The role of probiotics and postbiotics in modulating the gut microbiome-immune system axis in the pediatric age

The complex microbial community of the gut microbiome plays a fundamental role in driving development and function of the human immune system. This phenomenon is named the gut microbiome-immune system axis. When operating optimally, this axis influences both innate and adaptive immunity, which orchestrates the maintenance of crucial elements of host-microorganisms symbiosis, in a dialogue that modulates responses in the most beneficial way. Growing evidence reveals some environmental factors which can positively and negatively modulate the gut microbiome-immune system axis with consequences on the body health status. Several conditions which increasingly affect the pediatric age, such as allergies, autoimmune and inflammatory disorders, arise from a failure of the gut microbiome-immune system axis. Prenatal or postnatal modulation of this axis through some interventional strategies (including diet, probiotics and postbiotics), may lead to a positive gene-environment interaction with improvement of immune-modulatory effects and final positive effect on human health. In particular probiotics and postbiotics exerting pleiotropic regulatory actions on the gut-microbiome-immune system axis provide an innovative preventive and therapeutic strategy for many pediatric conditions

Oral contraceptives combined with interferon β in multiple sclerosis

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon b (IFN-b) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFNb-1a subcutaneously (SC) only (group 1), IFN-b-1a SC plus ethinylstradiol 20 mg and desogestrel 150 mg (group 2), or IFN-b-1a SC plus ethinylestradiol 40 mg and desogestrel 125 mg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures. Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81–1.14) in group 1, 0.84 (95% CI 0.66–1.02) in group 2, and 0.72 (95% CI 0.53–0.91) in group 3, with a decrease of 14.1% (p 5 0.24) and 26.5% (p 5 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadoliniumenhancing lesions was greater in group 3 than in group 1 (p 5 0.03). No significant differences were detected in other secondary endpoints. IFN-b or OC discontinuations were equally distributed across groups. Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research

Immunonutrition for Pediatric Patients With Cow's Milk Allergy: How Early Interventions Could Impact Long-Term Outcomes

Cow's milk allergy (CMA) is one of the most common food allergies and one of the main causes of food-induced anaphylaxis in the pediatric age. Moreover, up to 45% of CMA children develop other atopic manifestations later in life, a phenomenon commonly named atopic march. Thus, CMA imposes a significant cost to health care systems as well as to families, and has emerged as one of the most expensive allergic diseases. The immunonutrition strategy builds its foundation on the ability of selected dietary factors to modulate immune system development and function. Recent studies highlighted the potential of immunonutrition in the management of CMA. This review is focused on the mechanisms and long-term clinical outcomes of the immunonutrition approach in children with CMA. Introduction Much has changed during the recent decades regarding prevalence, persistence, and severity of clinical features and socio-economic burden of food allergy (FA) that currently affects up to 10% of children living in Western countries (1). Based on the immune mechanisms, FA may be classified as IgE-mediated, non-IgE-mediated, or a combination of both pathways (2). In addition, children presenting with FA in early life are at increased risk of developing other allergic manifestations later in life, such as allergic asthma and rhinitis, a phenomenon commonly named atopic march (AM) (3). With an estimated prevalence of up to 3%, cow's milk allergy (CMA) is one of the most common FA and one of the main causes of food-induced anaphylaxis in the pediatric age (4). This condition imposes a significant cost to health care systems as well as to families, and has emerged as one of the most expensive allergic diseases (4). Furthermore, early life CMA could be the first step of AM, which affects up to 45% of CMA children, also after the acquisition of immune tolerance to cow's milk proteins (CMP) (5–8). Both CMA and AM derive from a negative interaction between genetic and environmental factors (3) resulting in alteration in the gut microbiome (GM) and in immune system dysfunction. These modulatory effects are at least in part mediated by epigenetic mechanisms, and are now emerging as potential targets of intervention to facilitate the immune tolerance acquisition and to limit the occurrence of AM in CMA patients (5, 9–11). The traditional dietary management of CMA has greatly changed in the last few years, moving from a passive approach based on the strict elimination diet of CMP-containing foods, to a proactive one, able to change the CMA course (12). The discovery of the pivotal role of selected dietary factors in influencing immune system development and function has introduced the immunonutrition concept. The application of the immunonutrition approach in the management of CMA is paving the way to “active diet therapy,” an integrated dietary strategy able to facilitate the acquisition of immune tolerance and to prevent the occurrence of AM (5, 9, 13–15). The modern dietary management in CMA pediatric patients is focused on three targets: • Dietary education (allergen avoidance and healthy diet) • Ensure adequate intake of macro and micro-nutrients (stimulation of optimal body growth and development) • Active diet therapy (stimulation of immune tolerance and protection against AM occurrence). The immunonutrition approach could be promoted for all three of these targets. This review is focused on the objectives and long-term clinical outcomes of the immunonutrition approach in children affected by CM

Effect on cognition of estroprogestins combined with Interferon beta in multiple sclerosis: analysis of secondary outcomes from a randomized controlled trial

Introduction Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. Objectives We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Methods Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao’s Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined ‘cognitive impairment’. Results At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). Conclusions This study suggests that the combination of high-dose estroprogestins and IFN-β may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised

Tolerability of a new amino acid-based formula for children with IgE-mediated cow's milk allergy

Amino acid-based formula (AAF) is a relevant dietary strategy for paediatric patients affected by cow's milk allergy (CMA). The present study was designed to evaluate the hypoallergenicity of a new AAF in children with immunoglobulin (Ig)E-mediated CMA

Therapeutic effects elicited by the probiotic Lacticaseibacillus rhamnosus GG in children with atopic dermatitis. The results of the ProPAD trial

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting up to 20% of the pediatric population associated with alteration of skin and gut microbiome. Probiotics have been proposed for AD treatment. The ProPAD study aimed to investigate the therapeutic effects of the probiotic Lacticaseibacillus rhamnosus GG (LGG) in children with AD

Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level. Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis. Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects. Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19

Comparative Evaluation of Nasal and Small Intestine Expression of ACE2, TMPRSS2 and ACE1 and in Children and in Adults

Importance: Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seems to be lower in children compared to that in adults. Defining the pathophysiological mechanisms of such disease patterns maybe relevant for development of effective public health strategies. It has been hypothesised that the lower severity of SARS-CoV-2 infection in children could be due to the differential expression of angiotensin-converting enzyme 2 (ACE2), which serves as a virus receptor. Objective: To evaluate the expression of ACE2, ACE1, and TMPRSS2 genes at the level of the two most relevant entry sites for SARS-CoV-2, the upper respiratory tract and small intestine, in healthy children and adult subjects. Design, Setting, and Participants: This prospective study included healthy individuals of both sexes, aged 1-10 years in the paediatric population (n=30) and 20-80 years in the adult population (n=30). The participants were consecutively evaluated at two tertiary centres for paediatrics, gastroenterology, and otolaryngology. Main Measures: Expression of ACE2, ACE1, and TMPRSS2 genes in samples collected from the upper respiratory tract and small intestine. Results: We found no difference in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium between children and adult subjects. ACE2 expression was more abundant in the small intestine of children compared to that in adults. ACE1 expression was higher in the small intestine of adults compared to that in children. Intestinal TMPRSS2 expression was similar in the two study populations. Conclusions and Relevance: The general lower severity of SARS-CoV-2 infection in children does not seem to be related to a lower expression of ACE2 and/or TMPRSS2 in the respiratory tract or in the gastrointestinal tract. Other co-factors may confer protection against SARS-CoV-2 in children. The exploration of such factors is of pivotal importance for development of innovative protective strategies against SARS-CoV-2. Funding Statement: This work was supported in part by a grant of Regione Campania POR FESR 2014/2020, Task Force Covid-19 DGR 140 – 17 March 2020. Declaration of Interests: The authors have no other conflict of interests that are directly relevant to the content of this manuscript, which remains their sole responsibility. Ethics Approval Statement: The study was approved by the Ethics Committee of the University Federico II of Naples, Italy. Written informed consent was obtained from the adult participants and from the parents/tutors of minors

Cytomegalovirus-specific T cells restricted for shared and donor human leukocyte antigens differentially impact on cytomegalovirus reactivation risk after allogeneic hematopoietic stem cell transplantation

After allogeneic hematopoietic stem cell transplantation (HSCT), the emergence of circulating cytomegalovirus (CMV)- specific T cells correlates with protection from CMV reactivation, an important risk factor for non-relapse mortality. However, functional assays measuring CMV-specific cells are time-consuming and often inaccurate at early time-points. We report the results of a prospective single-center, non-interventional study that identified the enumeration of Dextramerpositive CMV-specific lymphocytes as a reliable and early predictor of viral reactivation. We longitudinally monitored 75 consecutive patients for 1 year after allogeneic HSCT (n=630 samples). The presence of ≥0.5 CMV-specific CD8+ cells/mL at day +45 was an independent protective factor from subsequent clinically relevant reactivation in univariate (P<0.01) and multivariate (P<0.05) analyses. Dextramer quantification correlated with functional assays measuring interferon-γ production, and allowed earlier identification of high-risk patients. In mismatched transplants, the comparative analysis of lymphocytes restricted by shared, donor- and host-specific HLA revealed the dominant role of thymic-independent CMV-specific reconstitution. Shared and donor-restricted CMV-specific T cells reconstituted with similar kinetics in recipients of CMV-seropositive donors, while donor-restricted T-cell reconstitution from CMV-seronegative grafts was impaired, indicating that in primary immunological responses the emergence of viral-specific T cells is largely sustained by antigen encounter on host infected cells rather than by cross-priming/presentation by non-infected donor-derived antigen-presenting cells. Multiparametric flow cytometry and high-dimensional analysis showed that shared-restricted CMV-specific lymphocytes display a more differentiated phenotype and increased persistence than donor-restricted counterparts. In this study, monitoring CMV-specific cells by Dextramer assay after allogeneic HSCT shed light on mechanisms of immune reconstitution and enabled risk stratification of patients, which could improve the clinical management of post-transplant CMV reactivations

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication