Maternal supplementation with LGG reduces vaccine-specific immune responses in infants at high-risk of developing allergic disease

Probiotics are defined as live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Among their pleiotropic effects, inhibition of pathogen colonization at the mucosal surface as well as modulation of immune responses are widely recognized as the principal biological activities of probiotic bacteria. In recent times, the immune effects of probiotics have led to their application as vaccine adjuvants, offering a novel strategy for enhancing the efficacy of current vaccines. Such an approach is particularly relevant in regions where infectious disease burden is greatest and where access to complete vaccination programs is limited. In this study, we report the effects of the probiotic, Lactobacillus rhamnosus GG (LGG) on immune responses to tetanus, Haemophilus influenzae type b (Hib) and pneumococcal conjugate (PCV7) vaccines in infants. This study was conducted as part of a larger clinical trial assessing the impact of maternal LGG supplementation in preventing the development of atopic eczema in infants at high-risk for developing allergic disease. Maternal LGG supplementation was associated with reduced antibody responses against tetanus, Hib, and pneumococcal serotypes contained in PCV7 (N = 31) compared to placebo treatment (N = 30) but not total IgG levels. Maternal LGG supplementation was also associated with a trend to increased number of tetanus toxoid-specific T regulatory in the peripheral blood compared to placebo-treated infants. These findings suggest that maternal LGG supplementation may not be beneficial in terms of improving vaccine-specific immunity in infants. Further clinical studies are needed to confirm these findings. As probiotic immune effects can be species/strain specific, our findings do not exclude the potential use of other probiotic bacteria to modulate infant immune responses to vaccines

Probiotic effects in allergic disease

The increasing prevalence of allergic disease has been linked to reduced microbial exposure in early life. Probiotics have recently been advocated for the prevention and treatment of allergic disease. This article summarises recent publications on probiotics in allergic disease, focusing on clinical studies of prevention or treatment of allergic disease. Studies employing the combined administration of pre-natal and post-natal probiotics suggest a role for certain probiotics (alone or with prebiotics) in the prevention of eczema in early childhood, with the pre-natal component of treatment appearing to be important for beneficial effects. On the other hand, current data are insufficient to support the use of probiotics for the treatment of established allergic disease, although recent studies have highlighted new hope in this area. Probiotic bacteria continue to represent the most promising intervention for primary prevention of allergic disease, and well-designed definitive intervention studies should now be a research priority

Epigenome targeting by probiotic metabolites

BACKGROUND: The intestinal microbiota plays an important role in immune development and homeostasis. A disturbed microbiota during early infancy is associated with an increased risk of developing inflammatory and allergic diseases later in life. The mechanisms underlying these effects are poorly understood but are likely to involve alterations in microbial production of fermentation-derived metabolites, which have potent immune modulating properties and are required for maintenance of healthy mucosal immune responses. Probiotics are beneficial bacteria that have the capacity to alter the composition of bacterial species in the intestine that can in turn influence the production of fermentation-derived metabolites. Principal among these metabolites are the short-chain fatty acids butyrate and acetate that have potent anti-inflammatory activities important in regulating immune function at the intestinal mucosal surface. Therefore strategies aimed at restoring the microbiota profile may be effective in the prevention or treatment of allergic and inflammatory diseases. PRESENTATION OF THE HYPOTHESIS: Probiotic bacteria have diverse effects including altering microbiota composition, regulating epithelial cell barrier function and modulating of immune responses. The precise molecular mechanisms mediating these probiotic effects are not well understood. Short-chain fatty acids such as butyrate are a class of histone deacetylase inhibitors important in the epigenetic control of host cell responses. It is hypothesized that the biological function of probiotics may be a result of epigenetic modifications that may explain the wide range of effects observed. Studies delineating the effects of probiotics on short-chain fatty acid production and the epigenetic actions of short-chain fatty acids will assist in understanding the association between microbiota and allergic or autoimmune disorders. TESTING THE HYPOTHESIS: We propose that treatment with specific probiotic bacteria under in vivo conditions would offer the ideal conditions to examine the microbiological, immunological and epigenetic mechanisms of action. Advances in epigenetic technology now allow investigators to better understand the complex biological properties of probiotics and their metabolites. IMPLICATIONS OF THE HYPOTHESIS: Determining the precise mechanisms of probiotic action will lead to more specific and efficacious therapeutic strategies in the prevention or treatment of chronic inflammatory conditions

Reduced neonatal regulatory T cell response to microbial stimuli associates with subsequent eczema in high risk infants

Background: Regulatory T cells (Treg) play an essential role in early immune programming and shaping the immune response towards a pro‐allergic or tolerant state. We evaluated cord blood Treg and cytokine responses to microbial and non‐microbial stimuli in infants at high risk of allergic disease and their associations with development of allergic disease in the first year. Methods: Cord blood mononuclear cells from 72 neonates were cultured with toll‐like receptors (TLR2) ligands: lipoteichoic acid (LTA) and heat‐killed Lactobacillus rhamnosus GG (HKL); TLR4 ligand: lipopolysaccharide (LPS); ovalbumin (OVA); anti‐CD3; or media for 48 h. Treg numbers and Treg cytokines were assessed in relation to allergic disease outcomes during the first year of life (eczema and atopic sensitization). Results: Infants with eczema (n = 24) had reduced percentages of FoxP3hiCD25hi Treg in LTA (p = 0.01, adj p = 0.005) and HKL (p = 0.04, adj p = 0.02) stimulated cultures as well as reduced IL‐10 (p = 0.01) production following HKL stimulation compared to those without eczema (n = 48). No differences in Treg or cytokine responses to LPS, OVA or anti‐CD3 were seen. Infants who developed sensitization had lower percentages of Treg following TLR2 stimulation (but not other stimuli) compared to non‐sensitized infants. Conclusions: High‐risk children who develop allergic disease in the first year of life have deficient Treg responses to microbial stimuli but not allergen from the time of birth, which may contribute to failure of immune tolerance development in infancy

Regulation of L-Selectin–mediated Rolling through Receptor Dimerization

L-selectin binding activity for its ligand expressed by vascular endothelium is rapidly and transiently increased after leukocyte activation. To identify mechanisms for upregulation and assess how this influences leukocyte/endothelial cell interactions, cell-surface dimers of L-selectin were induced using the coumermycin–GyrB dimerization strategy for cross-linking L-selectin cytoplasmic domains in L-selectin cDNA-transfected lymphoblastoid cells. Coumermycin- induced L-selectin dimerization resulted in an approximately fourfold increase in binding of phosphomanan monoester core complex (PPME), a natural mimic of an L-selectin ligand, comparable to that observed after leukocyte activation. Moreover, L-selectin dimerization significantly increased (by ∼700%) the number of lymphocytes rolling on vascular endothelium under a broad range of physiological shear stresses, and significantly slowed their rolling velocities. Therefore, L-selectin dimerization may explain the rapid increase in ligand binding activity that occurs after leukocyte activation and may directly influence leukocyte migration to peripheral lymphoid tissues or to sites of inflammation. Inducible oligomerization may also be a common mechanism for rapidly upregulating the adhesive or ligand-binding function of other cell-surface receptors

Non-destructive 3D Microtomography of Cerebral Angioarchitecture Changes Following Ischemic Stroke in Rats Using Synchrotron Radiation

A better understanding of functional changes in the cerebral microvasculature following ischemic injury is essential to elucidate the pathogenesis of stroke. Up to now, the simultaneous depiction and stereological analysis of 3D micro-architectural changes of brain vasculature with network disorders remains a technical challenge. We aimed to explore the three dimensional (3D) microstructural changes of microvasculature in the rat brain on 4, 6 hours, 3 and 18 days post-ischemia using synchrotron radiation micro-computed tomography (SRμCT) with a per pixel size of 5.2 μm. The plasticity of angioarchitecture was distinctly visualized. Quantitative assessments of time-related trends after focal ischemia, including number of branches, number of nodes, and frequency distribution of vessel diameter, reached a peak at 6 h and significantly decreased at 3 days and initiated to form cavities. The detected pathological changes were also proven by histological tests. We depicted a novel methodology for the 3D analysis of vascular repair in ischemic injury, both qualitatively and quantitatively. Cerebral angioarchitecture sustained 3D remodeling and modification during the healing process. The results might provide a deeper insight into the compensatory mechanisms of microvasculature after injury, suggesting that SRμCT is able to provide a potential new platform for deepening imaging pathological changes in complicated angioarchitecture and evaluating potential therapeutic targets for stroke

Sex differences in erythrocyte fatty acid composition of first-diagnosed, drug-naïve patients with major depressive disorders

Background: Since depression, sex hormones, and fatty acid status are interrelated, it is important to understand their relationships. In this study, we aimed to investigate sex differences in erythrocyte membrane fatty acid composition among first-diagnosed, drug-naïve patients with major depressive disorders.Methods: The study included 139 individuals with first-diagnosed, drug-naïve depression (male/female = 48/91) and 55 healthy controls (male/female = 24/31). The levels of erythrocyte membrane fatty acids were analyzed to compare the difference between males and females in both patients with depression and healthy controls, as well as to study their correlation with depressive symptoms.Results: In first-diagnosed, drug-naïve patients with major depressive disorders, sex disparities were observed in the levels of erythrocyte saturated fatty acids (SFAs) and n-6 PUFAs (such as C18:0, C20:4n6 and C22:4n6), where higher levels evident in females compared to in males. We found a noteworthy correlation between fatty acid levels and depressive symptoms, in which there is a significant association between female patients and depression but a weaker association between male patients and depression.Conclusion: Our findings demonstrate higher levels of n-6 PUFAs and SFAs in female patients with depression. The relationship between fatty acid composition and depressive symptoms was more prominent in females than males. These findings highlight the significance of considering sex as a crucial and interconnected factor in future investigations and potential adjunctive treatment for mood disorders by targeting fatty acid metabolism