Analyze the functioning of some rare bacteria
As part of its support for innovative companies, supported by the Nouvelle-Aquitaine region, the Pleiade project-team of the Inria centre at the University of Bordeaux recently approached the Bordeaux biotech company Ysopia Bioscience, which specializes in the research and development of therapeutic innovations based on the potential of the intestinal microbiome.
For Ysopia, the goal of this six-month partnership - launched under the sign of agility - was to verify whether a tool developed by the Pleiade and Dyliss teams (Metage2Metabo) could "help identify a certain category of bacteria, among the hundreds of species that make up the intestinal microbiota and interact with the organism," explains Sandrine Claus, Ysopia's scientific director. It also aimed to "allow visualization of the metabolic steps that are carried by rare bacteria, which are called 'keystones'".
Mapping bacterial networks
For the multidisciplinary Pleiade team - shared by Inria, CNRS and INRAE - which is very interested in bioinformatics (also known as computational biology), the research topic was particularly motivating from a scientific point of view: it provided an opportunity to discuss existing methodologies with biologists and to confront them with new raw data, in order to characterize the needs of the community and identify new developments to be made. "We are working, for example, on technologies to model and analyze the interactions between the many microorganisms that make up microbial ecosystems," says Clémence Frioux, a researcher in this team.
From large-scale data, linked to the sequencing of the DNA of these bacteria (also known as the metagenome), Pleiade has succeeded in inferring hypotheses on the functioning of the intestinal microbiota. The team has proposed "tools and methods to identify, among hundreds or thousands of species of bacteria, those whose roles are particularly important for certain metabolic functions". Metabolism corresponds to the chemical reactions that take place inside cells and allow them to stay alive or to develop. It is represented as networks in bioinformatics models.
Identify the effects of disturbances
"Our goal is to try to understand whether there are links between disturbances in the bacterial ecosystem and certain pathologies, such as obesity or Crohn's disease (a chronic inflammatory disease of the digestive tract)," says Sandrine Claus. The aim is also, if possible, to develop biotherapies that will soon make it possible to treat obesity and associated disorders (such as cardiovascular risks, type 2 diabetes, etc.).
This is the case, for example, with an oral biotherapy, recently successfully tested by Ysopia, which is based on a unique and essential live bacterial strain (Christensenella minuta). It has indeed been established, thanks to recent epidemiological studies, that this bacterium tends to disappear in the intestinal microbiota of people who suffer from obesity. This is known as dysbiosis, which corresponds to an imbalance in the biodiversity of the intestinal flora.
Processing samples on a supercomputer
Ysopia entrusted Pleiade with the raw data obtained from several sequencing studies carried out on mice (which may or may not have absorbed the Christensenella minuta bacterium). "I was responsible for installing several tools used by the team on the PlaFRIM scientific computing platform," says Eloïse Guillem, a software development engineer at the SED (Service d'expérimentation et de développement) of the Inria center at the University of Bordeaux. We're talking about big data, and one of the difficulties was to deploy Pleiade's software and that of the bioinformatics community on a part of the supercomputer with a large memory capacity, without interfering with the calculations being carried out in parallel by other researchers."
The calculations were able to begin immediately after the data were transferred. "I used bioinformatics tools and our in-house algorithms to model the metabolic networks of the bacteria present in the murine gut microbiota samples [from mice] as well as the interactions between these bacteria," adds Clémence Frioux. The goal: to analyze the functional potential of each microbiota, by characterizing the metabolic activities likely to be performed by these bacteria.
Use the tool in future tests
The results of these calculations led to several hypotheses on the functions carried by the "keystone" bacteria, which were presented to Ysopia, which develops (from living bacteria, reproduced in fermenters) drugs against chronic and disabling diseases. "The main objective of our collaboration was to validate Pleiade's Metage2Metabo tool - which has already been published in the prestigious scientific journal eLife - and it has been achieved," concludes Sandrine Claus. It is an open source tool, available for free download, and we will continue to use it, especially to process new clinical samples."
Especially since Ysopia Bioscience's research is not limited to treatments for obesity and Crohn's disease. The company - which has a laboratory at the Xavier Arnozan Hospital in Pessac - has already undertaken other research on biotherapies for asthma or dysfunctions of the intestine-brain axis (the biochemical signaling that occurs between the gastrointestinal tract and the central nervous system)... The therapeutic perspectives are numerous and only need to be confirmed. This first cooperation could lead to other types of research collaborations between Ysopia and Inria.
For more information:
- SLIMMEST, at the frontiers of biology, mathematics and computer science, Inria, 10/1/2021
- Obesity and trisomy 21: advances announced by two Bordeaux laboratories, France Bleu, 2/12/2021
- Ysopia Bioscience: positive results of the Phase 1 study evaluating an innovative biotherapy for the treatment of obesity, Mypharma-editions, 6/7/2021
- Podcast - Karine Clément, professor of nutrition at the Pitié-Salpêtrière Hospital, and Sandrine Claus, scientific director of Ysopia, discuss the links between gut microbiota and obesity, on the occasion of World Obesity Day, Ysopia Bioscience, 4/3/2021