Biology subjects

Bode, L.

Publications and source records attributed to Bode, L..

16 recordsLinked to original sources

bioRxiv2026

Maternal diet and genetics shape the human milk metabolome

Human milk contains a diverse array of metabolites that contribute to infant nutrition, immune development, and microbial colonization. The maternal factors shaping the milk metabolome, and the relative contribution of genetics or diet vs. other factors, remain poorly understood. Here, we profiled 458 milk metabolites in 349 one-month postpartum human milk samples and integrated metabolomic data with maternal diet, clinical, transcriptomic, and genomic measurements. Maternal diet was broadly associated with milk metabolite composition, with significant correlations identified between dietary features and 323 metabolites. Coffee consumption strongly predicted milk quinic acid and 1,3-dimethyluric acid abundance, while high-fiber dietary patterns were associated with metabolites including proline-betaine and N-acetylornithine. Integration of milk transcriptomic and metabolomic data via machine learning identified biologically plausible gene-metabolite pairs, including associations between QPRT expression and quinolinic acid, and DPEP1 and cysteine-glycine dipeptide. Genome-wide association analyses identified nine study-wide significant metabolite quantitative trait loci, including novel milk-specific associations near PDE6A affecting purine metabolites and near GNE affecting free sialic acid. Comparison with plasma metabolite studies demonstrated both shared and milk-specific genetic regulation of metabolites. Finally, we found that of all tested maternal features, diet explained the largest proportion of variation in the milk metabolome. Together, these findings demonstrate that the human milk metabolome reflects both maternal exposures and mammary gland-specific biology. This work establishes a framework for understanding how genetic and environmental factors shape milk composition.

genomics↗

bioRxiv2026

Interactions between human milk components and infant polygenic risk predict childhood atopy

BackgroundAlthough human milk (HM) confers important health benefits, how bioactive milk components (e.g., microbiota, oligosaccharides, and fatty acids) interact with infant genetics to influence childhood atopy remains poorly understood. ObjectiveWe investigated interactions between infant genomic susceptibility and exposure to maternal human milk components (HMCs) and assessed whether integrating these genetic and milk features improves prediction of childhood atopy. MethodsLeveraging infant genomic and maternal HMC data from the CHILD Cohort Study, we conducted gene-milk interaction analysis using linear regression models that integrated polygenic risk scores (PRS) of nursing infants with multiple HMC types. Gradient-boosting machines (GBMs) were used to evaluate predictive performance of HMCs and infant PRS for childhood atopy. ResultsChildhood atopy was associated with interactions between infant genomics (e.g., PRS associated with atopy) and exposure to specific human milk microbes (e.g., Abiotrophia, PBonf=0.005, {beta}=0.29), as well as networks of co-occurring HMCs (e.g., a module containing Bifidobacterium longum, 2-fucosyllactose, and eicosapentaenoic acid, P=0.009, {beta}=-12.3). A GBM integrating HMCs and infant PRS achieved the highest predictive performance for childhood atopy with an area under the curve (AUC) of 0.78, outperforming models based on individual HMC types or PRS alone (AUC range: 0.54-0.63). ConclusionIntegration of maternal HMC exposures with infant genomics reveals interaction effects that contribute to prediction of childhood atopy. Understanding how early-life exposures such as HMCs impact the health of children differently depending on their genomic profiles may facilitate the development of personalized intervention strategies to reduce the burden of these health outcomes during childhood. Key messagesO_LIInteractions between infant polygenic risk and exposure to human milk components are associated with childhood atopy. C_LIO_LINetworks of co-occurring human milk microbiota, oligosaccharides, and fatty acids may influence childhood atopy, with effects varying by infant genomic susceptibility. C_LIO_LIIntegration of human milk components with infant genomics improves prediction of childhood atopy compared with individual milk components or genomics alone. C_LI Capsule SummaryThis study demonstrates that interactions between infant polygenic risk and maternal milk components improve prediction of childhood atopy, highlighting opportunities for personalized early-life prevention strategies.

genomics↗

bioRxiv2025

Human milk components interact with infant genomics to modulate gut microbiota, childhood asthma and atopy

The benefits of breastfeeding are well established; however, the mechanisms by which human milk components (HMCs) impact childrens long-term health remain poorly understood. We leveraged datasets from the CHILD Cohort Study to explore how exposure to variable HMCs-- including oligosaccharides (HMOs), fatty acids (HMFAs), and microbiota (HMM)--may influence infants gut microbiota and risk of childhood asthma and atopy. We identified HMCs (e.g., HMO lacto-N-fucopentaose III and HMFA linoleic acid) associated with gut microbes and microbial networks implicated in atopic diseases. Additionally, we determined that HMCs (e.g., HMM Pseudomonas oryzihabitans) interact with infants polygenic risk scores (PRSs) to influence these gut microbial features. Integration of HMCs, gut microbiota, and disease-associated PRSs into an unsupervised machine-learning model that clustered two groups of infants with differing disease prevalence. Our findings suggest that HMCs influence childhood asthma and atopy through modifications to the gut microbiota and modulated by interactions with infant genomics.

genomics↗

bioRxiv2025

Environmental and Maternal Imprints on Infant Gut Metabolic Programming

Early life is a critical period for immune and metabolic programming, but developmental patterns remain underexplored in populations from low- and middle-income countries. Here, we profiled the microbiome and metabolome of 55 Bangladeshi mother-infant dyads over the first six months of life. Importantly, we observed an increase in microbially-derived bile amidates and N-acyl lipids with age in conjunction with reads matching the bile salt hydrolase/transferase (bsh) gene. While microbial source tracking confirmed maternal fecal seeding, a substantial environmental contribution was also highlighted. Differences in infant fecal metabolic profiles were associated with delivery mode, maternal milk composition, household assets, and household-level water treatment. C-section delivery and untreated drinking water were linked to transient metabolic differences, including increases in bile amidates, N-acyl lipids, and other host-microbe co-metabolic products, including acylcarnitines. Multi-omics analysis revealed specific microbial-metabolite relationships, highlighting how early environmental and maternal living circumstances shape metabolic gut programming through the microbiome.

microbiology↗

bioRxiv2025

Integrated omics analysis reveals human milk oligosaccharide biosynthesis programs in human lactocytes

Human milk oligosaccharides (HMOs) are integral to infant health. Yet, their complex biosynthesis pathways in the mammary gland during lactation remain under characterized. To address this knowledge gap, we performed integrated analyses of single-cell RNA-sequencing (scRNA-seq) datasets combined with select HMO concentration measures. We identify differential expression patterns of known HMO synthesis genes in epithelial subsets and nominate several candidate genes that vary with HMO concentration. Additionally, we identify novel gene patterns and transcription factors that may regulate the expression of HMO biosynthesis genes and the cellular pathways supporting HMO production. Finally, we demonstrate that co-expression of HMO synthesis genes and milk fat synthesis genes is limited, suggesting distinct epithelial cell subtypes may be responsible for the production of different milk components. Our study suggests that HMO synthesis may be achieved through cell type specialization within the lactocyte compartment.

systems biology↗

bioRxiv2024

The microbiome diversifies N-acyl lipid pools - including short-chain fatty acid-derived compounds

N-acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N-acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N-acyl lipid patterns from 2,700 public datasets, identifying 851 N-acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N-acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery.

bioinformatics↗

bioRxiv2024

Integrative genomic reconstruction of carbohydrate utilization networks in bifidobacteria: global trends, local variability, and dietary adaptation

Bifidobacteria are among the earliest colonizers of the human gut and are widely used as probiotics for their health-promoting properties. However, individual responses to probiotic supplementation may vary with strain type(s), microbiota composition, diet, or lifestyle conditions, highlighting the need for strain-level insights into the bifidobacterial metabolism of dietary and host glycans. Here, we systematically reconstructed 68 pathways involved in the utilization of mono-, di-, oligo-, and polysaccharides by analyzing the distribution of 589 curated metabolic functional roles (catabolic enzymes, transporters, transcriptional regulators) in 3083 non-redundant cultured Bifidobacterium isolates and metagenome-assembled genomes (MAGs) of human origin. Our analysis uncovered extensive inter- and intraspecies heterogeneity, including a distinct clade within the Bifidobacterium longum species capable of metabolizing -glucans. We also identified isolates of Bangladeshi origin that harbor unique gene clusters implicated in the breakdown of xyloglucan and human milk oligosaccharides. Thirty-eight predicted carbohydrate utilization phenotypes were experimentally validated in 30 geographically diverse Bifidobacterium isolates in vitro. Our large-scale genomic compendium expands the knowledge of bifidobacterial carbohydrate metabolism and can inform the rational design of probiotic and synbiotic formulations tailored to strain-specific nutrient preferences.

microbiology↗

bioRxiv2024

2'-Fucosyllactose Inhibits Human Norovirus Replication in Human Intestinal Enteroids

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide. Currently, there are no targeted antivirals for the treatment of HuNoV infection. Histo-blood group antigens (HBGAs) on the intestinal epithelium are cellular attachment factors for HuNoVs; molecules that block the binding of HuNoVs to HBGAs thus have the potential to be developed as antivirals. Human milk oligosaccharides (HMOs) are glycans in human milk with structures analogous to HBGAs. HMOs have been shown to act as decoy receptors to prevent the attachment of multiple enteric pathogens to host cells. Previous X-ray crystallography studies have demonstrated the binding of HMO 2-fucosyllactose (2FL) in the same pocket as HBGAs for some HuNoV strains. We evaluated the effect of 2FL on the replication of a globally dominant GII.4 Sydney [P16] HuNoV strain using human intestinal enteroids (HIEs) from adults and children. A significant reduction in GII.4 Sydney [P16] replication was seen in duodenal and jejunal HIEs from multiple adult donors, all segments of the small intestine from an adult organ donor and in two pediatric duodenal HIEs. However, 2FL did not inhibit HuNoV replication in two infant jejunal HIEs that had significantly lower expression of 1-2-fucosylated glycans. 2FL can be synthesized in large scale, and safety and tolerance have been assessed previously. Our data suggest that 2FL has the potential to be developed as a therapeutic for HuNoV gastroenteritis. IMPORTANCEHuman noroviruses infect the gastrointestinal tract and are a leading cause of acute gastroenteritis worldwide. Common symptoms of norovirus include diarrhea, vomiting and stomach cramps. Virus shedding and symptoms are prolonged and debilitating in immunocompromised patients. Currently, there are no approved vaccines or targeted antivirals for treating human norovirus infection. Human intestinal enteroids derived from intestinal stem cells allow the successful replication of norovirus in the laboratory and can be used as a physiologically relevant model system to evaluate antivirals. We discovered that 2fucosyllactose (2FL), an oligosaccharide naturally occurring in human milk, inhibits norovirus replication in HIEs from multiple donors and thus has the potential to be developed as a therapeutic for human norovirus. These findings have high translational potential since 2FL from several manufacturers have GRAS (generally recognized as safe) status and can be synthesized on a large scale for immediate application.

microbiology↗

bioRxiv2023

A bacterial sialidase mediates early life colonization by a pioneering gut commensal

The early microbial colonization of the gastrointestinal tract can lead to long-term impacts in development and overall human health. Keystone species, including Bacteroides spp., play a crucial role in maintaining the structure, diversity, and function of the intestinal ecosystem. However, the process by which a defined and resilient community is curated and maintained during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa and regulates the commensal colonization program during the first weeks of life. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. After examining the dynamics between pioneer gut Bacteroides species in the murine gut, we discovered that NanH enables vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, we demonstrate that NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and the microbiota mediated through host-derived glycans to promote stable intestinal colonization.

microbiology↗

bioRxiv2023

Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome

Human milk is a complex mix of nutritional and bioactive components that provide complete nutrition for the infant. However, we lack a systematic knowledge of the factors shaping milk composition and how milk variation influences infant health. Here, we used multi-omic profiling to characterize interactions between maternal genetics, milk gene expression, milk composition, and the infant fecal microbiome in 242 exclusively breastfeeding mother-infant pairs. We identified 487 genetic loci associated with milk gene expression unique to the lactating mammary gland, including loci that impacted breast cancer risk and human milk oligosaccharide concentration. Integrative analyses uncovered connections between milk gene expression and infant gut microbiome, including an association between the expression of inflammation-related genes with IL-6 concentration in milk and the abundance of Bifidobacteria in the infant gut. Our results show how an improved understanding of the genetics and genomics of human milk connects lactation biology with maternal and infant health.

genomics↗

bioRxiv2021

Human milk oligosaccharides reduce murine group B Streptococcus vaginal colonization with minimal impact on the vaginal microbiota

Group B Streptococcus (GBS) colonizes the vaginal mucosa of a significant percentage of healthy women and is a leading cause of neonatal bacterial infections. Currently, pregnant women are screened in the last month of pregnancy and GBS-positive women are given antibiotics during parturition to prevent bacterial transmission to the neonate. Recently, human milk oligosaccharides (HMOs) isolated from breastmilk were found to inhibit GBS growth and biofilm formation in vitro, and women that make certain HMOs are less likely to be vaginally colonized with GBS. Using in vitro human vaginal epithelial cells and a murine vaginal colonization model, we tested the impact of HMO treatment on GBS burdens and the composition of the endogenous microbiota by 16S rRNA amplicon sequencing. HMO treatment reduced GBS vaginal burdens in vivo with minimal alterations to the vaginal microbiota. HMOs displayed potent inhibitory activity against GBS in vitro, but HMO pretreatment did not alter adherence of GBS or the probiotic Lactobacillus rhamnosus to human vaginal epithelial cells. Additionally, disruption of a putative GBS glycosyltransferase ({Delta}san_0913) rendered the bacterium largely resistant to HMO inhibition in vitro and in vivo but did not compromise its adherence, colonization, or biofilm formation in the absence of HMOs. We conclude that HMOs are a promising therapeutic bioactive to limit GBS vaginal colonization with minimal impacts on the vaginal microenvironment. IMPORTANCEDuring pregnancy, GBS ascension into the uterus can cause fetal infection or preterm birth. Additionally, GBS exposure during labor creates a risk of serious disease in the vulnerable newborn and mother postpartum. Current recommended prophylaxis consists of administering broad-spectrum antibiotics to GBS-positive mothers during labor. Although antibiotics have significantly reduced GBS neonatal disease, there are several unintended consequences including altered neonatal gut bacteria and increased risk for other types of infection. Innovative preventions displaying more targeted antimicrobial activity, while leaving the maternal microbiota intact, are thus appealing. Using a mouse model, we found that human milk oligosaccharides (HMOs) reduce GBS burdens without perturbing the vaginal microbiota. We conclude that HMOs are a promising alternative to antibiotics to reduce GBS neonatal disease.

microbiology↗

bioRxiv2021

The Human Milk Oligosaccharide 3-Sialyllactose Promotes Inflammation Resolution and Reduces Atherosclerosis Development in Mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in the chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3sialyllactose (3SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3SL attenuates a selected set of inflammatory gene expression and promotes activity of LXR and SREBP. These acute anti-inflammatory effects of 3SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CTCF, IRF2, BCL6, and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

immunology↗

bioRxiv2020

Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multi-omics integration

AO_SCPLOWBSTRACTC_SCPLOWHuman Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we used a systems biology framework that integrated glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we constructed models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. We further explored selected enzyme activities through kinetic assay and their co-regulation through transcription factor analysis. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the ultimate goal of understanding and improving infant health and development. SO_SCPLOWIGNIFICANCEC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWSTATEMENTC_SCPLOWWith the HMO biosynthesis network resolved, we can begin to connect genotypes with milk types and thereby connect clinical infant, child and even adult outcomes to specific HMOs and HMO modifications. Knowledge of these pathways can simplify the work of synthetic reproduction of these HMOs providing a roadmap for improving infant, child, and overall human health with the specific application of a newly limitless source of nutraceuticals for infants and people of all ages.

systems biology↗

bioRxiv2020

Mucin-derived O-glycans supplemented to diet mitigate diverse microbiota perturbations

Microbiota-accessible carbohydrates (MACs) are powerful modulators of microbiota composition and function. These substrates are often derived from diet, such as complex polysaccharides from plants or human milk oligosaccharides (HMOs) during breastfeeding. Host-derived mucus glycans on gut-secreted mucin proteins may serve as a continuous endogenous source of MACs for resident microbes; here we investigate the potential role of purified, orally-administered mucus glycans in maintaining a healthy microbial community. In this study, we liberated and purified O-linked glycans from porcine gastric mucin and assessed their efficacy in shaping the recovery of a perturbed microbiota in a mouse model. We found that porcine mucin glycans (PMGs) and HMOs enrich for taxonomically similar resident microbes. We demonstrate that PMGs aid recovery of the microbiota after antibiotic treatment, suppress C. difficile abundance, delay the onset of diet-induced obesity, and increase relative abundance of resident Akkermansia muciniphila. In silico analysis revealed that genes associated with mucus utilization are abundant and diverse in prevalent gut commensals and rare in enteric pathogens, consistent with these glycan-degrading capabilities being selected for during host development and throughout evolution of the host-microbe relationship. Importantly, we identify mucus glycans as a novel class of prebiotic compounds that can be used to mitigate perturbations to the microbiota and provide benefits to host physiology.

microbiology↗

bioRxiv2020

Microbiota control of maternal behavior regulates early postnatal growth of offspring

Maternal-offspring bonding and maturation of maternal behavior is necessary during the early postnatal period of an infant to promote optimal development and growth. The regulation of maternal behavior is multifactorial relying both on sensory cues including auditory and olfactory signals emitted by the infant and received by the mother, as well as proper neuroendocrine responses including that of the oxytocin system. The intestinal microbiota has emerged as a critical regulator of growth and development in the early postnatal period of an individual’s life. While, this is best appreciated in the context of direct interactions between the microbiota and the infant, the microbiota can indirectly influence postnatal growth and development by regulating maternal factors. Here, we describe the identification of an intestinal E. coli strain that is pathogenic to the maternal-offspring system during the early postnatal stage of life and results in growth stunting of the offspring. However, rather than having a direct pathogenic effect on the infant, we found that this particular E. coli strain was pathogenic to the dams by interfering with the maturation of maternal behavior. The poor maternal behavior resulted in malnourishment of the pups and impaired IGF-1 signaling leading to the consequential stunted growth. Our work provides a new understanding of how the microbiota regulates postnatal growth and an additional variable that must be considered when studying the regulation of maternal behavior.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

Correcting for sparsity and non-independence in glycomic data through a system biology framework

Glycans are fundamental cellular building blocks, involved in many organismal functions. Advances in glycomics are elucidating the roles of glycans, but it remains challenging to properly analyze large glycomics datasets, since the data are sparse (each sample often has only a few measured glycans) and detected glycans are non-independent (sharing many intermediate biosynthetic steps). We address these challenges with GlyCompare, a glycomic data analysis approach that leverages shared biosynthetic pathway intermediates to correct for sparsity and non-independence in glycomics. Specifically, quantities of measured glycans are propagated to intermediate glycan substructures, which enables direct comparison of different glycoprofiles and increases statistical power. Using GlyCompare, we studied diverse N-glycan profiles from glycoengineered erythropoietin. We obtained biologically meaningful clustering of mutant cell glycoprofiles and identified knockout-specific effects of fucosyltransferase mutants on tetra-antennary structures. We further analyzed human milk oligosaccharide profiles and identified novel impacts that the mothers secretor-status on fucosylation and sialylation. Our substructure-oriented approach will enable researchers to take full advantage of the growing power and size of glycomics data.

systems biology↗