This randomised controlled trial examined the effect of a 4-week, high-dose (Lf-High, 600 mg/d) or low-dose (Lf-Low, 200 mg/d) oral lactoferrin (Lf) intervention v. placebo on immune cell responses to respiratory virus, immune cell subsets and systemic inflammation. In healthy older adults (n 103, ≥50 years old), ex vivo cytokine release of interferon (IFN)-α2, IFN-γ, IL-6 and TNF-α from rhinovirus A-16 (RV-16) or influenza A virus (H1N1) stimulated peripheral blood mononuclear cells, circulating immune cell subsets, and plasma IL-6, C-reactive protein (CRP) and TNF-α were assessed. Ninety-seven participants completed the 4-week intervention (Lf-High n 32, Lf-Low n 31, placebo n 34, withdrawals n 6). There was no difference in RV-16 or H1N1-induced IFN-γ release between groups. RV-16-induced IL-6 was lower in Lf-High v. placebo (P = 0·001), and RV-16-induced IFN-α2 was higher in Lf-High v. Lf-Low (P = 0·04). Lf-High increased total T cells (P = 0·03) and CD4+ T cells (P = 0·03) v. placebo. Lf-Low reduced neutrophil (P = 0·04), natural killer cell (P = 0·045), activated CD8+ T cell (P = 0·03) and γδ T cell (P = 0·03) frequency v. placebo. Plasma IL-6 (P = 0·004) and CRP (P = 0·03) were lower following Lf-High v. Lf-Low, but not placebo. Both high- and low-dose Lf altered ex vivo immune cell responses after 4 weeks. High-dose increased T-cell subsets, promoting adaptive immunity, and reduced systemic inflammation, while low-dose reduced proinflammatory and cytotoxic immune cells. High- and low-dose Lf supplements may have immunoceutical benefits in older adults.

A well-functioning immune system requires balanced immune responses. In vitro studies have shown that plant stanols contribute to restoring the T-helper (Th)1/Th2 ratio when it is imbalanced. However, effects of plant stanols on healthy immune responses are unknown. Therefore, we studied effects of recommended (2·5 g/d) or high (9·0 g/d) plant stanol intakes on the Th1/Th2 cytokine balance in immunologically healthy subjects. In two RCTs, peripheral blood mononuclear cells (PBMCs) were isolated, cultured, and stimulated with 5 µg/ml Phytohemagglutinin-M to study ex vivo cytokine production. In the first study, twenty participants consumed margarines (2·5 g/d plant stanols) or control for three weeks. In the second study, nineteen participants consumed margarines and yogurts (9·0 g/d plant stanols) or control for four weeks. T-cell cytokine concentrations were measured in culture medium and in study 2 a standardized Th1/Th2 index was calculated. Serum lipids and non-cholesterol sterols were also measured. Compliance was confirmed by significant increases in serum total cholesterol (TC)-standardized sitostanol and campestanol levels in both studies. Changes in ex vivo cytokine production and Th1/Th2 index did not differ between intervention and control groups. In the first study, no statistically significant changes were observed in lipid and lipoprotein concentrations. In the second study, LDL cholesterol significantly decreased compared to control (–0·77 (–1·11, –0·42) mmol/l; P < 0·001). Recommended (2·5 g/d) or high (9·0 g/d) intakes of plant stanols did not alter PBMC ex vivo cytokine production in immunologically healthy subjects. This suggests that plant stanols might only affect immune function when Th1/Th2 immune responses are imbalanced.

This study investigated the effects of Lacticaseibacillus rhamnosus HN001 supplementation on the architecture and gene expression in small intestinal tissues of piglets used as an animal model for infant humans. Twenty-four 10-d-old entire male piglets (4·3 (sd 0·59) kg body weight) were fed an infant formula (IF) (control) or IF supplemented with 1·3 × 105 (low dose) or 7·9 × 106 (high dose) colony-forming units HN001 per ml of reconstituted formula (n 8 piglets/treatment). After 24 d, piglets were euthanised. Samples were collected to analyse the histology and gene expression (RNAseq and qPCR) in the jejunal and ileal tissues, blood cytokine concentrations, and blood and faecal calprotectin concentrations. HN001 consumption altered (false discovery rate < 0·05) gene expression (RNAseq) in jejunal tissues but not in ileal tissues. The number of ileal goblet cells and crypt surface area increased quadratically (P < 0·05) as dietary HN001 levels increased, but no increase was observed in the jejunal tissues. Similarly, blood plasma concentrations of IL-10 and calprotectin increased linearly (P < 0·05) as dietary HN001 levels increased. In conclusion, supplementation of IF with HN001 affected the architecture and gene expression of small intestine tissue, blood cytokine concentration and frequencies, and blood calprotectin concentrations, indicating that HN001 modulated small intestinal tissue maturation and immunity in the piglet model.

Resistant starch (RS) has received increased attention due to its potential health benefits. This study was aimed to investigate the effects of dietary corn RS on immunological characteristics of broilers. A total of 320 broiler chicks were randomly allocated to five dietary treatments: normal corn–soyabean (NC) diet group, corn starch diet group, 4 %, 8 % and 12 % RS diet groups. This trial lasted for 42 d. The relative weights of spleen, thymus and bursa, the concentrations of nitric oxide (NO) and IL-4 in plasma at 21 d of age, as well as the activities of total nitric oxide synthase (TNOS) and inducible nitric oxide synthase (iNOS) in plasma at 21 and 42 d of age showed positive linear responses (P < 0·05) to the increasing dietary RS level. Meanwhile, compared with the birds from the NC group at 21 d of age, birds fed 4 % RS, 8 % RS and 12 % RS diets exhibited higher (P < 0·05) relative weight of bursa and concentrations of NO and interferon-γ in plasma. Birds fed 4 % RS and 8 % RS diets showed higher (P < 0·05) number of IgA-producing cells in the jejunum. While compared with birds from the NC group at 42 d of age, birds fed 12 % RS diet showed higher (P < 0·05) relative weight of spleen and activities of TNOS and iNOS in plasma. These findings suggested that dietary corn RS supplementation can improve immune function in broilers.

SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation resulting in significant damage to the lungs and other organ systems, including the kidneys, though symptoms and disease severity are quite variable depending on the intensity of exposure and presence of underlying conditions that may affect the immune response. The resulting disease, coronavirus disease 2019 (COVID-19), can cause multi-organ system dysfunction in patients requiring hospitalisation and intensive care treatment. Serious infections like COVID-19 often negatively affect nutritional status, and the resulting nutritional deficiencies may increase disease severity and impair recovery. One example is the viral infection measles, where associated vitamin A (VA) deficiency increases disease severity and appropriately timed supplementation during recovery reduces mortality and hastens recovery. VA may play a similar role in COVID-19. First, VA is important in maintaining innate and adaptive immunity to promote clearance of a primary infection as well as minimise risks from secondary infections. Second, VA plays a unique role in the respiratory tract, minimising damaging inflammation, supporting repair of respiratory epithelium and preventing fibrosis. Third, VA deficiency may develop during COVID-19 due to specific effects on lung and liver stores caused by inflammation and impaired kidney function, suggesting that supplements may be needed to restore adequate status. Fourth, VA supplementation may counteract adverse effects of SARS-CoV2 on the angiotensin system as well as minimises adverse effects of some COVID-19 therapies. Evaluating interactions of SARS-CoV2 infection with VA metabolism may thus provide improved COVID-19 therapy.

Se is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to coronavirus disease 2019 (COVID-19). Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.

Psychiatric disorders, especially depression, are frequent in patients with multiple sclerosis (MS). They are attributed both to the psychosocial impact of a chronic, usually progressive, disabling illness and to cerebral demyelination. Besides, drugs such as corticosteroids and possibly interferon (IFN) may also have depressogenic effects. Major depressive disorders and/or suicidal ideation are a major concern and efforts to identify and minimize these reactions are of much importance. Psychiatric side effects, particularly depression, are widely reported with IFN-α and have been suspected with IFN-β but are not yet fully established. Our review of the literature revealed that most studies discard an association between IFN-β and depression or suicide. However, few patients, especially those with a history of depression, might be at higher risk for depression when treated with IFN-β. Overall, considering the uncertainty of a link between IFN-β and depression and/or suicide, as well as the complete remission of psychiatric complications after IFN discontinuation and/or antidepressant treatment, physicians should closely monitor the psychiatric status of patients, but should not refrain from including them in IFN-β treatment programs, even when they have past or present depression.

Rumen fluid from slaughtered animals is one of the wastes of slaughterhouses released to the environment that, due to its high nitrogen and phosphorus contents, can lead to soil and groundwater pollution. Meanwhile, it contains ruminal microbes and some bioactive compounds such as enzymes, minerals, vitamins and organic acids. This study was designed to examine the potential of rumen fluid as a feed additive. Therefore, the effects of spray-dried rumen fluid (SDR) with 1% maltodextrin on the performance, blood metabolites and some cytokines of sucking dairy calves during the pre-weaning phase were investigated. Forty male Holstein calves, with a mean weight of 39.4 ± 3.7 kg and 7 ± 1 days old, were randomly assigned to four groups (n = 10 calves per group) in a completely randomized design. Experimental treatments were: control diet with no additive (CON); control diet with 0.5 g/day of SDR (SDR0.5); control diet with 1 g/day of SDR (SDR1); and control diet with 1.5 g/day of SDR (SDR1.5). Daily feed intake and average daily gain of calves were not affected by feeding SDR as a feed additive. Cholesterol concentration was significantly affected by the 20th and 40th days of the experiment and decreased linearly by increasing SDR feeding level. Levels of liver enzymes, including aspartate aminotransferase and alanine aminotransferase, in the blood decreased by feeding SDR at day 40 of the experiment. Serum concentration of interleukin-6 at day 20 was not affected by dried rumen fluid feeding, whereas at day 40, a significant effect was observed among experimental treatments. The lowest value was recorded for SDR1.5 v. control calves. At day 20, the serum concentration of interferon-γ was influenced by supplementing SDR, and the highest value was recorded for SDR1.5 calves. The inclusion of SDR with 1% maltodextrin in suckling dairy calves had beneficial effects on the stimulation of calves’ immune system.

At birth, when immune responses are insufficient, there begins the development of the defence capability against pathogens. Leptin and adiponectin, adipokines that are present in breast milk, have been shown to play a role in the regulation of immune responses. We report here, for the first time, the influence of in vivo adipokine supplementation on the intestinal immune system in early life. Suckling Wistar rats were daily supplemented with leptin (0·7 μg/kg per d, n 36) or adiponectin (35 μg/kg per d, n 36) during the suckling period. The lymphocyte composition, proliferation and cytokine secretion from mesenteric lymph node lymphocytes (on days 14 and 21), as well as intestinal IgA and IgM concentration (day 21), were evaluated. At day 14, leptin supplementation significantly increased the TCRαβ + cell proportion in mesenteric lymph nodes, in particular owing to an increase in the TCRαβ + CD8+ cell population. Moreover, the leptin or adiponectin supplementation promoted the early development CD8+ cells, with adiponectin being the only adipokine capable of enhancing the lymphoproliferative ability at the end of the suckling period. Although leptin decreased intestinal IgA concentration, it had a trophic effect on the intestine in early life. Supplementation of both adipokines modulated the cytokine profile during (day 14) and at the end (day 21) of the suckling period. These results suggest that leptin and adiponectin during suckling play a role in the development of mucosal immunity in early life.

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease characterised by multiple organ involvement and a large number of complications. SLE management remains complicated owing to the biological heterogeneity between patients and the lack of safe and specific targeted therapies. There is evidence that dietary factors can contribute to the geoepidemiology of autoimmune diseases such as SLE. Thus, diet therapy could be a promising approach in SLE owing to both its potential prophylactic effects, without the side effects of classical pharmacology, and its contribution to reducing co-morbidities and improving quality of life in patients with SLE. However, the question arises as to whether nutrients could ameliorate or exacerbate SLE and how they could modulate inflammation and immune function at a molecular level. The present review summarises preclinical and clinical experiences to provide the reader with an update of the positive and negative aspects of macro- and micronutrients and other nutritional factors, including dietary phenols, on SLE, focusing on the mechanisms of action involved.

Prebiotic supplementation modulates immune system development and function. However, less is known about the effects of maternal prebiotic consumption on offspring intestinal defences and immune system responsiveness. We investigated the effects of maternal short-chain fructo-oligosaccharide (scFOS) supplementation on mucin-secreting cells, ileal secretory IgA and cytokine secretion of weaned offspring and their humoral response to an oral vaccine against obligate intracellular Lawsonia intracellularis. Sows were fed a control diet (CTRL) or scFOS-supplemented diet during the last third of gestation and throughout lactation. At weaning, each litter was divided into two groups receiving a post-weaning CTRL or scFOS diet for a month. Pigs from the four groups were either non-vaccinated (n 16) or vaccinated (n 117) at day 33. Biomarkers related to intestinal defences and immune parameters were analysed 3 weeks later. SCFA production was assessed over time in suckling and weaned pigs. Maternal scFOS supplementation improved ileal cytokine secretions (interferon (IFN)-γ, P<0·05; IL-4, P=0·07) and tended to increase caecal goblet cell number (P=0·06). It increased IgA vaccine response in the serum (P<0·01) and ileal mucosa (P=0·08). Higher bacterial fermentative activity was observed during lactation (total faecal SCFA, P<0·001) and after weaning (colonic butyrate, P=0·10) in pigs from scFOS-supplemented mothers. No synergistic effect between maternal and post-weaning scFOS supplementation was observed. Therefore, maternal scFOS supplementation has long-lasting consequences by strengthening gut defences and immune response to a vaccine against an intestinal obligate intracellular pathogen. Prebiotic consumption by gestating and lactating mothers is decisive in modulating offspring intestinal immunity.

The aim of the paper is to show the various neurological and psychiatric symptoms in coeliac disease (CD). CD is a T cell-mediated, tissue-specific autoimmune disease which affects genetically susceptible individuals after dietary exposure to proline- and glutamine-rich proteins contained in certain cereal grains. Genetics, environmental factors and different immune systems, together with the presence of auto-antigens, are taken into account when identifying the pathogenesis of CD. CD pathogenesis is related to immune dysregulation, which involves the gastrointestinal system, and the extra-intestinal systems such as the nervous system, whose neurological symptoms are evidenced in CD patients. A gluten-free diet (GFD) could avoid cerebellar ataxia, epilepsy, neuropathies, migraine and mild cognitive impairment. Furthermore, untreated CD patients have more symptoms and psychiatric co-morbidities than those treated with a GFD. Common psychiatric symptoms in untreated CD adult patients include depression, apathy, anxiety, and irritability and schizophrenia is also common in untreated CD. Several studies show improvement in psychiatric symptoms after the start of a GFD. The present review discusses the state of the art regarding neurological and psychiatric complications in CD and highlights the evidence supporting a role for GFD in reducing neurological and psychiatric complications.

Epidemiological studies have established an association between obesity, insulin resistance, type 2 diabetes and a number of cancer types. Research has focused predominantly on altered endocrine factors, growth factors and signalling pathways, with little known in man about the immune involvement in the relevant pathophysiological processes. Moreover, in an era of exciting new breakthroughs in cancer immunotherapy, there is also a need to study the safety and efficacy of immunotherapeutics in the complex setting of inflammatory-driven obesity-associated cancer. This review addresses key immune cell subsets underpinning obesity-associated inflammation and describes how such immune compartments might be targeted to prevent and treat obesity-associated cancer. We propose that the modulation, metabolism, migration and abundance of pro- and anti-inflammatory cells and tumour-specific T cells might be therapeutically altered to both restore immune balance, alleviating pathological inflammation, and to improve anti-tumour immune responses in obesity-associated cancer.

Immunotherapy with interferon-alfa has become standard therapy in selected patients with viral hepatitis and chronic myelogenous leukemia. In addition, it is used in a variety of other diseases, both as standard therapy and in clinical trials. Its use is expected to expand in the following decade. Interferon can cause (severe) neuropsychiatric side effects. These side effects are discussed. Adequate management of these side effects is important, as is close collaboration between the oncologist and the psychiatrist. The cornerstone of management is patient education: this prevents interruption of therapy by patients who were not warned for neuropsychiatric side effects. Furthermore, patients should report in case of rapidly arising mood disorders. Interferon-alfa induced mood disorder is reported to be treatable. Three case descriptions illustrate this, but also illustrate some limits to successful treatment.

Lactococcus lactis ssp. lactis JCM5805 has been shown to be a rare lactic acid bacterium that can activate plasmacytoid dendritic cells in both murine and human species. In this study, we carried out a randomised placebo-controlled double-blind experiment to evaluate its effect on the pathogenesis of influenza-like illness during the winter season. A total of 213 volunteers were divided into two groups, which received either yogurt made with L. lactis JCM5805 or a placebo beverage daily for 10 weeks. In the JCM5805 group, the cumulative incidence days of ‘cough’ and ‘feverishness’, which are defined as major symptoms of an influenza-like illness, were significantly decreased compared with the placebo group. In addition, peripheral blood mononuclear cells prepared from volunteers were cultured in the presence of inactivated human influenza virus A/H1N1 (A/PR/8/34). IFN-α elicited by A/H1N1 tended to be higher in the JCM5805 group compared with the placebo group, and an IFN-α-inducible antiviral factor, interferon-stimulated gene 15 (ISG15), elicited by A/H1N1 was significantly higher in the JCM5805 group compared with the placebo group after the intake period. These results suggest that intake of JCM5805 is able to prevent the pathogenesis of an influenza-like illness via enhancement of an IFN-α-mediated response to the influenza virus.

Infection of pregnant cows with noncytopathic (ncp) bovine viral diarrhea virus (BVDV) induces rapid innate and adaptive immune responses, resulting in clearance of the virus in less than 3 weeks. Seven to 14 days after inoculation of the cow, ncpBVDV crosses the placenta and induces a fetal viremia. Establishment of persistent infection with ncpBVDV in the fetus has been attributed to the inability to mount an immune response before 90–150 days of gestational age. The result is ‘immune tolerance’, persistent viral replication and shedding of ncpBVDV. In contrast, we describe the chronic upregulation of fetal Type I interferon (IFN) pathway genes and the induction of IFN-γ pathways in fetuses of cows infected on day 75 of gestation. Persistently infected (PI) fetal IFN-γ concentrations also increased at day 97 at the peak of fetal viremia and IFN-γ mRNA was significantly elevated in fetal thymus, liver and spleen 14–22 days post maternal inoculation. PI fetuses respond to ncpBVDV infection through induction of Type I IFN and IFN-γ activated genes leading to a reduction in ncpBVDV titer. We hypothesize that fetal infection with BVDV persists because of impaired induction of IFN-γ in the face of activated Type I IFN responses. Clarification of the mechanisms involved in the IFN-associated pathways during BVDV fetal infection may lead to better detection methods, antiviral compounds and selection of genetically resistant breeding animals.

Depression is a frequent comorbid disorder of many inflammatory diseases and it is suggested that brain inflammatory processes have a pathogenic role in mood dysregulation. Several immunocompromised patients have been treated with cytokines and long-term treatments have resulted in a variety of neuropsychiatric side-effects. The objective of the study was to present evidence for an association between the induction of neuropsychiatric side-effects during treatment with interferon-α (IFN-α) and changes in serotonergic and immunological parameters. Moreover, the use of IFN-α-induced depression as a paradigm for research into the pathophysiology of depressive disorders in general will be discussed. This literature review focused on the relationships between tryptophan, serotonin, cytokines and depression associated with interferon treatment. Immunotherapy with IFN-α influences several immunological and serotonergic parameters, and induces in most patients neurovegetative, somatic and depressive symptoms. Literature findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy are secondary to cytokine induction and could be mediated by a reduced availability of tryptophan to the brain, resulting ultimately in decreased serotonergic activity. Changes in the metabolism of tryptophan and consequently of serotonin may play a role in the pathophysiology of interferon-induced depression. Studies on interferon-induced neuropsychiatric side-effects may be a promising research paradigm and shed light on the role of immunological and serotonergic factors in the pathogenesis of depressive disorders in general. However, first the appropriate symptomatology of the interferon-induced depressive states has to be documented.

Elderly adults have alterations in their gut microbiota and immune functions that are associated with higher susceptibility to infections and metabolic disorders. Probiotics and prebiotics, and their synbiotic combinations are food supplements that have been shown to improve both gut and immune function. The objective of this randomised, double-blind, placebo-controlled, cross-over human clinical trial was to study immune function and the gut microbiota in healthy elderly adults. Volunteers (n 37) consumed prebiotic galacto-oligosaccharides (GOS; 8 g/d), probiotic Bifidobacterium lactis Bi-07 (Bi-07; 109 colony-forming units/d), their combination (Bi-07 + GOS) and maltodextrin control (8 g/d) in four 3-week periods separated by 4-week wash-out periods. Immune function was analysed by determining the phagocytic and oxidative burst activity of monocytes and granulocytes, whole-blood response to lipopolysaccharide, plasma chemokine concentrations and salivary IgA levels. Gut microbiota composition and faecal SCFA content were determined using 16S ribosomal RNA fluorescence in situ hybridisation and HPLC, respectively. Primary statistical analyses indicated the presence of carry-over effects and thus measurements from only the first supplementation period were considered valid. Subsequent statistical analysis showed that consumption of Bi-07 improved the phagocytic activity of monocytes (P < 0·001) and granulocytes (P = 0·02). Other parameters were unchanged. We have for the first time shown that the probiotic Bi-07 may provide health benefits to elderly individuals by improving the phagocytic activity of monocytes and granulocytes. The present results also suggest that in the elderly, the effects of some probiotics and prebiotics may last longer than in adults.