Human Gut Microbiota and Obesity During Development

Obesity, particularly in children and adolescents, has become a significant public health problem that has reached “epidemic” status worldwide. The etiology of obesity is complex and involves lifestyle factors that are challenging to modify. The intestinal microbiota contribute to protection against pathogens, maturation of the immune system, and metabolic welfare of the host but, under some circumstances, can contribute to the pathogenesis of certain diseases. Over the last decade, novel evidence from animal and human studies has identified associations between human intestinal bacteria and host metabolism and obesity. Infancy is a critical period in the development of the gut microbiota: initial colonization is influenced not only by a number of early-life exposures, including birth mode, infant nutrition, or antibiotic use, but also by maternal factors during pregnancy, including maternal BMI, nutrition, gut microbial composition, and drug exposure, among others. Thus, an adequate nutritional and microbial environment during the perinatal period and early life may provide windows of opportunity to reduce the risk of obesity and overweight in our children by using targeted strategies aimed to modulate the gut microbiota during early life

The Role of Probiotics and Prebiotics in the Prevention and Treatment of Obesity

Obesity is a global pandemic complex to treat due to its multifactorial pathogenesis—an unhealthy lifestyle, neuronal and hormonal mechanisms, and genetic and epigenetic factors are involved. Scientific evidence supports the idea that obesity and metabolic consequences are strongly related to changes in both the function and composition of gut microbiota, which exert an essential role in modulating energy metabolism. Modifications of gut microbiota composition have been associated with variations in body weight and body mass index. Lifestyle modifications remain as primary therapy for obesity and related metabolic disorders. New therapeutic strategies to treat/prevent obesity have been proposed, based on pre- and/or probiotic modulation of gut microbiota to mimic that found in healthy non-obese subjects. Based on human and animal studies, this review aimed to discuss mechanisms through which gut microbiota could act as a key modifier of obesity and related metabolic complications. Evidence from animal studies and human clinical trials suggesting potential beneficial effects of prebiotic and various probiotic strains on those physical, biochemical, and metabolic parameters related to obesity is presented. As a conclusion, a deeper knowledge about pre-/probiotic mechanisms of action, in combination with adequately powered, randomized controlled follow-up studies, will facilitate the clinical application and development of personalized healthcare strategies.Supported by funds from European Union 7th FP KBBE.2013.2.2-02—MyNewGut Project (“Factors influencing the human gut microbiome and its effect on the development of diet-related diseases and brain development”, Grant Agreement 613979) and from Spanish Ministry of Economy and Competitiveness GD-Brain Projects (SAF2015-69265-c2.2)

Impact of Probiotics on the Prevention and Treatment of Gastrointestinal Diseases in the Pediatric Population

Despite the high prevalence of gastrointestinal disorders (GIDs) in infants and children, especially those categorized as functional GIDs (FGIDs), insufficient knowledge about their pathophysiology has limited both symptomatic diagnosis and the development of optimal therapies. Recent advances in the field of probiotics have made their potential use as an interesting therapeutic and preventive strategy against these disorders possible, but further efforts are still needed. In fact, there is great controversy surrounding this topic, generated by the high variety of potential probiotics strains with plausible therapeutic utility, the lack of consensus in their use as well as the few comparative studies available on probiotics that record their efficacy. Taking into account these limitations, and in the absence of clear guidelines about the dose and timeframe for successful probiotic therapy, our review aimed to evaluate current studies on potential use of probiotics for the prevention and treatment of the most common FGIDs and GIDs in the pediatric population. Furthermore, matters referring to know major action pathways and key safety recommendations for probiotic administration proposed by major pediatric health agencies shall also be discussed

Rapid and simultaneous determination of histidine metabolism intermediates in human and mouse microbiota and biomatrices

Histidine metabolism is a key pathway physiologically involved in satiety, recognition memory, skin, and neural protection and allergic diseases. Microbiologically-produced imidazole propionate induces type II diabetes and interferes with glucose lowering drugs. Despite their determinant health implications, no single method simultaneously assesses histidine metabolites in urine, feces, and microbiota. The aim of this study was to develop a simple, rapid, and sensitive method for the determination of histidine and its major bioactive metabolites histamine, N-acetylhistamine, imidazole-4-acetate, cis-urocanate, trans-urocanate, glutamate and imidazole propionate, using ultrahigh-performance liquid chromatography with electrospray ionization tandem mass spectrometry. An innovative simple extraction method from small aliquots of human and mice urine, feces and microbial cell extracts was coupled to separation in a 6.5 min chromatographic run. The successful performance allowed accurate and precise quantification of all metabolites in mouse feces, suggesting broad exchange of histidine metabolites between the gut and mice. Higher urine histamine, histamine to histidine ratio, and imidazole-4-acetate pointed to an underlying inflammatory or allergic process in mice compared to human subjects. N-acetylhistamine and imidazole propionate were detected in human and mouse feces, confirming its origin from gut microbial metabolism. Our novel and robust analytical method captured histidine metabolism in a single assay that will facilitate broad and deep histidine metabolic phenotyping assessing the impact of microbiota on host health in large-scale human observational and interventional studies.The authors are grateful to the Spanish Ministry of Education, Culture and Sports for the pre-doctoral fellowship granted to Inmaculada Acuña (FPU16/04587). Inmaculada Acuña participated in the PhD Program in Nutrition and Food Science of the University of Granada. The results of this manuscript are part of Inmaculada Acuña PhD thesis. This work was carried out within the frame of GP/EFSA/ENCO/380 2018/03/G04: OBEMIRISK: Knowledge platform for assessing the risk of Bisphenols on gut microbiota and its role in obesogenic phenotype: looking for biomarkers. This research was also funded by FEDER-Infrastructure-Consejería de Economía, Conocimiento, Empresas y Universidad: IE_2019-198.S

Short- and Long-Term Implications of Human Milk Microbiota on Maternal and Child Health

Conceptualization, C.C. and T.C.; searching and review of published articles: M.E.-M., E.D., M.G.-R., J.A.G.-S., T.C. and C.C.; writing—original draft preparation, M.E.-M., E.D., C.C., M.G.-R., J.A.G.-S. and T.C.; writing—review and editing, M.G.-R., J.A.G.-S. and T.C.; visualization, M.G.-R.; J.A.G.-S. and T.C.; supervision, T.C. and C.C. All authors have read and agreed to the published version of the manuscript.Human milk (HM) is considered the most complete food for infants as its nutritional composition is specifically designed to meet infant nutritional requirements during early life. HM also provides numerous biologically active components, such as polyunsaturated fatty acids, milk fat globules, IgA, gangliosides or polyamines, among others; in addition, HM has a "bifidogenic effect ", a prebiotic effect, as a result of the low concentration of proteins and phosphates, as well as the presence of lactoferrin, lactose, nucleotides and oligosaccharides. Recently, has been a growing interest in HM as a potential source of probiotics and commensal bacteria to the infant gut, which might, in turn, influence both the gut colonization and maturation of infant immune system. Our review aims to address practical approaches to the detection of microbial communities in human breast milk samples, delving into their origin, composition and functions. Furthermore, we will summarize the current knowledge of how HM microbiota dysbiosis acts as a short- and long-term predictor of maternal and infant health. Finally, we also provide a critical view of the role of breast milk-related bacteria as a novel probiotic strategy in the prevention and treatment of maternal and offspring diseases

Probiotic, Prebiotic, and Brain Development

Recently, a number of studies have demonstrated the existence of a link between the emotional and cognitive centres of the brain and peripheral functions through the bi-directional interaction between the central nervous system and the enteric nervous system. Therefore, the use of bacteria as therapeutics has attracted much interest. Recent research has found that there are a variety of mechanisms by which bacteria can signal to the brain and influence several processes in relation to neurotransmission, neurogenesis, and behaviour. Data derived from both in vitro experiments and in vivo clinical trials have supported some of these new health implications. While recent molecular advancement has provided strong indications to support and justify the role of the gut microbiota on the gut–brain axis, it is still not clear whether manipulations through probiotics and prebiotics administration could be beneficial in the treatment of neurological problems. The understanding of the gut microbiota and its activities is essential for the generation of future personalized healthcare strategies. Here, we explore and summarize the potential beneficial effects of probiotics and prebiotics in the neurodevelopmental process and in the prevention and treatment of certain neurological human diseases, highlighting current and future perspectives in this topic.This work was supported by the European Union’s 7th Framework Programme under grant agreement No. 613979 (MyNewGut Project 2013/KB/613979)Spanish Ministry of Economy and Competitiveness (MINECO) BFU2012-40254-C03-01.Tomás Cerdó participated in the Ph.D. Program in Biomedicine of the University of Granada and is a fellow of the FPI (BES-2013-065133) program at the Spanish Ministry of Economy and Competitiveness

Infant Formula Supplemented With Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids, and Synbiotics Is Associated With Neurocognitive Function and Brain Structure of Healthy Children Aged 6 Years: The COGNIS Study

This project has been funded by Laboratorios Ordesa, S.L. Contract University of Granada General Foundation, No. 3349 and SMARTFOODS (CIEN) Contract University of Granada General Foundation, No. 4003, Spanish Ministry of Economy, Industry and Competitiveness. Furthermore, the project has been partially funded by HORIZON 2020 EU DynaHEALTH Project (GA No. 633595).Background: Adequate nutrient intake during the first few months of life plays a critical role on brain structure and function development. Objectives: To analyze the long-term effects of an experimental infant formula (EF) on neurocognitive function and brain structure in healthy children aged 6 years compared to those fed with a standard infant formula or breastfed. Methods: The current study involved 108 healthy children aged 6 years and participating in the COGNIS Study. At 0–2 months, infants were randomized to receive up to 18 months of life a standard infant formula (SF) or EF enriched with milk fat globule membrane (MFGM), long-chain polyunsaturated fatty acids (LC-PUFAs) and synbiotics. Furthermore, a reference group of breastfed (BF) infants were also recruited. Children were assessed using neurocognitive tests and structural Magnetic Resonance Imaging (MRI) at 6 years old. Results: Experimental infant formula (EF) children showed greater volumes in the left orbital cortex, higher vocabulary scores and IQ, and better performance in an attention task than BF children. EF children also presented greater volumes in parietal regions than SF kids. Additionally, greater cortical thickness in the insular, parietal, and temporal areas were found in children from the EF group than those fed with SF or BF groups. Further correlation analyses suggest that higher volumes and cortical thickness of different parietal and frontal regions are associated with better cognitive development in terms of language (verbal comprehension) and executive function (working memory). Finally, arachidonic acid (ARA), adrenic acid (AdA), docosahexaenoic acid (DHA) levels in cheek cell glycerophospholipids, ARA/DHA ratio, and protein, fatty acid, and mineral intake during the first 18 months of life seem to be associated with changes in the brain structures at 6 years old. Conclusions: Supplemented infant formula with MFGM components, LC-PUFAs, and synbiotics seems to be associated to long-term effects on neurocognitive development and brain structure in children at 6 years old.Laboratorios OrdesaContract University of Granada General Foundation 3349SMARTFOODS (CIEN) Contract University of Granada General Foundation 4003Spanish Ministry of Economy, Industry and Competitiveness. FurthermoreEU DynaHEALTH Project 63359

The Effects of an Infant Formula Enriched with Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids and Synbiotics on Child Behavior up to 2.5 Years Old: The COGNIS Study

Although early life nutrition influences brain development and mental health, the long-term e ects of supplemented infant formula on children´s behavior remain unclear. We analyzed the e ects of a bioactive nutrients-enriched-infant formula on children’s behavior up to 2.5 years, compared to a standard infant formula or breastfeeding. Current analysis involved 70 children who were fed a standard infant formula (SF, n = 29) or a bioactive compounds enriched-infant formula (EF, n = 41), during their first 18 months of life, and 33 breastfed (BF) children (reference group) participating in the COGNIS study. Behavioral problems were evaluated using the Child Behavior Checklist at 18 months and 2.5 years. Di erent statistical analyses were performed using SPSS. EF children aged 2.5 years presented fewer pathological a ective problems than SF children. Besides, SF children were classified more frequently as bordering on internalizing problems than BF children. Rates of externalizing problems were increased in SF infants compared to EF and BF infants. Higher maternal IQ was found to have beneficial e ects on internalizing and total problem rate in their o spring at 18 months of life; finally, higher maternal educational level was related with fewer ADHD problems in children at 18 months, as well as internalizing, externalizing, total and anxiety problems in children aged 2.5 years. Our analysis suggests that enriched infant formula fed infants seem to show fewer behavioral problems up to 2.5 years compared to a standard infant formula-fed infants. In addition to type of early feeding, maternal IQ and educational level seem to play a key role on children behavioral development.Ordesa LaboratoriesS.L. Contract University of Granada General Foundation 3349SMARTFOODS (CIEN) Contract University of Granada General Foundation 4003Spanish Ministry of Economy, Industry and CompetitivenessHORIZON 2020 EU DynaHEALTH Project 633595Fundación Carolina, Madrid, SpainCatedra ORDESA-University of Granada, Spain as part of Special Issue "Early Nutrition and Re-programming of Health and Disease

A synbiotics, long chain polyunsaturated fatty acids, and milk fat globule membranes supplemented formula modulates microbiota maturation and neurodevelopment

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clnu.2022.05.013.Acknowledgments The authors wish to acknowledge the parents and children who participated in the study, and also the paediatricians and researchers of the EURISTIKOS team at the Department of Paediatrics as well as the Genetics Service at Centro de Instrumentación Científica e UGR for their contributions.Funding This project was supported by CDTI (Centro para el Desarrollo Tecnológico e Industrial) and FEDER (SMARTFOODS: IDI-20141206), Ordesa Laboratories, S.L. (Contract FE-UGR No. 3349), and The Spanish Ministry of Economy, Industry and Competitiveness, and partially supported by HORIZON 2020 EU DynaHEALTH Project (GA No.633595). Alicia Ruiz and Inmaculada Acuña were granted Ph.D. scholarships from the Spanish Ministry of Economy and Competitivity. Tomás Cerdó was granted a Ph.D. scholarship from Carlos III Health Institute. Natalia Sepúlveda-Valbuena was granted with a scholarship from Fundación Carolina, Madrid, Spain.Background & aims The critical window of concurrent developmental paths of the nervous system and gut microbiota in infancy provides an opportunity for nutritional interventions with potential health benefits later in life. Methods We compared the dynamics of gut microbiota maturation and explored its association with neurodevelopment at 12 months and 4 years of age in 170 full-term healthy infants fed a standard formula (SF) or a new formula (EF) based on standard formula supplemented with synbiotics, long chain polyunsaturated fatty acids (LC-PUFA) and bovine milk fat globule membranes (MFGM), including a breastfed reference group (BF). Results Using Dirichlet Multinomial Modelling, we characterized three microbial enterotypes (Mixed, anaerobic and aerobic profile; Bact, Bacteroides-dominant; Firm, Firmicutes-enriched) and identified a new enterotype dominated by an unidentified genus within Lachnospiraceae (U_Lach). Enterotypes were associated with age (Mixed with baseline, U_Lach with month 6, Bact and Firm with months 12 and 18). Trajectories or timely enterotype shifts in each infant were not random but strongly associated with type of feeding. Trajectories in SF shifted from initial Mixed to U_Lach, Bact or Firm at month. Microbiota maturation in EF split into a fast trajectory as in SF, and a slow trajectory with Mixed to U_Lach, Bact or Firm transitions at months 12 or 18, as in BF. EF infants with slow trajectories were more often in–home reared and born by vaginal delivery to mothers with pre-pregnancy lean BMI. At 12 months of age, language and expressive language scores were significantly higher in EF infants with fast trajectories than in BF. Neurodevelopmental outcomes were similar between EF infants with slow trajectories and BF at 12 months and 4 years of age. Conclusions Feeding a synbiotics, LC-PUFA and MFGM supplemented formula in a specific infant environment promoted probiotic growth and retarded gut microbiota maturation with similar neurodevelopment outcomes to breastfed infants.CDTI (Centro para el Desarrollo Tecnológico e Industrial) and FEDER (SMARTFOODS: IDI- 20141206)Ordesa Laboratories, S.L. (Contract FE-UGR No. 3349)Spanish Ministry of Economy, Industry and CompetitivenessHORIZON 2020 EU DynaHEALTH Project (GA No.633595