The human gut microbiota provides physiologic attributes that we have not had to evolve on our own, including the ability to process otherwise indigestible dietary glycans. Bacteroides thetaiotaomicron {B. theta) and Bacteroides ovatus, two members of the microbiota, have diverse but only partially overlapping abilities to process dietary and host-derived glycans - evolved features that likely influence their fitness in the crowded gut ecosystem. At least one of these organisms, 6. f/iefa, prioritizes metabolism of plant pectic glycans over host mucin glycans, suggesting that it has evolved to avoid using the host mucosa as a nutrient base when dietary glycans are abundant. I will define and compare the carbohydrate utilization hierarchies of these two species to determine if they evolved the same or different priorities. Moreover, I will explore the molecular mechanisms that underlie glycan prioritization in B. tfieta, allowing me to test the fitness value of this phenomenon in vivo in the gnotobiotic mouse gut. I will also explore the mechanisms through which 6. ovatus targets the abundant and sometimes less soluble hemicellulose class of plant cell wall glycans, a group of substrates that B. theta is not able to metabolize. Deletion of hemicellulose utilization genes from the S. ovatus genome followed by in vivo competition of the resulting hemicellulose-deficient mutants with their isogenic parents, will reveal if expression of these phenotypes provides a fitness advantage or disadvantage in gnotobiotic mice fed a diet rich in these substrates. Finally, I will explore the possibility that glycan utilization phenotypes can be laterally transferred between Bacteroides species, a phenomenon that our data suggest occurs naturally. Support of this hypothesis will yield fundamental mechanistic information about genomic evolution of glycan utilization among microbiota bacteria. My current training environment, Jeffrey Gordon's lab at Washington University Medical School, provides a unique place to begin this research and may be the only lab in the world equipped with all of the necessary tools to answer the experimental questions at hand. My career development plan includes building a robust research foundation in the Gordon lab and transitioning into an independent career as a tenure track Assistant Professor. The experimental and professional training achieved during this mentored research proposal will provide the experience I need to be successful on my own.

Public Health Relevance

Human gut bacteria are essential for the transformation of complex dietary polysaccharides, many of which we cannot digest on our own, into forms that we readily absorb. I will characterize the dynamic interrelationships between abundant plant glycans that enter our diets and the physiology and evolution of our gut bacteria. The results will reveal which dietary glycans bacteria 'can'metabolize and which ones they 'want'to metabolize, providing new knowledge about how our gut microbiota harvests dietary nutrients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Pudlo, Nicholas A; Urs, Karthik; Kumar, Supriya Suresh et al. (2015) Symbiotic Human Gut Bacteria with Variable Metabolic Priorities for Host Mucosal Glycans. MBio 6:e01282-15
Abbott, D Wade; Martens, Eric C; Gilbert, Harry J et al. (2015) Coevolution of yeast mannan digestion: Convergence of the civilized human diet, distal gut microbiome, and host immunity. Gut Microbes 6:334-9
Martens, Eric C; Kelly, Amelia G; Tauzin, Alexandra S et al. (2014) The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes. J Mol Biol 426:3851-65
Cameron, Elizabeth A; Kwiatkowski, Kurt J; Lee, Byung-Hoo et al. (2014) Multifunctional nutrient-binding proteins adapt human symbiotic bacteria for glycan competition in the gut by separately promoting enhanced sensing and catalysis. MBio 5:e01441-14
Larsbrink, Johan; Rogers, Theresa E; Hemsworth, Glyn R et al. (2014) A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes. Nature 506:498-502
Rogers, Theresa E; Pudlo, Nicholas A; Koropatkin, Nicole M et al. (2013) Dynamic responses of Bacteroides thetaiotaomicron during growth on glycan mixtures. Mol Microbiol 88:876-90
Hehemann, Jan-Hendrik; Kelly, Amelia G; Pudlo, Nicholas A et al. (2012) Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes. Proc Natl Acad Sci U S A 109:19786-91
Cameron, Elizabeth A; Maynard, Mallory A; Smith, Christopher J et al. (2012) Multidomain Carbohydrate-binding Proteins Involved in Bacteroides thetaiotaomicron Starch Metabolism. J Biol Chem 287:34614-25
Koropatkin, Nicole M; Cameron, Elizabeth A; Martens, Eric C (2012) How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol 10:323-35
Marcobal, Angela; Barboza, Mariana; Sonnenburg, Erica D et al. (2011) Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe 10:507-14

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