Research Interests:

An integral component of human life is peaceful co-habitation with trillions of microbial guests. The densest and most diverse microbial community resides within the gut and examples of its contribution to human physiology include increasing the nutritional value of foods we consume, helping us resist gut pathogens, and by interfacing with and influencing the immune system. To fully harness the gut microbiota to influence human health and disease, researchers and clinicians require a better understanding of, a) how our gut community assembles, b) how it can be manipulated in a targeted fashion, and c) the chemical language by which microbes interact with and influence the host.

The Wesener Lab’s long-term goals are to develop strategies that allow for rational modulation of the gut microbiota and its interactions with the host to promote human health. We are particularly interested in how carbohydrates, from the diet or synthesized by microbes, direct specific interspecies interactions. We blend microbiology, biochemistry, systems biology, and animal models to understand the role of carbohydrates as a nutrient source that alters microbiota function and as a target of host immunoregulatory proteins in the gut.

Research Projects in the Lab:

1. Bacterial carbohydrates as a nutrient that enables interspecies cross-feeding.

Carbohydrates in the gut strongly influence microbiota structure and function by providing a carbon source that supports bacterial growth. Some of this carbon is transformed into a carbohydrate cloak that covers all bacteria and often contains structurally distinct epitopes or monosaccharides. We hypothesize that human gut bacteria have evolved specific machinery to recognize and utilize bacterially-derived carbohydrates, including from probiotic supplements, and that these interspecies interactions guide community assembly and function. Results from this project will help scientists better understand the nutrient landscape of microbial communities and suggest new pre-/probiotic strategies to manipulate the gut microbiota.

2.  Recognition of microbial carbohydrates by host immune receptors.

Increasing evidence suggests that the gut microbiota modulates both local and systemic immune phenotypes that influence clinical outcomes for indications including inflammatory bowel disease (IBS) or response to cancer immunotherapy treatment. The mechanisms and molecular targets that immune cells use to sense microbes and direct a response are still being elucidated. We hypothesize that carbohydrate antigens produced by bacteria in the human gut are targeted by soluble and cell-bound immunoregulatory proteins that influence host homeostasis and disease. Results from this project should provide a mechanistic understanding of how gut microbes interact with the host and may provide new tools to manipulate the immune system.

3. Ingestible chemical probes to study gut biochemistry in vivo.

In vivo quantitative measures of microbiota function are required to better understand host-microbe-diet interactions. We are leveraging chemistry and mass spectrometry to develop microscopic ingestible probes that pass through the gastrointestinal system before being recovered and analyzed. We anticipate using this activity-based technology to define functional differences in microbial communities and to better stratify populations for potential microbiota-targeted or -based therapeutic interventions.

Publications:

Wesener, D.A., Beller, Z.W., Peters, S.L., Rajabi, A., Dimartino G., Giannone R.J., Hettich R.L., Gordon, J.I. Microbiota functional activity biosensors for characterizing nutrient metabolism in vivo. eLife. 2021. 10, e64478.

Wolf, A.R., Wesener, D.A., Cheng, J., & Gordon, J.I., et al. Bioremediation of a common product of food processing by a human gut bacterium. Cell Host Microbe. 2019. 26, 463-477.

Wesener, D.A.*, Levengood, M.R.*, Kiessling L.L. Comparing galactan biosynthesis in Mycobacterium tuberculosis and Corynebacterium diphtheriae. J. Biol. Chem. 2017. 292, 2944-2955.

Wesener, D.A., Wangkanont, K., McBride, R., & Kiessling, L.L., et al. Recognition of microbial glycans by human intelectin-1. Nat. Struct. Mol. Biol. 2015. 22, 603-610.

Wesener, D.A., Dugan, A., Kiessling L.L. Recognition of microbial glycans by soluble human lectins. Curr. Opin. Struct. Biol. 2017. 44, 168-178.

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