Periodic Reporting for period 4 - Healthybiota (Microbiota-host interactions for integrative metabolic health reprogramming)
Periodo di rendicontazione: 2023-12-01 al 2024-05-31
Obesity is a metabolic disease leading to various health risks and reduced life expectancy. We live in symbiosis with trillions of bacteria commonly known as the microbiota. The microbiota influences the whole-body metabolism by affecting the energy balance on multiple levels. This project addressed the importance of the microbiota, and its changes in mediating the benefits of various beneficial metabolic stimuli. We demonstrated that microbiota critically contributes to the physiological changes occurring during caloric restriction and temperature alterations. The project also led to a discovery of new bacterial species that are sufficient to improve metabolic health, and provided insights into the potential mechanism of action on a cellular and molecular level. Finally, the project led to a generation of new computational resources and microbiota catalogues for both mouse and human, which enable microbiome analysis at unprecedented depth.
We have designed bioinformatics tools that enable profiling the microbiota of mice and human. Using these tools, we generated a comprehensive mouse microbiota genome catalogue and compared it to the human one. We uncovered that caloric restriction (CR), a beneficial metabolic stimulus that prolongs healthspan, leads to changes in the microbiota composition in human and mice. Transplantation of the CR-adapted microbiota is sufficient to phenocopy the beneficial effects of the CR itself to the new host. We also uncovered that exposure to warmer temperatures improves bone strength through the changes in the microbiota composition. We described in part the mechanisms by which these microbiota changes lead to improved bone and overall metabolic health. Specifically, at least in part, this was mediated by the temperature-induced increases in the polyamine biosynthesis. As for the CR-related mechanisms, our data point to the critical importance of the decrease in the bacterial lipopolysaccharide biosynthesis, which promotes anti-inflamatory immune response in the host. We also identified a potential bacterial candidates that mediate the temperature-induced effects, and which are by them selfs sufficient to promote improved metabolic health. Our data indicates that the newly identified bacterial species could have large therapeutic implications as potential novel treatment against various metabolic diseases.
Our newly developed bioinformatics pipelines enable unprecedented depth (of over 95%) in identifying the microbiota species that are present in the sequenced samples, and in discovering bacterial species that are present at different levels during certain metabolically-beneficial conditions. We used these tools to compare the metagenomics changes with the changes in metabolomics, which allowed us to gain functional and mechanistic explanations of the microbiota importance during the metabolically healthy stimuli, and to narrow down several bacterial species as candidates that could mediate these effects. We conclusively demonstrated the importance of the identified bacterial species in improving metabolic diseases, such as obesity and impaired insulin sensitivity. We also determined their importance in potentially limiting the age-related deterioration of the bone strength, and their capacity in preventing the age-related metabolic diseases, such as osteoporosis. Finally, our work provided mechanistic insights into the molecular and cellular machinery by which microbiota communicates with the host, and further analysed the overall compositional changes of various organs induced by the microbiota, in particular the adipose tissues and the intestine.