Multi-omics association studies on type 2 diabetes

Research output: Book/ReportPh.D. thesis

  • Huanzi Zhong
An increased aging population and the global explosion of obesity have resulted in an increasing prevalence of type 2 diabetes mellitus (T2D), a heterogeneous non-communicable disease (NCD) associated with long-term, high blood glucose levels and macrovascular and microvascular complications affecting multiple organs. This worldwide health issue has in turn continuously spurred research to address the complex pathogenesis and develop more effective and safe treatment regimens for T2D. During the past decade, a number of studies have repeatedly reported gut microbial alterations in metabolic disorders including T2D, whereas few have dissected causal relationships and specific mechanisms whereby the gut microbiota can affect disease development and may provide options for treatment. The major aim of this PhD thesis was to complement the list of reliable associations of gut microbial alterations with T2D onset and to investigate potentially novel microbiota-mediated mechanisms in commonly used anti-T2D regimens. We conducted plasma lipidomics and fecal metagenomics and metaproteomics in a T2D cohort enrolled in Suzhou, China and identified distinct multi-omics profiles characterizing newly-diagnosed, treatment-naïve T2D patients (TN-T2D), Pre-DM individuals and individuals with normal glucose tolerance (NGT). These characteristics included T2D-related reductions in multiple butyrate-producing bacteria and Akkermansia muciniphila, NGT-related enrichment in several human antimicrobial peptides and a specific enrichment of Escherichia coli in Pre-DM. In a randomized clinical trial (RCT) with 94 Chinese TN-T2D patients subjected to a 3-month treatment with two oral anti-diabetic drugs, we reported that Acarbose (belonging to the class of alpha-glucosidase inhibitors) induced marked alterations in plasma bile acids (BAs), gut microbial composition, and genes encoding BA-transforming enzymes. In turn, microbiome-based stratified analyses showed that TN-T2D patients with an enterotype driven by a high abundance of Bacteroides prior to treatment showed more reductions in plasma secondary BAs as well as more beneficial outcomes of Acarbose treatment than patients characterized by an enterotype driven by a high abundance of Prevotella. Likewise, we further revealed that the metabolic responses to dietary fibers in school-aged Dutch children differed in relation to enterotypes. Another aim of the PhD thesis was to explore extensive host-microbiota interplays and lifelong developmental trajectories of the gut microbiota on the basis of several large-scale cohorts of school-aged children and adults of a wide range of ages. By controlling for main confounders affecting the gut microbiota including medicines and geographic locations that might reflect many unmeasured variables such as genetics, dietary habits and lifestyle, we have revealed age-dependent sex differences in gut microbiota in the Pinggu cohort established in Beijing, China, and confirmed these universal sex differences in three independent adult cohorts from China, Israel and the Netherland. By contrast, no such sex differences in the gut microbiota were found in Dutch children before puberty. Finally, we performed parallel DNA extraction on a mock microbial community and real human fecal samples using six extraction methods, revealing significant differences ingenome coverage and abundance of fungi and bacteria between methods, and recommended a rapid, cost-effective method for future large-scale metagenomic studies as its performance iscomparable to a labor-intensive, time-consuming standardized protocol. Overall, our results confirm reproducible and robust gut microbial shifts in the T2D development, highlight the universal and reliable associations between age, sex and gut microbiota in multiple human populations and emphasize the importance of benchmarking protocolsin human gut metagenomic studies. Longitudinal cohorts as well as in vivo studies are required to dissect the underlying mechanisms of these host-microbiota interplays and their roles in modulating host health and metabolism during lifetime.
Original languageEnglish
PublisherDepartment of Biology, Faculty of Science, University of Copenhagen
Number of pages171
Publication statusPublished - 2020

ID: 251251081