Gut microbiome response to pharmaceutical drug therapies in obesity and diabetes

Millions of people worldwide suffer from lifestyle-induced obesity, which may result in health complications and comorbidities, like hypertension, type 2 diabetes (T2D), or cardiovascular diseases. The gut microbiota, i.e., the collection of microorganisms living in the gastrointestinal (GI) tract, has been associated with the development and progression of obesity and metabolic dysfunction. Gut dysbiosis and microbial metabolite crosstalk with intestinal receptors, possibly affecting host immune regulatory processes and energy metabolism. This PhD project applied animal models of obesity and T2D to address intestinal changes induced by pharmacological drug therapies and explored the microbial community structure of both faecal and intestinal tissue samples with different molecular laboratory and sequencing methods.

The first study assessed the anti-obesity effects of treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, or the dual GLP-1/GLP-2 receptor agonist GUB09-145 in a diet-induced obese (DIO) mouse model. Changes to the faecal gut microbiome following 4 weeks of treatment were analysed using 16S rRNA amplicon and shotgun metagenomics sequencing and showed shifts in low-abundant species, correlating with changes in metabolic phenotype exhibited by lowered caloric intake, improved glycaemic control and insulin sensitivity.

The second study investigated the local intestinal response to treatment with a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in a diabetic mouse model. Five different gut sections were sampled, and bacterial DNA and host mRNA were isolated using a dual purification kit and analysed with full-length 16S rRNA and RNA sequencing. 8 weeks of treatment did not significantly alter the bacterial composition at genus level, but both ileal and colonic host gene expression profiles changed in relation to PPAR-γ effects on immune system and lipid handling. Collectively, the two studies investigated gut microbiome response to pharmaceutical drug therapies and observed possible connections between microbe-host-drug relationships. These mechanisms should be explored more in depth in faecal microbiota transplantation (FMT) proof-of-concept studies.