Host-Microbiota Interactions in Obesity: An Interdisciplinary Approach to understand Obesity-Induced Insulin Resistance and Type 2 Diabetes

About the Project

Title: Host-Microbiota Interactions in Obesity - An Interdisciplinary Approach to understand Obesity-Induced Insulin Resistance and Type 2 Diabetes

Synopsis: This project explores the connection between translocation of gut bacteria, the resulting anti-microbial IgG production, metabolic inflammation and insulin resistance in obesity. It seeks to establish the link between elevated IgG levels and the incidence of type 2 diabetes, while identifying microbiota species involved in these processes.

Details: The prevalence of obesity is rising worldwide, leading to an unprecedented medical burden from obesity-associated comorbidities. Obesity is characterised by a chronic inflammatory state which promotes insulin resistance—a key mechanism in the development of obesity-associated diseases such as type 2 diabetes (T2D). Increased production of IgG and its accumulation in adipose tissue is one of the factors that contribute significantly to insulin resistance in diet-induced obesity models (https://pubmed.ncbi.nlm.nih.gov/39674176/, https://pubmed.ncbi.nlm.nih.gov/38717136/). Our most recent work demonstrates that increased IgG levels in obesity depend on the composition of the microbiota and are caused by the translocation of gut bacteria, triggering an immune response and the production of bacteria-specific IgG. Additionally, our preliminary analysis indicates that in humans, circulating levels of IgG correlate in males with body mass index (BMI) and fasting insulin levels.

Alteration in the composition of the gut microbiota occurs in many chronic diseases, including inflammatory bowel disease (IBD), cirrhosis, cancer, multiple sclerosis (MS), and obesity. While shifts in the relative abundance of gut microbes may not play a causal role in diseases, certain microbes can exert a dominant effect and alter host functions. Bacterial translocation, by engaging the systemic immune system, is one mechanism by which the altered microbiota contributes to human inflammatory diseases. However, it is difficult to assess which subsets of commensal gut microbiota constituents translocate across the gut barrier.

This project aims to:

• Identify bacteria translocating in obesity and causing systemic IgG production. The student will use serum samples from obese (non-diabetic) and lean individuals to isolate the microbial fraction (derived from a surrogate faecal community) that is bound by serum IgG. This method has been used recently to identify translocating bacteria in patients with IBD (https://pubmed.ncbi.nlm.nih.gov/35976997/).
• Validate in a large cohort of individuals the presence of a higher burden of anti-microbial IgG in obese individuals using an ELISA assay measuring serum IgG reactivity against translocating gut bacteria. Plates will be coated with bacterial extract from species identified above (depending on commercial availability/ collaborations).
• Evaluate the association between increased IgG levels and the incidence of T2D using UK Biobank, a large-scale population-based study (n=500,000). The analysis will use an aetiological framework to explore potential biological pathways linking IgG to T2D and employ unadjusted and adjusted Cox regression models to evaluate the association for IgG levels with incidence of T2D while adjusting for relevant confounders (age, sex, BMI, etc).

This interdisciplinary project bridges immunology, microbiology, and epidemiology to address the causes of T2D, one of the four most common non-communicable diseases (NCDs). By investigating how dysregulation of the gut microbiota in obesity contributes to metabolic inflammation and insulin resistance, the research challenges traditional views of NCDs solely as lifestyle-related conditions and highlight the importance of the study of host-pathogen interactions to fully comprehend the complex mechanisms driving T2D. Finally, this project will explore the novel concept that IgG acts as a rheostat for insulin sensitivity, which could have significant implications for how we comprehend the interaction between metabolism, infection, host-pathogen interactions and inflammatory diseases.

Potential impacts: This project will open new avenues for targeted interventions addressing underlying microbial and immune mechanisms of T2D:

• Preventing expansion of invading bacterial species using diets or transplantation of protective microbial communities.
• Lowering IgG levels using FcRn blocking antibodies (approved for treatment of some IgG-mediated autoimmune diseases).

Training: This PhD will provide with a unique training opportunity at the intersection of cardiometabolic research, immunology, microbiota and health data science. It will benefit from teams with complementary expertise in cardiometabolic inflammation and immunology (Benezech), health data science (Kimenai) and microbiota analysis (Glendinning and Benezech). Their combined expertise offers a robust foundation for the student, fostering a dynamic environment for intellectual growth. The student will have many opportunities for collaboration and cross-disciplinary learning. The exceptional research facilities and supportive atmosphere at both the INCR, Usher Institute and Roslin Institute will greatly enhance the student’s experience.

The student will be trained and supervised in the lab by an experienced senior technician (main techniques: microbiota isolation, flow-cytometry, cell-sorting, ELISA, multiplex bead arrays). The student will be able to enrol in a wide range of training courses to develop their skills in R and statistics, as well as microbiota analysis (full length 16s rRNA analysis). In addition, the UoE offers PhD students a wide range of training courses in transferable skills to facilitate successful completion of a PhD and development of the student’s career beyond the PhD.

The student will be invited to present their work at internal seminars as well as conferences, with training in presentation skills and responding to scientific critique. Our laboratories encourage and participate in public engagement activities and patients’ outreach, which will further enrich the student academic journey. For example, the Metabolic obesity and diabetes theme interact regularly with the Diabetes peer group of the Niddrie General Practice.

Recruitment: Background in immunology or cardiovascular science is required. Some lab experience is desirable (flow-cytometry). An affinity/strong interest with epidemiology, health data science or statistics is highly desired.

Apply: All applications must be submitted through the Future Medicine PhD fellowships website.