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The Impact of Human Milk Oligosaccharides on the Gut Microbiota of Infants at Risk of Type 1 Diabetes

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Title: The Impact of Human Milk Oligosaccharides on the Gut Microbiota of Infants at Risk of Type 1 Diabetes
Author: Renwick, Simone
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Allen-Vercoe, Emma
Abstract: Shifts in gut microbiota composition have been widely associated with development of type 1 diabetes (T1D), although no T1D-promoting species have been consistently identified. Consequently, the functional output of the gut microbiota may be more predictive of T1D progression than its composition. Human milk oligosaccharides (HMOs), which are undigestible, complex carbohydrates, are suspected of having anti-diabetic properties. However, the ability of HMOs to modulate the T1D-associated infant gut microbiota has yet to be characterized. As such, this thesis sought to investigate two hypotheses: (1) the metabolic output of the gut microbiota of T1D-progressors can be distinguished from that of healthy controls; and (2) HMOs can be used to induce beneficial changes to the composition and function of the T1D-associated gut microbiota. To address these hypotheses, the composition and function of microbial communities representing the gut microbiota of three T1D-progressors and four healthy controls were characterized using mutli-omics tools following single treatments with pooled HMOs (pHMOs) and 2’fucosyllactose (2’FL), the most common HMO structure used to fortify infant formula. The growth responses of pure cultures of 330 bacterial strains isolated from these communities were also assessed following exposure to pHMOs. Lastly, the HMO structure preferences of the communities and strains were determined. Several T1D-associated taxonomic and functional features were identified, including lower levels of several short-chain fatty acids (SCFAs) and increased secretion of Alistipes-derived lipopolysaccharide (LPS). Although communities treated with pHMOs displayed only mild changes in composition compared to controls, significantly higher concentrations of health-associated metabolites, including various SCFAs, were observed. In contrast, 2’FL continuously yielded results similar to controls. HMOs interacted with a wider diversity of non-Bifidobacterium species grown axenically than was previously known. Tested strains displayed a range of HMO structure-based specificities, although a large amount of strain-level heterogeneity was observed in growth responses and structure preferences. Furthermore, strains exhibited differing growth responses to pHMOs depending on culture conditions (monoculture vs. community). Finally, no significant differences were observed in the types of HMO structures utilized by T1D-progressor and healthy communities or strains. Overall, this study has considerably expanded our knowledge of the interactions between the T1D-gut microbiota and HMOs.
Date: 2022
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Embargoed Until: 2022-10-01

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