Evaluation of the Effect of Limosilactobacillus fermentum CECT5716 on Gastrointestinal Infections in Infants: A Systematic Review and Meta-Analysis

Reducing the incidence of gastrointestinal infections (GIs) that occur at early stages to mitigate hospitalizations and treatments with adverse effects is a promising strategy for providing well-being to infants and their families. This systematic review and meta-analysis explores whether the early administration of Limosilactobacillus fermentum CECT5716 might be effective as a preventive therapy for GIs. We reviewed the literature to identify randomized controlled trials (RCTs) investigating the effectiveness of milk formulas supplemented with L. fermentum CECT5716 administered to infants at early stages to reduce the incidence of GIs. The MEDLINE (via PubMed), Web of Science (WoS), and Cochrane Central Register of Controlled Trials (via CENTRAL) databases were searched up to 15 June 2021. GI data from the included studies were synthesized in a random-effects model. Three RCTs were finally selected including 435 infants. There was a significant reduction in the incidence rate of GIs for those receiving L. fermentum CECT5716 compared with those receiving placebo (IRR: 0.52, 95% CI: 0.36–0.74, p = 0.0004). Heterogeneity between studies was moderate (I2 = 54.5%). Based on the present systematic review and meta-analysis, the administration of L. fermentum CECT5716 at doses from 1 × 109 to 8.4 × 108 cfu/day in milk formulas may prevent GIs in infants up to 12 months old. Longer-term studies including a higher number of infants are needed to determine whether the use of this probiotic during the early stages of life is an efficient way to reduce the incidence of GIs

Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies

BPV is supported by a grant to postdoctoral researchers at foreign universities and research centers from the Alfonso Martín Escudero Foundation, Spain.Introduction Obesity is a disorder characterized by a disproportionate increase in body weight in relation to height, mainly due to the accumulation of fat, and is considered a pandemic of the present century by many international health institutions. It is associated with several non-communicable chronic diseases, namely, metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cancer. Metabolomics is a useful tool to evaluate changes in metabolites due to being overweight and obesity at the body fluid and cellular levels and to ascertain metabolic changes in metabolically unhealthy overweight and obese individuals (MUHO) compared to metabolically healthy individuals (MHO). Objectives We aimed to conduct a systematic review (SR) of human studies focused on identifying metabolomic signatures in obese individuals and obesity-related metabolic alterations, such as inflammation or oxidative stress. Methods We reviewed the literature to identify studies investigating the metabolomics profile of human obesity and that were published up to May 7th, 2019 in SCOPUS and PubMed through an SR. The quality of reporting was evaluated using an adapted of QUADOMICS. Results Thirty-three articles were included and classified according to four types of approaches. (i) studying the metabolic signature of obesity, (ii) studying the differential responses of obese and non-obese subjects to dietary challenges (iii) studies that used metabolomics to predict weight loss and aimed to assess the effects of weight loss interventions on the metabolomics profiles of overweight or obese human subjects (iv) articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans. Conclusion The present SR provides state-of-the-art information about the use of metabolomics as an approach to understanding the dynamics of metabolic processes involved in human obesity and emphasizes metabolic signatures related to obesity phenotypes.ODRH has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement n° 609020 - Scientia Fellows

Plausible Biological Interactions of Low- and Non-Calorie Sweeteners with the Intestinal Microbiota: An Update of Recent Studies

Julio Plaza-Díaz is part of the “UGR Plan Propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”. Francisco J. Ruiz-Ojeda and Belén Pastor-Villaescusa are supported by a grant to postdoctoral researchers at foreign universities and research centers from the “Fundación Alfonso Martín-Escudero”, Madrid, Spain. We are grateful to Belen Vazquez-Gonzalez for assistance with the illustration service.Sweeteners that are a hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. The effects of sweeteners on gut microbiota composition have not been completely elucidated yet, and numerous gaps related to the effects of nonnutritive sweeteners (NNS) on health still remain. The NNS aspartame and acesulfame-K do not interact with the colonic microbiota, and, as a result, potentially expected shifts in the gut microbiota are relatively limited, although acesulfame-K intake increases Firmicutes and depletes Akkermansia muciniphila populations. On the other hand, saccharin and sucralose provoke changes in the gut microbiota populations, while no health effects, either positive or negative, have been described; hence, further studies are needed to clarify these observations. Steviol glycosides might directly interact with the intestinal microbiota and need bacteria for their metabolization, thus they could potentially alter the bacterial population. Finally, the effects of polyols, which are sugar alcohols that can reach the colonic microbiota, are not completely understood; polyols have some prebiotics properties, with laxative effects, especially in patients with inflammatory bowel syndrome. In this review, we aimed to update the current evidence about sweeteners’ effects on and their plausible biological interactions with the gut microbiota

KD Diagnosis Does Not Increase Cardiovascular Risk in Children According to Dynamic Intima–Media Roughness Measurements

Background: Kawasaki Disease (KD) is a generalized vasculitis in childhood with possible long-term impact on cardiovascular health besides the presence of coronary artery lesions. Standard vascular parameters such as carotid intima–media thickness (cIMT) have not been established as reliable markers of vascular anomalies after KD. The carotid intima–media roughness (cIMR) representing carotid intimal surface structure is considered a promising surrogate marker for predicting cardiovascular risk even beyond cIMT. We therefore measured cIMR in patients with a history of KD in comparison to healthy controls to investigate whether KD itself and/or KD key clinical aspects are associated with cIMR alterations in the long-term. Methods: We assessed cIMR in this case-control study (44 KD, mean age in years (SD); 13.4 (7.5); 36 controls, mean age 12.1 (5.3)) approximately matched by sex and age. Different clinical outcomes such as the coronary artery status and acute phase inflammation data were analyzed in association with cIMR values. Results: When comparing all patients with KD to healthy controls, we detected no significant difference in cIMR. None of the clinical parameters indicating the disease severity, such as the persistence of coronary artery aneurysm, were significantly associated with our cIMR values. However, according to our marginally significant findings (p = 0.044), we postulate that the end-diastolic cIMR may be rougher than the end-systolic values in KD patients. Conclusions: We detected no significant differences in cIMR between KD patients and controls that could confirm any evidence that KD predisposes patients to a subsequent general arteriopathy. Our results, however, need to be interpreted in the light of the low number of study participants

Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial

Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).This research was funded by the Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products (codes and beneficiaries: EC10-243, Ramón Cañete, Reina Sofía Hospital, Córdoba; EC10-056, Ángel Gil, University of Granada and Virgen de las Nieves University Hospital, Granada; EC10-281, Rosaura Leis, Clinic University Hospital of Santiago, Santiago de Compostela; and EC10-227, Gloria Bueno, Lozano Blesa University Clinical Hospital, Zaragoza

Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial

Background: Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. Methods: The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. Results: Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumptionSpanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health ProductsInstituto de Salud Carlos III-Fondo de Investigación Sanitaria (FONDOS FEDER), Redes temáticas de investigación cooperativa RETIC Red SAMID RD12/0026/001

Estudio de los efectos del tratamiento de metformina junto con recomendaciones de estilo de vida saludable en el índice de masa corporal, sensibilidad a la insulina, biomarcadores inflamatorios y de riesgo cardiovascular en niños obesos según el estado puberal

Overweight and obesity in children are one of the most challenging health problems to address (Centers for Disease Control and Prevention (CDC) 2011). Obesity plays an important pathophysiologic role in the development of insulin resistance, dyslipidemia, and hypertension, leading to type 2 diabetes (T2D) and risk of early cardiovascular disease (CVD) (Freedman et al. 1999; Weiss et al. 2004). For pediatric patients, several investigations have confirmed that an intensive lifestyle intervention can increase weight loss and insulin sensitivity and reduce the risk of developing T2D (Diabetes Prevention Program Research Group et al. 2002). Nevertheless, a single-strategy lifestyle intervention is not always effective (Kelly et al. 2016). Additionally, efforts have been made to identify effective and safe drugs to manage pediatric obesity. Metformin is an oral antihyperglycemic agent approved by the Food Drug Administration (FDA) to treat T2D in adults and children aged >10 years and considered a first-line agent in T2D by the European Medicines Agency (EMEA). Significant weight loss induced by metformin has been demonstrated in overweight/obese adult patients with/without T2D (Golay 2008), also a decrease in cardiovascular risk profile (De Jager et al. 2005; Škrha et al. 2007; Ersoy et al. 2008; Kelly et al. 2012) and in inflammatory biomarkers as well (De Jager et al. 2005; Škrha et al. 2007; Stocker et al. 2007; Ersoy et al. 2008; Alvim de Lima et al. 2009; Chakraborty et al. 2011; Esteghamati et al. 2012; Kelly et al. 2012). Nevertheless, evidence regarding the effects of metformin in pediatric obesity is scarce. McDonagh et al. (McDonagh et al. 2014) examined the literature in obese children by a systematic review and meta-analysis. The authors concluded that the maximum reduction in body mass index (BMI) due to metformin compared to the effects of lifestyle interventions alone was in studies ranged from 6-12 months. Furthermore, metformin appears to improve the lipid profile in obese adolescents (Kay et al. 2001; Atabek & Pirgon 2008; Clarson et al. 2009). However, little is known about the effects of metformin on obesity-related complications such as cardiovascular risk and inflammation. Seven studies have evaluated the effects of metformin (1000-2000 mg/d for 3-6 months) on such conditions related to obesity in obese children and/or adolescents (Burgert et al. 2008; Clarson et al. 2009; Yanovski et al. 2011; Evia-Viscarra et al. 2012; Gómez-Díaz et al. 2012; Mauras et al. 2012; Kendall et al. 2013), obtaining some promising results. However, randomized clinical trials (RCTs) on this topic did not show a homogeneous distribution according to the pubertal stage. Puberty might exert as a potential modifier on the effect of metformin in childhood. Actually, a recent review highlights the usefulness of stratifying randomization by Tanner stage and sex to avoid large imbalances between groups in linear growth velocity and other factors associated with pubertal maturation that may affect changes in BMI (Kelly et al. 2016). Hence, we designed an RCT to determine whether metformin would have an effect on reducing the BMI z-score and improving cardiovascular and inflammatory risk biomarkers in obese children and to assess whether that effect differed depending on pubertal stage and sex.Tesis Univ. Granada. Programa Oficial de Doctorado en: Nutrición y Ciencias de los AlimentosFinancial support for María Belén Pastor Villaescusa was from the “BIONIT Group (CTS-461)” and the “CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN)”, Instituto de Salud Carlos III, Madrid, Spain.The present trial was funded by the Spanish Ministry of Health, Social and Equality, General Department of Pharmacy and Health Products Codes: EC10-243, EC10-056, EC10-281, EC10-227

Evaluation of the Effect of Limosilactobacillus fermentum CECT5716 on Gastrointestinal Infections in Infants: A Systematic Review and Meta-Analysis

Reducing the incidence of gastrointestinal infections (GIs) that occur at early stages to mitigate hospitalizations and treatments with adverse effects is a promising strategy for providing well-being to infants and their families. This systematic review and meta-analysis explores whether the early administration of Limosilactobacillus fermentum CECT5716 might be effective as a preventive therapy for GIs. We reviewed the literature to identify randomized controlled trials (RCTs) investigating the effectiveness of milk formulas supplemented with L. fermentum CECT5716 administered to infants at early stages to reduce the incidence of GIs. The MEDLINE (via PubMed), Web of Science (WoS), and Cochrane Central Register of Controlled Trials (via CENTRAL) databases were searched up to 15 June 2021. GI data from the included studies were synthesized in a random-effects model. Three RCTs were finally selected including 435 infants. There was a significant reduction in the incidence rate of GIs for those receiving L. fermentum CECT5716 compared with those receiving placebo (IRR: 0.52, 95% CI: 0.36–0.74, p = 0.0004). Heterogeneity between studies was moderate (I2 = 54.5%). Based on the present systematic review and meta-analysis, the administration of L. fermentum CECT5716 at doses from 1 × 109 to 8.4 × 108 cfu/day in milk formulas may prevent GIs in infants up to 12 months old. Longer-term studies including a higher number of infants are needed to determine whether the use of this probiotic during the early stages of life is an efficient way to reduce the incidence of GIs

Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial.

Metformin has shown its effectiveness in treating obesity in adults. However, little research has been conducted in children, with a lack of attention on pubertal status. The objectives were to determine whether oral metformin treatment reduces BMI z score, cardiovascular risk, and inflammation biomarkers in children who are obese depending on pubertal stage and sex. This was a randomized, prospective, double-blind, placebo-controlled, multicenter trial, stratified according to pubertal stage and sex, conducted at 4 Spanish clinical hospitals. Eighty prepubertal and 80 pubertal nondiabetic children who were obese aged 7 to 14 years with a BMI >95th percentiles were recruited. The intervention included 1 g/d of metformin versus placebo for 6 months. The primary outcome was a reduction in BMI z score. Secondary outcomes comprised insulin resistance, cardiovascular risk, and inflammation biomarkers. A total of 140 children completed the study (72 boys). Metformin decreased the BMI z score versus placebo in the prepubertal group (-0.8 and -0.6, respectively; difference, 0.2; P = .04). Significant increments were observed in prepubertal children treated with metformin versus placebo recipients in the quantitative insulin sensitivity check index (0.010 and -0.007; difference, 0.017; P = .01) and the adiponectin-leptin ratio (0.96 and 0.15; difference, 0.81; P = .01) and declines in interferon-γ (-5.6 and 0; difference, 5.6; P = .02) and total plasminogen activator inhibitor-1 (-1.7 and 2.4; difference, 4.1; P = .04). No serious adverse effects were reported. “Metformin decreased the BMI z score and improved inflammatory and cardiovascular-related obesity parameters only in prepubertal children, but a differential effect of metformin was not observed in prepubertal compared to pubertal children. Nevertheless, the doses per kilogram of weight administrated may have had an impact on the metformin effect. Further investigations are necessary.