Biology subjects

Bode, L.

Publications and source records attributed to Bode, L..

4 recordsLinked to original sources

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↗