Evan Lee
Program: Computational and Systems Biology
Current advisor: Jeffrey I. Gordon, MD
Undergraduate university: University of California-Berkeley
Research summary
Undernutrition remains a persistent challenge globally and is linked to 45% of deaths of children under the age of 5. Intestinal abundance of Prevotella copri, a saccharolytic microbe prevalent in non-Westernized populations, has been associated with increased weight for length Z-score (WLZ) in clinical studies of therapeutic foods for moderate acute malnutrition. We have used a gnotobiotic mouse model colonized with a defined human gut microbial community to demonstrate that P. copri colonization promotes ponderal growth (weight gain) in a dietary context rich in plant polysaccharides. P. copri encodes and highly expressed a genetic locus for degradation of arabinan and its colonization was associated with increased depletion of arabinose from cecal polysaccharides. We observed increased fitness of bacteria capable of arabinose utilization, as well as upregulation of their genes involved in arabinose catabolism and amino acid synthesis, suggesting its potential role in cross-feeding organisms which encode less comprehensive carbohydrate utilization machinery.
However, it remains unclear whether it is the direct products of glycan metabolism or other metabolites that mediate beneficial effects of P. copri colonization, and whether these signals are produced by P. copri alone or through cross-feeding interactions with other community members. Similarly, current methods do not enable inference of bidirectional differential expression (DE) from microbiomes that is robust to confounding changes in community composition and organism abundances, making it challenging to deconvolute the direct effects of P. copri from those that depend on cross-fed organisms.
My current work in the lab involves the benchmarking of existing DE testing methods for this analytical challenge in the context of microbial community transcriptomics. I used previously published simulated microbial community DNA and RNA sequencing data as well as new ‘mock community’ samples prepared from defined mixtures of bacterial cultures to benchmark existing methods. We observed that all current methods exhibit low sensitivity for organisms with low abundance, and that no existing methods perform adequately in the presence of confounding differential abundance, varying prevalence, or global transcription rate changes or their compositional effects on other organisms. We then applied approaches to metatranscriptomic datasets from our gnotobiotic mouse model and show that only the model nominated by our mock community comparisons successfully inferred P. copri cross-feeding dynamics which were validated in vitro. My ongoing work uses experimental and computational approaches to generalize testing of metatranscriptomic methods under real operating conditions in which they are applied.
Graduate publications
Hibberd MC, Webber DM, Rodionov DA, Henrissat S, Chen RY, Zhou C, Lynn HM, Wang Y, Chang HW, Lee EM, Lelwala-Guruge J, Kazanov MD, Arzamasov AA, Leyn SA, Lombard V, Terrapon N, Henrissat B, Castillo JJ, Couture G, Bacalzo NP Jr, Chen Y, Lebrilla CB, Mostafa I, Das S, Mahfuz M, Barratt MJ, Osterman AL, Ahmed T, Gordon JI. 2024 Bioactive glycans in a microbiome-directed food for children with malnutrition. Nature, 625(7993):157-65.
Chang HW, Lee EM, Wang Y, Zhou C, Pruss KM, Henrissat S, Chen RY, Kao C, Hibberd MC, Lynn HM, Webber DM, Crane M, Cheng J, Rodionov DA, Arzamasov AA, Castillo JJ, Couture G, Chen Y, Balcazo NP Jr, Lebrilla CB, Terrapon N, Henrissat B, Ilkayeva O, Muehlbauer MJ, Newgard CB, Mostafa I, Das S, Mahfuz M, Osterman AL, Barratt MJ, Ahmed T, Gordon JI. 2024 Prevotella copri and microbiota members mediate the beneficial effects of a therapeutic food for malnutrition. Nat Microbiol, 9(4):922-37.
Lee EM, Verma M, Palaniappan N, Pope EM, Lee S, Blacher L, Neerumalla P, An W, Campbell T, Brown C, Hurst S, Marshall B, Hershey T, Nunes V, López de Heredia M, Urano F.. 2023 Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders. Front Genetics, 14():1198171.