Estudio metabolómico de la interacción huesped-microbiota intestinal en la enfermedad cardiometabólica. Detección temprana, prevención y tratamiento

Resumen

Cardiometabolic disease (CMD) is a clustering of cardiometabolic risk factors including obesity, hypertension, fatty liver disease, type 2 diabetes, and cardiovascular disease. Recent studies show a role for host-microbiota co-metabolism and Western diets in the onset and development of this disease. High-fat and high-sugar dietary habits are among the main causes of CMD mortality with fast increment nowadays. The study of the metabolic pathways involved and the identification of specific biomarkers for early detection of CMD seems essential in patient management. This thesis aims to improve our understanding of the progression of CMD, to discover the firsts alterations in the development of the disease, as well as to identify potential sub-clinical CMD biomarkers through the analysis of changes in serum, urine, and fecal metabolism. Design and methods: Male and female Wistar rats, 16 weeks old, were fed with a high-fat and sucrose diet (HFD) for 12 weeks to induce CMD, both in conventional and specific-pathogen-free (SPF) housing conditions. Moreover, male and female Wistar rats, 3 weeks old, were fed with a high-fructose diet (HFR) for 16 weeks to induce CMD. Serum, urine, and fecal samples and microbiota diversity were analyzed by Nuclear magnetic resonance (1H NMR) and Denaturant gradient gel electrophoresis (DGGE) or Sequencing, respectively. The effect of fecal microbiota transplantation (FMT) and probiotics were tested on the microbiota modulation. Results: HFD and HFR induced metabolic and clinical alterations related to CMD in young and adult rats. The metabolomic profile of serum, urine, and fecal samples demonstrated differences in the metabolism of HFD and HFR groups in different metabolic pathways and cores. These differences in the rats metabolome are sex specific with different alterations in male and female rats. Moreover, host-microbiota co-metabolites were also altered after HFD and HFR diets. Microbiome sequencing and fecal DNA DGGE revealed changes in the microbiota composition that suggest lower microbiota diversity in the HFD and HFR groups. Interestingly, HFD induces strong whereas HFR only moderate microbiota composition changes. The longitudinal metabolomic profiling of HFD rats suggest that microbiota composition changes precede alterations in host metabolism in the development of CMD in rats. Additionally, our results suggest that diet has stronger effects in microbiota composition than restricted exposure to bacterial communities. Finally, modulation of microbiota with probiotics, but not with fecal microbiota transplantation, ameliorates CMD in a sex specific manner. Overall our work demonstrates that the association between host-microbiota co-metabolism and cardiometabolic disease is highly dependent on dietary patterns, sex, environmental exposure to bacterial communities and age. These dependences and the metabolic effect of these multiple factors can be detected by NMR metabolomics. Metabolomics profiling may be an effective way for improving cardiometabolic disease clinical management and patient risk stratification.