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Human Milk Microbiota and Oligosaccharides: A Glimpse into Benefits, Diversity, and Correlations.
Moubareck, CA
Nutrients. 2021;(4)
Abstract
Human milk represents a cornerstone for growth and development of infants, with extensive array of benefits. In addition to exceptionally nutritive and bioactive components, human milk encompasses a complex community of signature bacteria that helps establish infant gut microbiota, contributes to maturation of infant immune system, and competitively interferes with pathogens. Among bioactive constituents of milk, human milk oligosaccharides (HMOs) are particularly significant. These are non-digestible carbohydrates forming the third largest solid component in human milk. Valuable effects of HMOs include shaping intestinal microbiota, imparting antimicrobial effects, developing intestinal barrier, and modulating immune response. Moreover, recent investigations suggest correlations between HMOs and milk microbiota, with complex links possibly existing with environmental factors, genetics, geographical location, and other factors. In this review, and from a physiological and health implications perspective, milk benefits for newborns and mothers are highlighted. From a microbiological perspective, a focused insight into milk microbiota, including origins, diversity, benefits, and effect of maternal diet is presented. From a metabolic perspective, biochemical, physiological, and genetic significance of HMOs, and their probable relations to milk microbiota, are addressed. Ongoing research into mechanistic processes through which the rich biological assets of milk promote development, shaping of microbiota, and immunity is tackled.
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Galacto-oligosaccharides supplementation in prefrail older and healthy adults increased faecal bifidobacteria, but did not impact immune function and oxidative stress.
Wilms, E, An, R, Smolinska, A, Stevens, Y, Weseler, AR, Elizalde, M, Drittij, MJ, Ioannou, A, van Schooten, FJ, Smidt, H, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(5):3019-3031
Abstract
BACKGROUND & AIMS Ageing is associated with an increased risk of frailty, intestinal microbiota perturbations, immunosenescence and oxidative stress. Prebiotics such as galacto-oligosaccharides (GOS) may ameliorate these ageing-related alterations. We aimed to compare the faecal microbiota composition, metabolite production, immune and oxidative stress markers in prefrail elderly and younger adults, and investigate the effects of GOS supplementation in both groups. METHODS In a randomised controlled cross-over study, 20 prefrail elderly and 24 healthy adults received 21.6 g/day Biotis™ GOS (containing 15.0 g/day GOS) or placebo. Faecal 16S rRNA gene-based microbiota and short-chain fatty acids were analysed at 0, 1 and 4 weeks of intervention.Volatile organic compounds were analysed in breath, and stimulated cytokine production, CRP, malondialdehyde, trolox equivalent antioxidant capacity (TEAC) and uric acid (UA) in blood at 0 and 4 weeks. RESULTS Principle coordinate analysis showed differences in microbial composition between elderly and adults (P≤0.05), with elderly having lower bifidobacteria (P≤0.033) at baseline. In both groups, GOS affected microbiota composition (P≤0.05), accompanied by increases in bifidobacteria (P<0.001) and decreased microbial diversity (P≤0.023). Faecal and breath metabolites, immune and oxidative stress markers neither differed between groups (P ≥ 0.125) nor were affected by GOS (P ≥ 0.236). TEAC values corrected for UA were higher in elderly versus adults (P<0.001), but not different between interventions (P ≥ 0.455). CONCLUSIONS Elderly showed lower faecal bifidobacterial (relative) abundance than adults, which increased after GOS intake in both groups. Faecal and breath metabolites, parameters of immune function and oxidative stress were not different at baseline, and not impacted by GOS supplementation. CLINICALTRIALS. GOV WITH STUDY ID NUMBER NCT03077529.
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Prebiotic Galactooligosaccharide Supplementation in Adults with Ulcerative Colitis: Exploring the Impact on Peripheral Blood Gene Expression, Gut Microbiota, and Clinical Symptoms.
Wilson, B, Eyice, Ö, Koumoutsos, I, Lomer, MC, Irving, PM, Lindsay, JO, Whelan, K
Nutrients. 2021;(10)
Abstract
Prebiotics may promote immune homeostasis and reduce sub-clinical inflammation in humans. This study investigated the effect of prebiotic galactooligosaccharide (GOS) supplementation in colonic inflammation. Seventeen patients with active ulcerative colitis (UC) consumed 2.8 g/d GOS for 6 weeks. At baseline and 6 weeks, gene expression (microarray), fecal calprotectin (ELISA), microbiota (16S rRNA), short-chain fatty acids (SCFAs; gas-liquid chromatography), and clinical outcomes (simple clinical colitis activity index (SCCAI), gastrointestinal symptom rating scale (GSRS), and Bristol stool form scale (BSFS)) were measured. Following prebiotics, clinical scores (SCCAI), fecal calprotectin, SCFAs, and pH were unchanged. Five genes were upregulated and two downregulated. Normal stool proportion (BSFS) increased (49% vs. 70%, p = 0.024), and the incidence (46% vs. 23%, p = 0.016) and severity (0.7 vs. 0.5, p = 0.048) of loose stool (GSRS), along with urgency (SCCAI) scores (1.0 vs. 0.5, p = 0.011), were reduced. In patients with a baseline SCCAI ≤2, prebiotics increased the relative abundance of Bifidobacterium from 1.65% (1.97) to 3.99% (5.37) (p = 0.046) and Christensenellaceae from 0.13% (0.33) to 0.31% (0.76) (p = 0.043). Prebiotics did not lower clinical scores or inflammation but normalized stools. Bifidobacterium and Christensenellaceae proportions only increased in patients with less active diseases, indicating that the prebiotic effect may depend on disease activity. A controlled study is required to validate these observations.
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The Role of Human Milk Oligosaccharides and Probiotics on the Neonatal Microbiome and Risk of Necrotizing Enterocolitis: A Narrative Review.
Nolan, LS, Rimer, JM, Good, M
Nutrients. 2020;(10)
Abstract
Preterm infants are a vulnerable population at risk of intestinal dysbiosis. The newborn microbiome is dominated by Bifidobacterium species, though abnormal microbial colonization can occur by exogenous factors such as mode of delivery, formula feeding, and exposure to antibiotics. Therefore, preterm infants are predisposed to sepsis and necrotizing enterocolitis (NEC), a fatal gastrointestinal disorder, due to an impaired intestinal barrier, immature immunity, and a dysbiotic gut microbiome. Properties of human milk serve as protection in the prevention of NEC. Human milk oligosaccharides (HMOs) and the microbiome of breast milk are immunomodulatory components that provide intestinal homeostasis through regulation of the microbiome and protection of the intestinal barrier. Enteral probiotic supplements have been trialed to evaluate their impact on establishing intestinal homeostasis. Here, we review the protective role of HMOs, probiotics, and synbiotic combinations in protecting a vulnerable population from the pathogenic features associated with necrotizing enterocolitis.
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Immunomodulation by Human Milk Oligosaccharides: The Potential Role in Prevention of Allergic Diseases.
Zuurveld, M, van Witzenburg, NP, Garssen, J, Folkerts, G, Stahl, B, Van't Land, B, Willemsen, LEM
Frontiers in immunology. 2020;:801
Abstract
The prevalence and incidence of allergic diseases is rising and these diseases have become the most common chronic diseases during childhood in Westernized countries. Early life forms a critical window predisposing for health or disease. Therefore, this can also be a window of opportunity for allergy prevention. Postnatally the gut needs to mature, and the microbiome is built which further drives the training of infant's immune system. Immunomodulatory components in breastmilk protect the infant in this crucial period by; providing nutrients that contain substrates for the microbiome, supporting intestinal barrier function, protecting against pathogenic infections, enhancing immune development and facilitating immune tolerance. The presence of a diverse human milk oligosaccharide (HMOS) mixture, containing several types of functional groups, points to engagement in several mechanisms related to immune and microbiome maturation in the infant's gastrointestinal tract. In recent years, several pathways impacted by HMOS have been elucidated, including their capacity to; fortify the microbiome composition, enhance production of short chain fatty acids, bind directly to pathogens and interact directly with the intestinal epithelium and immune cells. The exact mechanisms underlying the immune protective effects have not been fully elucidated yet. We hypothesize that HMOS may be involved in and can be utilized to provide protection from developing allergic diseases at a young age. In this review, we highlight several pathways involved in the immunomodulatory effects of HMOS and the potential role in prevention of allergic diseases. Recent studies have proposed possible mechanisms through which HMOS may contribute, either directly or indirectly, via microbiome modification, to induce oral tolerance. Future research should focus on the identification of specific pathways by which individual HMOS structures exert protective actions and thereby contribute to the capacity of the authentic HMOS mixture in early life allergy prevention.
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Effects of oligosaccharide-sialic acid (OS) compound on maternal-newborn gut microbiome, glucose metabolism and systematic immunity in pregnancy: protocol for a randomised controlled study.
Wang, S, Peng, R, Qin, S, Liu, Y, Yang, H, Ma, J
BMJ open. 2019;(9):e026583
Abstract
INTRODUCTION The gut microbiota participates in multiple human biological processes, including metabolism and immune responses. During pregnancy, the dynamics of gut microbiota is involved in physiological adaptation. The disturbed profile of microbiome is associated with maternal complications, such as gestational diabetes mellitus (GDM), which further transfers to the offspring and influence their metabolic and immunological functions in the long term. Prebiotics targeting the gut microbiota and modulating metabolic and immune functions have been shown to be effective in non-pregnant populations with metabolic syndrome. Hence, we propose the use of a prebiotic supplement, oligosaccharide-sialic acid (OS) from the first trimester until delivery in pregnant women, can benefit maternal/new-born gut microbiome, glucose metabolism and innate immunity. METHODS AND ANALYSIS In this prospective double-blinded randomised clinical trial, recruited singleton pregnancies will be stratified by body mass index (BMI) and randomly assigned to consume the OS preparation or placebo daily from the first trimester. At seven later time points (before and after recruitment in the first trimester, in the middle and third trimesters, before delivery, at birth and 42 days postpartum), compliance will be evaluated and/or biological samples will be collected. Along with maternal clinical information, questionnaires on lifestyle and infant development will be recorded. The primary outcomes are the effect of OS on the maternal-offspring gut microbiome and GDM incidence. The secondary outcomes are maternal glycolipid biochemical parameters, cytokine profiles, weight gain during pregnancy and infant morbidities, growth and development. The study aims to validate the effects of OS on reducing maternal morbidity within different BMI groups. The multiple dimensional dataset generated from the study includes clinical and lifestyle-related information, various biological markers and associated protective or risk factors for morbidity and prognosis. An extended follow-up through 42 days after birth could further explore the intrauterine influence on the long-term health of offspring. ETHICS AND DISSEMINATION This protocol has been approved by Peking University First Hospital, National Unit of Clinical Trial Ethics Committee (reference number: 164). The results are expected to be published in scientific manuscripts by 2021. TRIAL REGISTRATION NUMBER ChiCTR1800017192.
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Maternal and Infant Factors Associated with Human Milk Oligosaccharides Concentrations According to Secretor and Lewis Phenotypes.
M Tonon, K, B de Morais, M, F V Abrão, AC, Miranda, A, B Morais, T
Nutrients. 2019;(6)
Abstract
Human milk oligosaccharides (HMOs) are multifunctional carbohydrates naturally present in human milk that act as prebiotics, prevent pathogen binding and infections, modulate the immune system and may support brain development in infants. HMOs composition is very individualized and differences in HMOs concentrations may affect the infant's health. HMOs variability can be partially explained by the activity of Secretor (Se) and Lewis (Le) genes in the mother, but non-genetic maternal factors may also be involved. In this cross-sectional, observational study, 78 single human milk samples ranging from 17 to 76 days postpartum (median: 32 days, IQR: 25-46 days) were collected from breastfeeding Brazilian women, analyzed for 16 representative HMOs by liquid chromatography coupled to mass spectrometry and associations between maternal and infant factors with HMOs concentrations were investigated. HMOs concentrations presented a high variability even in women with the same SeLe phenotype and associations with maternal allergic disease, time postpartum and with infant's weight, weight gain and sex. Overall, we present unprecedented data on HMOs concentrations from breastfeeding Brazilian women and novel associations of maternal allergic disease and infant's sex with HMOs concentrations. Differences in HMOs composition attributed to maternal SeLe phenotype do not impact infant growth, but higher concentrations of specific HMOs may protect against excessive weight gain.
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Effects of short-chain fructooligosaccharides on faecal bifidobacteria and specific immune response in formula-fed term infants: a randomized, double-blind, placebo-controlled trial.
Paineau, D, Respondek, F, Menet, V, Sauvage, R, Bornet, F, Wagner, A
Journal of nutritional science and vitaminology. 2014;(3):167-75
Abstract
The aim of this study was to evaluate the effect of an infant formula supplemented with short-chain fructooligosaccharides (scFOS) on faecal concentration of bifidobacteria. Sixty-one healthy formula-fed infants participated in this double-blind controlled trial and were randomized to receive either the scFOS-supplemented formula (4 g/L scFOS) or the placebo-supplemented formula (4 g/L maltodextrins) until the age of 4 mo. Stool samples were analyzed for bifidobacteria at enrolment and at the age of 2 and 3 mo and for antipoliovirus IgA at the age of 4 mo. Parents completed a questionnaire to assess digestive tolerance. Change in faecal bifidobacteria after 2 mo were higher with scFOS compared to the placebo. At 4 mo, specific IgA tended to be higher with the scFOS group than with the placebo. Somatic growth and digestive tolerance were similar between groups. This study confirms that scFOS-supplemented formula can increase the concentration of faecal bifidobacteria while being well tolerated.
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Galactooligosaccharide supplementation reduces stress-induced gastrointestinal dysfunction and days of cold or flu: a randomized, double-blind, controlled trial in healthy university students.
Hughes, C, Davoodi-Semiromi, Y, Colee, JC, Culpepper, T, Dahl, WJ, Mai, V, Christman, MC, Langkamp-Henken, B
The American journal of clinical nutrition. 2011;(6):1305-11
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Abstract
BACKGROUND Acute psychological stress induced by academic exams is associated with dysregulated gastrointestinal and immune function. OBJECTIVE We examined whether supplementation with galactooligosaccharides reduced gastrointestinal dysfunction and the percentage of days with cold or flu in academically stressed undergraduate students. DESIGN In a randomized, double-blind study, subjects (n = 427) received 0, 2.5, or 5.0 g galactooligosaccharides for 8 wk around the time of fall final exams. Levels of stress and cold or flu symptom intensity (SI; 0 = not experiencing to 3 = severe) were recorded daily. The SI from 9 cold or flu symptoms was summed with 1 d of cold or flu defined as a sum >6. The Gastrointestinal Symptom Response Scale was completed weekly. RESULTS Stress was positively related to diarrhea, indigestion, and reflux syndromes and with abdominal pain, average daily cold or flu SI score, and the percentage of days with cold or flu. Gastrointestinal symptom scores for diarrhea (P = 0.0298), constipation (P = 0.0342), abdominal pain (P = 0.0058), and indigestion (P = 0.0003) syndromes were lower after galactooligosaccharide supplementation. The cold or flu SI score was affected by galactooligosaccharides and stress (P < 0.0001); 2.5 g was associated with a lower SI score across all levels of stress, but 5.0 g was protective only at lower levels of stress. The percentage of days with cold or flu was associated with galactooligosaccharides within different body mass index categories (P = 0.0002), wherein a 40% reduction in the percentage of days with cold or flu was observed in normal-weight individuals with 5.0 g galactooligosaccharides. This effect was not observed in overweight or obese individuals. CONCLUSIONS Acute psychological stress was directly related to symptoms of gastrointestinal dysfunction and cold or flu. Galactooligosaccharide supplementation reduced these symptoms and the number of days with cold or flu. This trial was registered at clinicaltrials.gov as NCT01137760.
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Clinical trial: the microbiological and immunological effects of synbiotic consumption - a randomized double-blind placebo-controlled study in active Crohn's disease.
Steed, H, Macfarlane, GT, Blackett, KL, Bahrami, B, Reynolds, N, Walsh, SV, Cummings, JH, Macfarlane, S
Alimentary pharmacology & therapeutics. 2010;(7):872-83
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Abstract
BACKGROUND Crohn's disease is an inflammatory illness in which the immune response against gut microorganisms is believed to drive an abnormal immune response. Consequently, modification of mucosal bacterial communities, and the immune effects they elicit, might be used to modify the disease state. AIM: To investigate the effects of synbiotic consumption on disease processes in patients with Crohn's disease. METHODS A randomized, double-blind placebo-controlled trial was conducted involving 35 patients with active Crohn's disease, using a synbiotic comprising Bifidobacterium longum and Synergy 1. Clinical status was scored and rectal biopsies were collected at the start, and at 3- and 6-month intervals. Transcription levels of immune markers and mucosal bacterial 16S rRNA gene copy numbers were quantified using real-time PCR. RESULTS Significant improvements in clinical outcomes occurred with synbiotic consumption, with reductions in both Crohn's disease activity indices (P = 0.020) and histological scores (P = 0.018). The synbiotic had little effect on mucosal IL-18, INF-gamma and IL-1beta; however, significant reductions occurred in TNF-alpha expression in synbiotic patients at 3 months (P = 0.041), although not at 6 months. Mucosal bifidobacteria proliferated in synbiotic patients. CONCLUSION Synbiotic consumption was effective in improving clinical symptoms in patients with active Crohn's disease.