What we eat greatly influences how we function and affects our propensity to get diseases such as obesity and diabetes. A major goal of Biomedical Research is to uncover which nutrients and metabolites affect our physiology on the one hand and, which of our genes mediate the physiological response to these molecules on the other. We have recently developed an innovative interspecies systems biology model of the nematode C. elegans and its bacterial diet to address these questions. We have used this model to uncover bacterially derived micronutrients and metabolites that affect gene expression, development and fertility in the worm, and to identify a C. elegans metabolic regulatory network that mediates the response to bacterial nutrients. The effects of different bacteria (and their molecules) are mediated via the animal's intestine, which functions as both a digestive and endocrine system. In the next project we will more precisely define the genes that are affected by different bacterial diets, as well as by vitamin B12 and propionic acid - molecules that are central mediators of the effects we observed. In addition, we will use systems-level phenotypic assays and genetic interaction screens to link diet-induced gene expression changes to physiological outputs such as altered developmental rate, fertility, and lifespan and the ability t response to propionic acid toxicity. Finally, we will dissect the precise mechanisms by which metabolic networks communicate with gene regulatory networks and vice versa using a set of transcription factors that are involved in mediating the response to nutritional cues.
We obtain nutrients not only from our diet, but also from the bacteria that inhabit our gut, which are known as the microbiota. Such nutrients include metabolites like the short chain fatty acid propionic acid as well as the micronutrient vitamin B12, both of which are central to our studies. While there is no doubt that nutrients contribute to our physiology and our propensity to get sick, little is known about which nutrients affect which physiological trait, and the mechanisms by which nutritional input is translated into a physiological output. We will continue to use the interspecies systems biology paradigm that we developed to precisely dissect the mechanisms by which propionic acid and vitamin B12 interact and contribute to a variety of physiological traits and diseases.
|Na, Huimin; Ponomarova, Olga; Giese, Gabrielle E et al. (2018) C. elegans MRP-5 Exports Vitamin B12 from Mother to Offspring to Support Embryonic Development. Cell Rep 22:3126-3133|
|Hu, Queenie; D'Amora, Dayana R; MacNeil, Lesley T et al. (2018) The Caenorhabditis elegans Oxidative Stress Response Requires the NHR-49 Transcription Factor. G3 (Bethesda) 8:3857-3863|
|Hu, Queenie; D'Amora, Dayana R; MacNeil, Lesley T et al. (2017) The Oxidative Stress Response in Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2. Genetics 206:1909-1922|
|Zhang, Jingyan; Holdorf, Amy D; Walhout, Albertha Jm (2017) C. elegans and its bacterial diet as a model for systems-level understanding of host-microbiota interactions. Curr Opin Biotechnol 46:74-80|
|García-González, Aurian P; Ritter, Ashlyn D; Shrestha, Shaleen et al. (2017) Bacterial Metabolism Affects the C. elegans Response to Cancer Chemotherapeutics. Cell 169:431-441.e8|
|Yilmaz, L Safak; Walhout, Albertha Jm (2017) Metabolic network modeling with model organisms. Curr Opin Chem Biol 36:32-39|
|Fuxman Bass, Juan I; Reece-Hoyes, John S; Walhout, Albertha J M (2016) Gene-Centered Yeast One-Hybrid Assays. Cold Spring Harb Protoc 2016:pdb.top077669|
|Watson, Emma; Olin-Sandoval, Viridiana; Hoy, Michael J et al. (2016) Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. Elife 5:|
|Fuxman Bass, Juan I; Reece-Hoyes, John S; Walhout, Albertha J M (2016) Colony Lift Colorimetric Assay for ?-Galactosidase Activity. Cold Spring Harb Protoc 2016:pdb.prot088963|
|Fuxman Bass, Juan I; Reece-Hoyes, John S; Walhout, Albertha J M (2016) Zymolyase-Treatment and Polymerase Chain Reaction Amplification from Genomic and Plasmid Templates from Yeast. Cold Spring Harb Protoc 2016:pdb.prot088971|
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