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Translating neonatal microbiome science into commercial innovation: metabolism of human milk oligosaccharides as a basis for probiotic efficacy in breast-fed infants.
Mills, DA, German, JB, Lebrilla, CB, Underwood, MA
Gut microbes. 2023;(1):2192458
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Abstract
For over a century, physicians have witnessed a common enrichment of bifidobacteria in the feces of breast-fed infants that was readily associated with infant health status. Recent advances in bacterial genomics, metagenomics, and glycomics have helped explain the nature of this unique enrichment and enabled the tailored use of probiotic supplementation to restore missing bifidobacterial functions in at-risk infants. This review documents a 20-year span of discoveries that set the stage for the current use of human milk oligosaccharide-consuming bifidobacteria to beneficially colonize, modulate, and protect the intestines of at-risk, human milk-fed, neonates. This review also presents a model for probiotic applications wherein bifidobacterial functions, in the form of colonization and HMO-related catabolic activity in situ, represent measurable metabolic outcomes by which probiotic efficacy can be scored toward improving infant health.
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Milk: A Scientific Model for Diet and Health Research in the 21st Century.
German, JB, Lebrilla, C, Mills, DA
Frontiers in nutrition. 2022;:922907
Abstract
The origin of lactation and the composition, structures and functions of milk's biopolymers highlight the Darwinian pressure on lactation as a complete, nourishing and protective diet. Lactation, under the driving pressure to be a sustainable bioreactor, was under selection pressure of its biopolymers with diverse functions acting from the mammary gland through the digestive system of the infant. For example, milk is extensively glycosylated and the glycan structures and their functions are now emerging. Milk contains free oligosaccharides; complex polymers of sugars whose stereospecific linkages are not matched by glycosidic enzymes within the mammalian infant gut. These glycan polymers reach the lower intestine undigested. In this microbe-rich environment, bacteria compete to release and ferment the sugars via different hydrolytic strategies. One specific type of bacteria, Bifidobacterium longum subsp. infantis, (B. infantis) is uniquely equipped with a repertoire of genes encoding enzymes capable of taking up, hydrolyzing and metabolizing the complex glycans of human milk. This combination of a distinct food supply and unique genetic capability shapes the composition and metabolic products of the entire microbial community within the lower intestine of breast fed infants. The intestinal microbiome dominated by B. infantis, shields the infant from the growth of gram negative enteropathogens and their endotoxins as a clear health benefit. The world is facing unprecedented challenges to produce a food supply that is both nourishing, safe and sustainable. Scientists need to guide the future of agriculture and food in response to these 21st century challenges. Lactation provides an inspiring model of what that future research strategy could be.
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Effects of a Novel High-Quality Protein Infant Formula on Energetic Efficiency and Tolerance: A Randomized Trial.
Kuehn, D, Zeisel, SH, Orenstein, DF, German, JB, Field, CJ, Teerdhala, S, Knezevic, A, Patil, S, Donovan, SM, Lönnerdal, B
Journal of pediatric gastroenterology and nutrition. 2022;(4):521-528
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Abstract
OBJECTIVES Protein overfeeding in infants can have negative effects, such as diabetes and childhood obesity; key to reducing protein intake from formula is improving protein quality. The impact of a new infant formula [study formula (SF)] containing alpha-lactalbumin, lactoferrin, partially hydrolyzed whey, and whole milk on growth and tolerance compared to a commercial formula (CF) and a human milk reference arm was evaluated. METHODS This randomized, double-blind trial included healthy, singleton, term infants, enrollment age ≤14 days. Primary outcome was mean daily weight gain. Secondary outcomes were anthropometrics, formula intake, serum amino acids, adverse events, gastrointestinal characteristics, and general disposition. RESULTS Non-inferiority was demonstrated. There were no differences between the formula groups for z scores over time. Formula intake [-0.33 oz/kg/day, 95% confidence interval (CI): -0.66 to -0.01, P = 0.05] and mean protein intake (-0.13 g/kg/day, 95% CI: -0.26 to 0.00, P = 0.05) were lower in the SF infants, with higher serum essential amino acid concentrations (including tryptophan) compared to the CF infants. Energetic efficiency was 14.0% (95% CI: 8.3%, 19.7%), 13.0% (95% CI: 6.0%, 20.0%), and 18.1% (95% CI: 9.4%, 26.8%) higher for weight, length, and head circumference, respectively, in SF infants compared to the CF infants. SF infants had significantly fewer spit-ups and softer stool consistency than CF infants. CONCLUSIONS The SF resulted in improved parent-reported gastrointestinal tolerance and more efficient growth with less daily formula and protein intake supporting that this novel formula may potentially reduce the metabolic burden of protein overfeeding associated with infant formula.
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Bifidobacteria-mediated immune system imprinting early in life.
Henrick, BM, Rodriguez, L, Lakshmikanth, T, Pou, C, Henckel, E, Arzoomand, A, Olin, A, Wang, J, Mikes, J, Tan, Z, et al
Cell. 2021;(15):3884-3898.e11
Abstract
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients to specialized microbes that in turn benefit the host's immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon β (IFNβ) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.
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Helping Mom Help Baby: Nutrition-Based Support for the Mother-Infant Dyad During Lactation.
Ford, EL, Underwood, MA, German, JB
Frontiers in nutrition. 2020;:54
Abstract
Lactation and breastfeeding support the short- and long-term health of both mother and infant, yet the success of these processes depend upon individual and combined factors of the pair. Complications during pregnancy and delivery greatly affect the likelihood that a mother will be capable of breastfeeding for at least the recommended 6 months. Guidelines for women regarding postpartum diet and lifestyle management also fail to reflect the diversity of mother-infant pairs and their circumstances. In our analysis of the literature, we have identified a categorical deficit in modern scientific discourse regarding human lactation; namely, that postpartum involves full-body contribution of resources and thus requires the application of nutrition from a systemic perspective.
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Dietary Considerations in Autism Spectrum Disorders: The Potential Role of Protein Digestion and Microbial Putrefaction in the Gut-Brain Axis.
Sanctuary, MR, Kain, JN, Angkustsiri, K, German, JB
Frontiers in nutrition. 2018;5:40
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Children with autism spectrum disorder (ASD) display high incidence of gastrointestinal (GI) co-morbidities. Growing evidence now shows an association between diet and ASD, demonstrating that impaired gut function may worsen both GI and behavioural symptoms associated with ASD. The aim of this review was to examine the existing literature to further understand the connection between gut structure and function and ASD. This review found children with ASD and gut co-morbidities exhibit poor protein digestion, impaired gut-barrier integrity and a compromised gut microbiome. A potential mechanistic explanation is that the elevated level of undigested proteins is negatively affecting the integrity of the gut. Based on these findings, the authors conclude it is urgent to perform more experimental and clinical research on the “fragile gut” in children with ASD in order to move towards advancements in individualised clinical practice.
Abstract
Children with autism spectrum disorders (ASD), characterized by a range of behavioral abnormalities and social deficits, display high incidence of gastrointestinal (GI) co-morbidities including chronic constipation and diarrhea. Research is now increasingly able to characterize the "fragile gut" in these children and understand the role that impairment of specific GI functions plays in the GI symptoms associated with ASD. This mechanistic understanding is extending to the interactions between diet and ASD, including food structure and protein digestive capacity in exacerbating autistic symptoms. Children with ASD and gut co-morbidities exhibit low digestive enzyme activity, impaired gut barrier integrity and the presence of antibodies specific for dietary proteins in the peripheral circulation. These findings support the hypothesis that entry of dietary peptides from the gut lumen into the vasculature are associated with an aberrant immune response. Furthermore, a subset of children with ASD exhibit high concentrations of metabolites originating from microbial activity on proteinaceous substrates. Taken together, the combination of specific protein intakes poor digestion, gut barrier integrity, microbiota composition and function all on a background of ASD represents a phenotypic pattern. A potential consequence of this pattern of conditions is that the fragile gut of some children with ASD is at risk for GI symptoms that may be amenable to improvement with specific dietary changes. There is growing evidence that shows an association between gut dysfunction and dysbiosis and ASD symptoms. It is therefore urgent to perform more experimental and clinical research on the "fragile gut" in children with ASD in order to move toward advancements in clinical practice. Identifying those factors that are of clinical value will provide an evidence-based path to individual management and targeted solutions; from real time sensing to the design of diets with personalized protein source/processing, all to improve GI function in children with ASD.
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Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.
Smith, CE, Follis, JL, Dashti, HS, Tanaka, T, Graff, M, Fretts, AM, Kilpeläinen, TO, Wojczynski, MK, Richardson, K, Nalls, MA, et al
Molecular nutrition & food research. 2018;(3)
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Abstract
SCOPE Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. METHODS AND RESULTS A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. CONCLUSION Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
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Enzymes in Human Milk.
Dallas, DC, German, JB
Nestle Nutrition Institute workshop series. 2017;:129-136
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Abstract
Milk proteins are a complex and diverse source of biological activities. Beyond their function, intact milk proteins also act as carriers of encrypted functional sequences that, when released as peptides, exert biological functions, including antimicrobial and immunomodulatory activity, which could contribute to the infant's competitive success. Research has now revealed that the release of these functional peptides begins within the mammary gland itself. A complex array of proteases produced in mother's milk has been shown to be active in the milk, releasing these peptides. Moreover, our recent research demonstrates that these milk proteases continue to digest milk proteins within the infant's stomach, possibly even to a larger extent than the infant's own proteases. As the neonate has relatively low digestive capacity, the activity of milk proteases in the infant may provide important assistance to digesting milk proteins. The coordinated release of these encrypted sequences is accomplished by selective proteolytic action provided by an array of native milk proteases and infant-produced enzymes. The task for scientists is now to discover the selective advantages of this protein-protease-based peptide release system.
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Consumption of a high-fat meal containing cheese compared with a vegan alternative lowers postprandial C-reactive protein in overweight and obese individuals with metabolic abnormalities: a randomised controlled cross-over study.
Demmer, E, Van Loan, MD, Rivera, N, Rogers, TS, Gertz, ER, German, JB, Zivkovic, AM, Smilowitz, JT
Journal of nutritional science. 2016;5:e9
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One independent risk factor for cardiovascular disease (CVD) is postprandial inflammation i.e. inflammation in the hours immediately following a meal. The aim of this study was to determine the effects of consuming two mixed isoenergetic meals high in saturated fat from cheese compared with a non-dairy cheese alternative plus palm oil on postprandial inflammatory and metabolic markers. The study is a randomised, cross-over trial in which investigators were blind to treatment order. All participants received both treatments. Treatment order was randomly assigned using a random allocation sequence generator. Results show that more than half (55 %) of the measured serum inflammatory markers significantly changed over the 6 h postprandial period from baseline. After calculating the total concentration of each inflammatory marker (over the 6 h postprandial time), only C-reactive protein was different between the two test meals. Authors conclude that while dietary recommendations encourage a decreased consumption of saturated fat to minimise CVD risk, saturated fat in the form of cheese lowers postprandial inflammation compared with plant sources of saturated fat.
Abstract
Dietary recommendations suggest decreased consumption of SFA to minimise CVD risk; however, not all foods rich in SFA are equivalent. To evaluate the effects of SFA in a dairy food matrix, as Cheddar cheese, v. SFA from a vegan-alternative test meal on postprandial inflammatory markers, a randomised controlled cross-over trial was conducted in twenty overweight or obese adults with metabolic abnormalities. Individuals consumed two isoenergetic high-fat mixed meals separated by a 1- to 2-week washout period. Serum was collected at baseline, and at 1, 3 and 6 h postprandially and analysed for inflammatory markers (IL-6, IL-8, IL-10, IL-17, IL-18, TNFα, monocyte chemotactic protein-1 (MCP-1)), acute-phase proteins C-reactive protein (CRP) and serum amyloid-A (SAA), cellular adhesion molecules and blood lipids, glucose and insulin. Following both high-fat test meals, postprandial TAG concentrations rose steadily (P < 0·05) without a decrease by 6 h. The incremental AUC (iAUC) for CRP was significantly lower (P < 0·05) in response to the cheese compared with the vegan-alternative test meal. A treatment effect was not observed for any other inflammatory markers; however, for both test meals, multiple markers significantly changed from baseline over the 6 h postprandial period (IL-6, IL-8, IL-18, TNFα, MCP-1, SAA). Saturated fat in the form of a cheese matrix reduced the iAUC for CRP compared with a vegan-alternative test meal during the postprandial 6 h period. The study is registered at clinicaltrials.gov under NCT01803633.
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Addition of a dairy fraction rich in milk fat globule membrane to a high-saturated fat meal reduces the postprandial insulinaemic and inflammatory response in overweight and obese adults.
Demmer, E, Van Loan, MD, Rivera, N, Rogers, TS, Gertz, ER, German, JB, Smilowitz, JT, Zivkovic, AM
Journal of nutritional science. 2016;:e14
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Meals high in SFA, particularly palmitate, are associated with postprandial inflammation and insulin resistance. Milk fat globule membrane (MFGM) has anti-inflammatory properties that may attenuate the negative effects of SFA-rich meals. Our objective was to examine the postprandial metabolic and inflammatory response to a high-fat meal composed of palm oil (PO) compared with PO with an added dairy fraction rich in MFGM (PO+MFGM) in overweight and obese men and women (n 36) in a randomised, double-blinded, cross-over trial. Participants consumed two isoenergetic high-fat meals composed of a smoothie enriched with PO with v. without a cream-derived complex milk lipid fraction ( dairy fraction rich in MFGM) separated by a washout of 1-2 weeks. Serum cytokines, adhesion molecules, cortisol and markers of inflammation were measured at fasting, and at 1, 3 and 6 h postprandially. Glucose, insulin and lipid profiles were analysed in plasma. Consumption of the PO + MFGM v. PO meal resulted in lower total cholesterol (P = 0·021), LDL-cholesterol (P = 0·046), soluble intracellular adhesion molecule (P = 0·005) and insulin (P = 0·005) incremental AUC, and increased IL-10 (P = 0·013). Individuals with high baseline C-reactive protein (CRP) concentrations (≥3 mg/l, n 17) had higher (P = 0·030) insulin at 1 h after the PO meal than individuals with CRP concentrations <3 mg/l (n 19). The addition of MFGM attenuated this difference between CRP groups. The addition of a dairy fraction rich in MFGM attenuated the negative effects of a high-SFA meal by reducing postprandial cholesterol, inflammatory markers and insulin response in overweight and obese individuals, particularly in those with elevated CRP.