generation in Peyer's patches (PPs). Administration of a live biotherapeutic releasing the ATP-degrading enzyme apyrase to malnourished pups restores SIgA levels and ameliorates stunted growth. SIgA is instrumental in improving the growth and intestinal immune competence of mice while they are continuously fed a malnourished diet. The analysis of microbiota composition suggests that amplification of endogenous SIgA may exert a dominant function in correcting malnourishment dysbiosis and its consequences on host organisms, irrespective of the actual microbial ecology.

Malnutrition and Dietary Habits Alter the Immune System Which May Consequently Influence SARS-CoV-2 Virulence: A Review.

COVID-19, resulting from the SARS-CoV-2 virus, is a major pandemic that the world is fighting. SARS-CoV-2 primarily causes lung infection by attaching to the ACE2 receptor on the alveolar epithelial cells. However, the ACE2 receptor is also present in intestinal epithelial cells, suggesting a link between nutrition, virulence and clinical outcomes of COVID-19. Respiratory viral infections perturb the gut microbiota. The gut microbiota is shaped by our diet; therefore, a healthy gut is important for optimal metabolism, immunology and protection of the host. Malnutrition causes diverse changes in the immune system by repressing immune responses and enhancing viral vulnerability. Thus, improving gut health with a high-quality, nutrient-filled diet will improve immunity against infections and diseases. This review emphasizes the significance of dietary choices and its subsequent effects on the immune system, which may potentially impact SARS-CoV-2 vulnerability.

Control of immunity via nutritional interventions.

Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.

Nutrition and immunity: lessons for COVID-19.

The role of the immune system is to protect the individual against pathogenic organisms. Nutrition is one of multiple factors that determines the immune response and good nutrition is important in supporting the immune response. Immunity can be impaired in older people, particularly those who are frail, in those living with obesity, in those who are malnourished and in those with low intakes of micronutrients. The immune impairments associated with nutritional inadequacy increase susceptibility to infection and permit infections to become more severe, even fatal. The adverse impact of poor nutrition on the immune system, including its inflammatory component, may be one of the explanations for the higher risk of more severe outcomes from infection with SARS-CoV-2 seen in older people and in those living with obesity. Studies of individual micronutrients including vitamin D and zinc suggest roles in reducing severity of infection with SARS-CoV-2. Good nutrition is also important in promoting a diverse gut microbiota, which in turn supports the immune system. The importance of nutrition in supporting the immune response also applies to assuring robust responses to vaccination. There are many lessons from the study of nutrition and immunity that are relevant for the battle with SARS-CoV-2.

Leptin Deficiency, Caused by Malnutrition, Makes You Susceptible to SARS-CoV-2 Infection but Could Offer Protection from Severe COVID-19.

In much of the developing world, severe malnutrition is the most prevalent cause of immunodeficiency and affects up to 50% of the population in some impoverished communities. As yet, we do not know how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will behave in populations with immunodeficiency caused by malnourishment. Interestingly, researchers are now speculating that, in some instances, a defective cellular immune system could paradoxically be a protective factor against severe disease in certain patients contracting SARS-CoV and SARS-CoV-2. This could be linked to the absence of T-cell activation. Based on available information presented here, it is plausible that the hyperimmune response, and subsequent cytokine storm often associated with severe coronavirus disease 2019 (COVID-19), could be "counteracted" by the defective immune response seen in individuals with malnutrition-induced leptin deficiency. In this paper, we proposed a theory that although those with malnutrition-linked leptin deficiency are at risk of SARS-CoV-2 infection, they are at lower risk of developing severe COVID-19.

[de la evidencia y algoritmo adaptado Immunonutrition in fast-track surgical patients - Evidence review and adapted algorithm]. / Inmunonutrición del paciente quirúrgico en los procedimientos fast-track: revisión de la evidencia y algoritmo adaptado.

INTRODUCTION: Surgical stress predisposes patients to have immune dysfunction and an increased risk of infection. Malnourished surgical patients have higher postoperative morbidity and mortality rates, higher readmission rates, and higher hospital costs. The use of an immunomodulatory formula is associated in the ESPEN guidelines with a reduction in wound healing problems, suture failure, and infectious and global complications. Several authors have suggested that, since most clinical trials evaluating the efficacy of immunonutrition have been carried out in a traditional perioperative setting, it would be interesting to investigate its efficacy in a more controlled setting, such as in the ERAS (Enhanced Recovery after Surgery) protocol. The objective of this work was: a) to define the role that immunonutrition should play in ERAS protocols based on the best scientific evidence available; b) to analyze the difficulties that continue to exist in real-life clinical practice to screen the nutritional risk of patients; c) to make a proposal of algorithms adapted to the characteristics of our environment regarding the screening, assessment, and nutritional treatment of surgical patients in fast-track surgery.

INTRODUCCIÓN: El estrés quirúrgico predispone a los pacientes a la disfunción inmune y a un mayor riesgo de infección. Los pacientes quirúrgicos desnutridos presentan una mayor morbimortalidad posoperatoria, mayores tasas de reingreso y costes hospitalarios más elevados. En las guías de la ESPEN se asocia el uso de una fórmula inmunomoduladora a una reducción significativa de los problemas de la cicatrización de heridas, de los fallos de la sutura y de las complicaciones infecciosas y globales. Varios autores han sugerido que, dado que la mayoría de los ensayos clínicos que evalúan la eficacia de la inmunonutrición se han realizado en un entorno perioperatorio tradicional, sería interesante investigar su eficacia en un entorno más controlado, como en el protocolo ERAS (Enhanced Recovery after Surgery). El objetivo de este trabajo es: a) definir el papel que debe jugar la inmunonutrición en los protocolos ERAS sobre la base de la mejor evidencia científica; b) analizar las dificultades que siguen existiendo en la práctica clínica real para realizar el cribado del riesgo nutricional del paciente; c) proponer unos algoritmos adaptados a las características de nuestro entorno sobre el cribado, la valoración y el tratamiento nutricional del paciente quirúrgico en modalidad fast-track.

Immune response and gut microbiota of mice on a diet mimicking eating habits of elderly with risk of malnutrition development.

The number of elderlies is increasing but prevalence of malnutrition has been reported. The aim of the study was to determine the significance of short-term nutritional deficiencies in mice. Immune status was assessed through flow cytometry of leucocytes in Peyer's patches (PP) and mesenteric lymph nodes (MLN), and intestinal microbiota was evaluated by terminal restriction fragment length polymorphism (T-RFLP). C57BL/6NCrl mice fed standard diet (StD) or experimental diet high in fat, and low in carbohydrates, protein, fibre, vitamins, and minerals (ExpD) for 2 or 4 weeks. ExpD-animals gained less weight, increased liver lipids, and developed splenomegaly. Diet affected regulatory T-cells, gut homing receptors and TLR2 and TLR4 in PP and MLN and the microbiota was influenced. Partial least squares models on flow cytometry- and T-RFLP data demonstrated correlations between microbial communities and immune phenotyping. Our model shows similarities to malnourished elderly and interactions between intestinal bacteria and the immune system.

Plasmodium chabaudi Infection Alters Intestinal Morphology and Mucosal Innate Immunity in Moderately Malnourished Mice.

Plasmodium falciparum is a protozoan parasite which causes malarial disease in humans. Infections commonly occur in sub-Saharan Africa, a region with high rates of inadequate nutrient consumption resulting in malnutrition. The complex relationship between malaria and malnutrition and their effects on gut immunity and physiology are poorly understood. Here, we investigated the effect of malaria infection in the guts of moderately malnourished mice. We utilized a well-established low protein diet that is deficient in zinc and iron to induce moderate malnutrition and investigated mucosal tissue phenotype, permeability, and innate immune response in the gut. We observed that the infected moderately malnourished mice had lower parasite burden at the peak of infection, but damaged mucosal epithelial cells and high levels of FITC-Dextran concentration in the blood serum, indicating increased intestinal permeability. The small intestine in the moderately malnourished mice were also shorter after infection with malaria. This was accompanied with lower numbers of CD11b+ macrophages, CD11b+CD11c+ myeloid cells, and CD11c+ dendritic cells in large intestine. Despite the lower number of innate immune cells, macrophages in the moderately malnourished mice were highly activated as determined by MHCII expression and increased IFNγ production in the small intestine. Thus, our data suggest that malaria infection may exacerbate some of the abnormalities in the gut induced by moderate malnutrition.

Environmental, Metabolic, and Inflammatory Factors Converge in the Pathogenesis of Moderate Acute Malnutrition in Children: An Observational Cohort Study.

Acute malnutrition affects more than 50 million children worldwide. These children are at an increased risk of morbidity and mortality from infectious disease. However, the pathogenesis of acute malnutrition and mechanisms underlying the increased risk and poor outcomes from infection are not well understood. Our objective was to identify differences in inflammation and inflammatory responses between children with moderate acute malnutrition (MAM) and healthy controls (HCs), and search for environmental, pathophysiological, and metabolic factors that may influence this response. Sixteen children with MAM and 16 HCs aged 18-36 months were studied in Nairobi, Kenya. None of the children had symptoms of an infectious disease (fever, diarrhea, or cough) in the 2 weeks before enrollment and sample collection. Demographic and health data were provided by their primary caregivers. Blood samples were collected to measure various biomarkers and the response to an inflammatory stimulus. Children with MAM were more frequently from households with contaminated water, crowding, and unstable income sources. They also had increases in basal inflammation, circulating bacterial lipopolysaccharide (LPS), markers of intestinal damage, and an exaggerated whole blood inflammatory response to LPS. Metabolic changes in children with MAM led to increased plasma levels of long-chain fatty acids, which were found to contribute to the pro-inflammatory state. These exploratory findings suggest convergence of multiple factors to promote dysregulated inflammatory responses and prompt several mechanistic hypotheses that can be pursued to better understand the pathogenesis of MAM.

COVID-19 and nutritional deficiency: a review of existing knowledge.

COVID-19 has resulted in an ongoing global pandemic, which spread largely among people who have had close contact with the infected person. The immunopathology of the SARS-CoV-2 virus includes the production of an excess amount of pro-inflammatory cytokines "a cytokine-storm". The respiratory system (main), cardiovascular system and the gastrointestinal tract are the most affected body systems during viral infection. It has been found that most of the patients who require admission to hospital are elderly or have chronic underlying diseases. Higher cases of malnutrition and co-morbidities like diabetes mellitus and cardiovascular diseases are reported in elderly patients due to which, the immune system weakens and hence, the response to the virus is diminished in magnitude. A deficiency of micronutrients results in impaired immune responses leading to improper secretion of cytokines, alterations in secretory antibody response and antibody affinity which increases susceptibility to viral infection. The deficiency of various micronutrients in COVID-19 patient can be treated by appropriate nutritional supplements, prescribed after evaluating the patients' nutritional status. Here we aim to highlight the role of a few particular nutrients namely Vitamin D, Vitamin C, Omega-3 fatty acids, Zinc and Magnesium along with the synergistic roles they play in enhancing immunity and thus, maintaining homeostasis.

Factors Associated with Lymph Node Count in Mucosal Squamous Cell Carcinoma Neck Dissection.

OBJECTIVE/HYPOTHESIS: Decreased lymph node count (LNC) from neck dissection (ND) for mucosal head and neck squamous cell carcinoma (HNSCC) patients is correlated with decreased survival. Advanced age and low BMI due to undernutrition from dysphagia from advanced T-stage tumors are common in patients with HNSCC. We studied the relationship between these two well-described causes for immune dysfunction and LNC in patients undergoing neck dissection. STUDY DESIGN: We conducted a retrospective review at a single tertiary care institution of patients with HNSCC that underwent neck dissection from 2006 to 2017. METHODS: Stepwise linear and logistic regression analyses were performed on 247 subjects to identify independent significant factors associated with 1) the LNC per neck level dissected; 2) advanced T-stage. One-way ANOVA was utilized to demonstrate differences between the p16 positive and negative subgroups. RESULTS: Low BMI (<23 vs. ≥23) (P = .03), extra nodal extension (ENE) (P = .0178), and advanced age (P = .005) were associated with decreased LNC per neck level dissected on multivariable analysis. Higher T-stage (P = .0005) was correlated with low BMI (<23) after controlling for the effects of tobacco, smoking, sex, ECE, and p16 status. p16+ patients, on average had higher BMI, were younger and produced a higher nodal yield (P < .0001, .007, and .035). CONCLUSIONS: Patient intrinsic factors known to correlate with decreased immune function and worse outcomes, including p16 negative status, advanced age, and low BMI from undernutrition and ENE are associated with low nodal yield in neck dissections. LNC may be a metric for anti-tumor immune function that correlates with prognosis and T-stage. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1516-1521, 2021.

Pre-Digested Protein Enteral Nutritional Supplementation Enhances Recovery of CD4+ T Cells and Repair of Intestinal Barrier in HIV-Infected Immunological Non-Responders.

AIDS patients with immune non-response are prone to malnutrition, intestinal barrier damage, thus aggravating chronic immune activation and inflammation. However, nutritional interventions targeting malnutrition may be beneficial to restore immune function, improve clinical outcomes, and reduce mortality remains largely unclear. This work aimed to evaluate the efficacy of a nutritional supplement in HIV-infected immune non-responders (INRs). The subjects received oral supplementation of a pre-digested protein nutrition formula for three months. We show that the CD4+ T and CD8+ T cell counts were significantly increased after supplementation of the pre-digested enteral nutritional supplement. Among all pro-inflammatory cytokines in the serum, only IL-1ß level was significantly decreased, while TNF-ß was significantly increased (P < 0.05). The levels of intestinal mucosal damage markers, diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS), decreased significantly (P < 0.05) after the nutritional intervention. Moreover, at month 3 after the intervention, the body weight, body mass index, albumin, and hemoglobin of all subjects were significantly increased (P < 0.05). The correlation analysis demonstrated a significantly negative correlation of CD4+ T cell count with levels of DAO (r = -0.343, P = 0.004), D-lactate (r = -0.250, P = 0.037), respectively, and a significantly positive correlation of IL-1ß level with levels of DAO (r = 0.445, P < 0.001), D-lactate (r = 0.523, P < 0.001), and LPS (r = 0.622, P < 0.001). We conclude that the pre-digested enteral nutrition supplement is effective for HIV-infected INRs.

Reduced rotavirus vaccine efficacy in protein malnourished human-faecal-microbiota-transplanted gnotobiotic pig model is in part attributed to the gut microbiota.

The low efficacy of human rotavirus (HRV) vaccines in low- and middle-income countries (LMIC) remains a major challenge for global health. Protein-calorie malnutrition (kwashiorkor) affects the gut microbiota and compromises immune development, leading to environmental enteropathy, vaccine failures, and increased susceptibility to enteric diseases in young children. Relationship between diet and reduced vaccine efficacy in developing countries is not well established; therefore, we investigated the interconnections between the host-microbiota-nutrition-HRV vaccine using HRV-vaccinated, human infant faecal microbiota (HIFM)-transplanted neonatal gnotobiotic pigs fed with a protein deficient or sufficient diet. The microbiota from faecal, intestinal (duodenum, ileum, jejunum, and colon), and systemic tissue (liver, spleen, and mesenteric lymph node [MLN]) samples was analysed before and after HRV challenge using MiSeq 16S rRNA sequencing. Overall, microbiota from deficient fed HIFM pigs displayed, compared to the sufficient group, significantly higher Shannon index, especially in the faeces and lower intestines; higher level of Proteus and Enterococcus, and lower level of Bifidobacterium, Clostridium, and Streptococcus in the three types of samples collected (P<0.05); and higher unique operational taxonomic units (OTUs), especially in the systemic tissues. Further, the multivariate analysis between microbiota and immunologic data showed that 38 OTUs at the genus level correlated (r2≤0.5 or ≥-0.5; P<0.05) with at least one host immune response parameter (regulatory [Tregs and transforming growth factor-ß], effectors [interferon (IFN)-γ+ CD4+ and CD8+ T cells, IFN-γ and interleukin (IL)-12], and inflammatory [tumour necrosis factor-α, IL-17 and IL-22]) and with opposite trends between diet groups. Differences described above were increased after HRV challenge. We demonstrated that a protein deficient diet affects the composition of the gut microbiota and those changes may further correlate with immune responses induced by HRV and perturbed by the deficient diet. Thus, our findings suggest that the reduced efficacy of HRV vaccine observed in Gn pig model is in part attributed to the altered microbiota composition.

Dietary Regulation of Memory T Cells.

Memory T cells are a fundamental component of immunological memory, providing rapid and potent host protection against secondary challenges. As such, memory T cells are key targets in the design of vaccination strategies and cancer immunotherapies, making it critical to understand the factors and mechanisms that regulate their biology. Diet is an environmental feature that impacts virtually all aspects of host physiology. However, the influence of specific dietary regiments and nutritional components on the immune system is only just starting to be uncovered. This article will review literature regarding the impact of diet and nutrition on memory T cell development, maintenance and function. It was recently shown that caloric restriction without undernutrition enhances memory T cell function, while diets high in fiber are also beneficial. However, memory T cell responses are dysfunctional in extreme nutritional states, such as undernutrition and diet-induced obesity. Therefore, diet and host nutritional status are major regulators of memory T cell biology and host fitness. To define the dietary balance required to promote optimal memory T cell responses could allow for the implementation of rational diet-based therapies that prevent or treat disease. Furthermore, that certain dietary regiments can enhance memory T cell function indicates the possibility of harnessing the underlying mechanisms in the design of novel vaccination strategies and cancer immunotherapies.

Incidental COVID-19 in a heart-kidney transplant recipient with malnutrition and recurrent infections: Implications for the SARS-CoV-2 immune response.

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Lessons Learned from Experimental Human Model of Zinc Deficiency.

Zinc is an essential element for humans, and its deficiency was documented in 1963. Nutritional zinc deficiency is now known to affect over two billion subjects in the developing world. Conditioned deficiency of zinc in many diseases has also been observed. In zinc-deficient dwarfs from the Middle East, we reported growth retardation, delayed sexual development, susceptibility to infections, poor appetite, and mental lethargy. We never found a zinc-deficient dwarf who survived beyond the age of 25 y. In an experimental model of human mild zinc deficiency, we reported decreased thymulin (a thymopoietic hormone) activity in Th1 cells, decreased mRNAs of IL-2 and IFN-gamma genes, and decreased activity of natural killer cells (NK) and T cytotoxic T cells. The effect of zinc deficiency on thymulin activity and IL-2 mRNA was seen within eight to twelve weeks of the institution of zinc-deficient diet in human volunteers, whereas lymphocyte zinc decreased in 20 weeks and plasma zinc decreased in 24 weeks after instituting zinc-deficient diet. We hypothesized that decreased thymulin activity, which is known to proliferate Th1 cells, decreased the proliferation differentiation of Th1 cells. This resulted in decreased generation of IL-2 and IFN-gamma. We observed no effect in Th2 cell function; thus, zinc deficiency resulted in an imbalance of Th1 to Th2 function resulting in decreased cell-mediated immunity. Zinc therapy may be very useful in many chronic diseases. Zinc supplementation improves cell-mediated immunity, decreases oxidative stress, and decreases generation of chronic inflammatory cytokines in humans. Development of sensitive immunological biomarkers may be more sensitive than an assay of zinc in plasma and peripheral blood cells for diagnosis of marginal zinc deficiency in human.

Malnutrition Decreases Antibody Secreting Cell Numbers Induced by an Oral Attenuated Human Rotavirus Vaccine in a Human Infant Fecal Microbiota Transplanted Gnotobiotic Pig Model.

Human rotavirus (HRV) is a leading cause of morbidity and mortality in children, especially in developing countries. Malnutrition is prevalent in these countries, which may contribute to the decreased oral vaccine efficacy, posing a concern for global health. Neonatal gnotobiotic (Gn) pigs closely resemble human infants in their anatomy, physiology, and outbred status and are a unique model to investigate malnutrition, oral live attenuated HRV (AttHRV) vaccination, and subsequent virulent HRV (VirHRV) challenge. We evaluated the impact of malnutrition on AttHRV vaccine efficacy and B cell immune responses in neonatal germfree (GF) or Gn pigs transplanted with human infant fecal microbiota (HIFM). Pigs were fed either deficient or sufficient bovine milk diets. Malnutrition did not significantly affect the serum and intestinal contents total or HRV-specific IgG and IgA antibody titers pre VirHRV challenge. However, HRV-specific IgG and IgA antibody secreting cells (ASCs) were reduced in blood or intestinal tissues following AttHRV vaccination and pre VirHRV challenge in deficient HIFM transplanted pigs. Furthermore, post-VirHRV challenge, deficient HIFM pigs had decreased total Ig and HRV-specific IgG and IgA antibody titers in serum or intestinal contents, in addition to decreased HRV-specific IgG and IgA ASCs in blood and ileum, compared with sufficient HIFM pigs. Our results indicate that deficient diet impairs B cell mucosal, and systemic immune responses following HRV vaccination, and challenge. The impaired immune responses contributed to the decreased protective efficacy of the AttHRV vaccine, suggesting that malnutrition may significantly reduce the effectiveness of oral HRV vaccines in children in developing countries.

Moringa oleifera treatment increases Tbet expression in CD4+ T cells and remediates immune defects of malnutrition in Plasmodium chabaudi-infected mice.

BACKGROUND: Malaria is a worldwide problem that affects millions of people yearly. In rural areas where anti-malarial drugs are not easily accessible, many people use herbal treatments, such as Moringa oleifera, to treat a variety of diseases and ailments including malaria. While Moringa is reported to possess potent and curative anti-malarial properties, previous studies have mostly been restricted to assessment of parasitaemia. In this study, the effect of Moringa on malaria immunity in a murine model was investigated. METHODS: Using a high dose (60 mg/mouse) for a short time (7 days) or low dose Moringa (30 mg/mouse) for a longer time (3 weeks), cytokine production, and Tbet expression by effector CD4+ T cells (Teff) were determined. Mice were also treated with Moringa after infection (curatively) or before infection (prophylactically) to determine the effect of the plant extract on parasitaemia and immunity. Given that Moringa also possess many nutritional benefits, the contribution of Moringa on malnourished malaria infected mice was determined. Malnutrition was induced by limiting access to food to only 4 h a day for 4 weeks, while control mice had unlimited access to mouse laboratory chow. All data was collected by flow cytometry and analysed using one-Way ANOVA or two tailed Student's t test. RESULTS: Moringa-treated mice had increased numbers of effector CD4+ T cells accompanied by an increase in Tbet expression compared to control untreated mice. Mice that were treated with Moringa curatively also exhibited increased effector CD4+ T cell numbers, IFN-gamma and TNF secretion. Interestingly, the mice that were treated prophylactically had significantly higher Tbet expression. In the absence of adaptive immunity, high parasitaemia was observed in the RAG1 knockout mice. The food limited mice (malnourished) had reduced numbers of CD4+ T cells, TNF proportions, and significantly greater Tbet expression compared to the control group. Supplementation with Moringa in the limited group slightly restored CD4+ T cell activation, IL-2, and IL-10 production. CONCLUSIONS: Taken together, these data suggest that Moringa treatment leads to increased CD4+ T cell activation, Th1 differentiation and production of pro-inflammatory cytokines after malaria infection. Thus, Moringa may be immunologically useful in the treatment of malaria and malnutrition. Further investigations are required to identify the active components in Moringa.