Identification of therapeutically exploitable targets contributing to weight loss and metabolic disease improvement after metabolic surgery in the microbiota-host-interactome

• Applicant: Dr. Rima Chakaroun
• Subject Area: Endocrinology, Diabetology, Metabolism ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462524713

The gut microbiome has emerged as a diagnostic, prognostic and therapeutic key regulator mediating risk factors related to obesity, metabolic syndrome, T2D and cardiovascular disease alongside treatment effects. Bariatric surgery is the single most effective treatment to tackle cardiometabolic diseases in obesity. Additionally, gained knowledge on the mechanisms by which bariatric surgery contributes to weight loss, improvement of glucose and lipid metabolism as well as cardiac health has led to a myriad of less invasive treatment options. Further exploitable targets such as modification of the gut microbial community after bariatric surgery have not been fully characterized, leaving their therapeutic potential thus untapped. During my research stay at the Wallenberg Laboratory for Cardiovascular and Metabolic Research in Gothenburg, Sweden, I aim to characterize relevant microbiome and metabolome targets at the interface of gut microbiome-host communication by identifying bacterial species, functional modules and metabolites related to disease alleviation after bariatric surgery. The project will consist of an exploratory approach to identify metabolic response patterns and related microbiotal and metabolic variables in a host-confounder-aware approach using multi-systems-analyses in Aim 1. Tackling these targets mechanistically will be done by establishing in vitro and in vivo validation methods in Aim 2 geared at à-priori putative microbial targets i.e. carbohydrate and amino acid potential: In a first step I will study the metabolic fermentation of inoculations from subjects with the phenotype of interest in vitro by using the established SHIRM system available at the hosting institution to validate whether changes in the host could indeed emanate from the functional shifts of the gut microbiome. For this, I will be able to recreate the intestinal conditions and modifications thereof brought on by bariatric surgery in SHIRM. I will then use an in silico approach to check for relevant bacterial consortia or single bacteria, which could drive the observed metabolic shifts and will subsequently use an in vivo approach to check whether the functional and compositional shift in microbiome is necessary and sufficient for the phenotype observed. Results from Aim 1 and the expertise gained in the application of the methods in AIM 2 for validation of à-priori knowledge will allow testing a myriad of exploitable targets and defining potential mechanisms, which can be translated into clinical studies and translational pipelines in personalized metabolic medicine far beyond the horizon of this fellowship.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Fredrik Bäckhed, Ph.D.