Arjan P. Vos

Dietary supplementation of neutral and acidic oligosaccharides enhances Th1-dependent vaccination responses in mice

Immunomodulatory effects of oligosaccharide preparations that resemble chemical and functional aspects of human milk oligosaccharides (HMOS) were studied for the development of new concepts in infant nutrition. A dose range of 1–5% (w/w) dietary pectin‐derived acidic oligosaccharides (AOS) was tested in a murine influenza vaccination model. In addition, combinations of AOS and a 9:1 mixture of galacto‐oligosaccharides and long‐chain fructo‐oligosaccharides (GOS/FOS) were tested at a fixed total dietary dose of 2% (w/w). It was found that AOS significantly enhanced vaccine‐specific delayed‐type hypersensitivity (DTH) responses in a dose‐dependent manner. This was accompanied by a reduction in T‐helper2 (Th2) cytokine production by splenocytes in vitro. Overall, this indicates that the systemic immune response to the vaccine was Th1‐skewed by the dietary intervention. Combinations of GOS/FOS and AOS were more effective in enhancing DTH responses than either of the oligosaccharides alone, suggesting interaction effects between these agents. Similar to effects in infants, supplementation of the murine diets with GOS/FOS and combinations of GOS/FOS and AOS for 6‐wk enhanced the proportion of fecal bifidobacteria and lactobacilli, but AOS alone did not. In conclusion, these data indicate that GOS/FOS and AOS enhance systemic Th1‐dependent immune responses in a murine vaccination model. As Th1‐responses are weak in early life in humans, this might suggest that application of these oligosaccharides in infant formulas will be beneficial for the development of the infants immune system.

TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors

TLRs play a major role in microbe‐host interactions and innate immunity. Of the 10 functional TLRs described in humans, TLR2 is unique in its requirement to form heterodimers with TLR1 or TLR6 for the initiation of signaling and cellular activation. The ligand specificity of TLR2 heterodimers has been studied extensively, using specific bacterial and synthetic lipoproteins to gain insight into the structure‐function relationship, the minimal active motifs, and the critical dependence on TLR1 or TLR6 for activation. Different from that for specific well‐defined TLR2 agonists, recognition of more complex ligands like intact microbes or molecules from endogenous origin requires TLR2 to interact with additional coreceptors. A breadth of data has been published on ligand‐induced interactions of TLR2 with additional pattern recognition receptors such as CD14, scavenger receptors, integrins, and a range of other receptors, all of them important factors in TLR2 function. This review summarizes the roles of TLR2 in vivo and in specific immune cell types and integrates this information with a detailed review of our current understanding of the roles of specific coreceptors and ligands in regulating TLR2 functions. Understanding how these processes affect intracellular signaling and drive functional immune responses will lead to a better understanding of host‐microbe interactions and will aid in the design of new agents to target TLR2 function in health and disease.

Supplementation with a Fish Oil-Enriched, High-Protein Medical Food Leads to Rapid Incorporation of EPA into White Blood Cells and Modulates Immune Responses within One Week in Healthy Men and Women

Immune modulatory effects of EPA and DHA are well described. However, these fatty acids must be effectively incorporated into cell membrane phospholipids to modify cell function. To address the absence of human data regarding short-term incorporation, the present study investigated the incorporation of EPA and DHA into white blood cells (WBC) at different time points during 1 wk of supplementation with a medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides. Additionally, the effects on ex vivo immune function were determined. In a single-arm, open label study, 12 healthy men and women consumed 2 × 200 mL of medical food providing 2.4 g EPA, 1.2 g DHA, 39.7 g protein (including 4.4 g L-leucine), and 5.6 g oligosaccharides daily. Blood samples were taken at d 0 (baseline), 1, 2, 4, and 7. Within 1 d of nutritional intervention, the percentage of EPA in phospholipids of WBC increased from 0.5% at baseline to 1.3% (P < 0.001). After 1 wk, the percentage of EPA rose to 2.8% (P < 0.001). Additionally, the production of proinflammatory cytokines in LPS-stimulated whole blood cultures was significantly increased within 1 wk. Nutritional supplementation with a fish oil-enriched medical food significantly increased the percentage of EPA in phospholipids of WBC within 1 wk. Simultaneously, ex vivo immune responsiveness to LPS increased significantly. These results hold promise for novel applications such as fast-acting nutritional interventions in cancer patients, which should be investigated in future studies.

Altered host-microbe interaction in HIV: a target for intervention with pro- and prebiotics.

The intestinal immune system is severely affected by HIV and circulating microbial products from the intestinal tract that provide an ongoing source of systemic inflammation and concomitant viral replication. In addition, HIV-infected individuals can have a deregulated immune response that may hamper the anti-viral capacity of the host. Various probiotic organisms and prebiotic agents have been shown to enhance intestinal epithelial barrier functions, reduce inflammation, and support effective Th-1 responses. As these characteristics may benefit HIV patients, this review aims to provide a theoretical framework for the development of probiotic and prebiotic interventions specifically for this population.

Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma.

BackgroundAsthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma.MethodsTo mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined.ResultsLactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells.ConclusionThese findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma.

Specific prebiotic oligosaccharides modulate the early phase of a murine vaccination response

The immune-modulatory effect of specific prebiotic oligosaccharides was shown in previous preclinical and clinical studies. To enhance the understanding of this effect, kinetic aspects of immune modulation and the correlation between microbiological and immunological parameters were investigated in a murine vaccination model. C57BL/6 mice were supplemented with short-chain galactooligosaccharides and long-chain fructooligosaccharides (ratio 9:1; Immunofortis()) in combination with pectin-derived acidic oligosaccharides. The timing of supplementation was varied around the primary (day 0) and secondary (day 21) vaccinations. Supplementation before the primary vaccination was necessary to increase delayed-type hypersensitivity responses (DTH) significantly at day 30. Supplementation after day 8 did not affect the DTH response at day 30, indicating that immune modulation occurred during the early phase. Therefore, correlation analysis of microbiological and immunological parameters was performed in a shortened experiment to focus on the early phase. At day 9 post-priming, the percentages of cecal lactobacilli were correlated to the DTH responses (p=0.01). Furthermore, the results suggested that yet unidentified factors may play a role. Additional analysis of intestinal Peyers patch major lymphocyte populations did not show effects of supplementation. In conclusion, a specific oligosaccharide mixture was shown to exert its immune-modulatory effect during the early phase of a murine immune response. The results are consistent with a role of the microbiota and possibly other factors in oligosaccharide-induced immune modulation. Furthermore, the results demonstrate that it is critical to consider kinetic aspects of immune-modulatory and prebiotic effects in order to study their interaction in a meaningful way.

A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides

Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohns disease (CD) are chronic relapsing inflammatory disorders of the gastrointestinal tract. The interaction between a disturbed microbial composition, the intestinal mucosal barrier and the mucosal immune system plays an important role in IBD and its chronicity. It has been indicated that due to the altered microbial composition the balance between T regulatory cells (Treg) and T helper cells (Th) 17 is disturbed, leading to an inflammatory state. The present study shows that oral intake of a specific multi fibre mix (MF), designed to match the fibre content of a healthy diet, counteracts IBD-like intestinal inflammation and weight loss in dextran sodium sulphate treated mice. This reduction in inflammation might be brought about, at least in part, by the MF-induced decrease in inflammatory cytokines, increase in IL-10 and the relative increase in Treg cells in the mesenteric lymph nodes (MLN). Moreover, the Treg percentage in the MLN correlates with the percentage of tolerogenic lamina propria derived CD103+RALDH+dendritic cells in the MLN, suggesting that these play a role in the observed effects. In children with CD exclusive enteral nutrition (EEN) is a widely used safe and effective therapy. Optimizing enteral nutritional concepts with the tested fibre mix, know to modulate the gut microbiota composition, SCFA production and inflammatory status (as indicated by the present study) could possibly further improve efficacy in inducing remission.

The combination of Bifidobacterium breve with non-digestible oligosaccharides suppresses airway inflammation in a murine model for chronic asthma.

Over the last decade, there has been a growing interest in the use of interventions that target the intestinal microbiota as a treatment approach for asthma. This study is aimed at exploring the therapeutic effects of long-term treatment with a combination of Bifidobacterium breve with non-digestible oligosaccharides on airway inflammation and remodeling. A murine ovalbumin-induced chronic asthma model was used. Pulmonary airway inflammation; mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; expression of Foxp3 in blood Th cells; in vitro T cell activation; mast cell degranulation; and airway remodeling were examined. The combination of B. breve with non-digestible oligosaccharides suppressed pulmonary airway inflammation; reduced T cell activation and mast cell degranulation; modulated expression of pattern recognition receptors, cytokines and transcription factors; and reduced airway remodeling. The treatment induced regulatory T cell responses, as shown by increased Il10 and Foxp3 transcription in lung tissue, and augmented Foxp3 protein expression in blood CD4+CD25+Foxp3+ T cells. This specific combination of beneficial bacteria with non-digestible oligosaccharides has strong anti-inflammatory properties, possibly via the induction of a regulatory T cell response, resulting in reduced airway remodeling and, therefore, may be beneficial in the treatment of chronic inflammation in allergic asthma.

Probiotics in the Management of Lung Diseases

The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For example, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohns disease. Probiotics have been defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus, Bifidobacterium, and Saccharomyces, and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases.

Rapid EPA and DHA incorporation and reduced PGE2 levels after one week intervention with a medical food in cancer patients receiving radiotherapy, a randomized trial

BACKGROUND & AIMS In cancer patients, metabolic alterations, reduced immune competence and anti-cancer treatment can increase the risk of infections. A rapid-acting nutritional intervention might reduce this risk and support overall treatment. The present study investigated whether one week of intervention with a specific medical food led to fatty acid incorporation and functional immunological changes. METHODS In a randomized, double-blind study, 38 cancer patients receiving radiotherapy consumed daily for one week 400 ml of specific medical food, which is high in protein and leucine, and enriched with fish oil and specific oligosaccharides (Active group), or iso-caloric/iso-nitrogenous product (Control group). Blood samples were taken at day 0 (baseline) and day 7. RESULTS After one week of intervention, the incorporation of EPA and DHA in white blood cells was significantly higher in the Active group (2.6% and 2.6% of total fatty acids) compared to the Control group (1.0% and 2.2% of total fatty acids) (p < 0.001 and p < 0.05). Serum PGE2 levels decreased in the Active group and increased in the Control group (p < 0.01). No differences were observed on cytokine production in LPS-stimulated whole blood cultures. CONCLUSIONS In cancer patients receiving radiotherapy, nutritional intervention with a specific medical food rapidly increased the percentage EPA and DHA in white blood cell phospholipids and reduced serum levels of the inflammatory mediator PGE2 within one week. CLINICAL REGISTRATION NUMBER: NTR2121.