LiBacPain

Irritable bowel syndrome (IBS) is characterized by abdominal pain and/or discomfort, bloating and bowel dysfunction such as constipation, diarrhea, or mixed bowel patterns. While IBS is not a life-threatening disease, it can be responsible for an important alteration of quality of life (QoL) affecting all its dimensions. This alteration of QoL can be similar or even superior to that observed in other chronic diseases such as diabetes, renal failure or Crohn’s disease. The absence of knowledge about etiology, the extent of the symptoms and the poor efficiency of therapeutics available make IBS extremely difficult to treat and to diagnose. IBS is a multifactorial pathology sharing a bacterial dysbiosis of the microbiota with several gastrointestinal diseases. The lack of knowledge on the effects of the microbiota on the host is still a major lock to develop effective therapies against these diseases. We are developing a new concept that microbiota bacteria associated with the intestinal mucosa, including Escherichia coli (E. coli), are able to modify the host's physiology through their production of lipid molecules; elucidating the composition of bacterial secretion driving IBS will lead to the identification of specific drugs. We studied the bacterium Echerichia coli Nissle 1917, a microbiota bacterium used as a probiotic and recently tested orally as an alternative treatment for IBS. Our work shows that this bacterium produces GABA (gamma aminobutyric acid) linked to an asparagine and to a 12-carbon fatty acid. Together, these three molecules form a lipopeptide, C12AsnGABAOH. We synthesized this lipid molecule in order to quantify it and evaluate its effect on the host. This molecule is able to cross the intestinal barrier and to reach the sensory nerves where it decreases the activation of sensory neurons. The treatment of hypersensitive mice with C12AsnGABAOH made them normosensitive. As this lipopeptide does not alter the physiology or the motility of the intestine, a patent has been filed for its use as an analgesic. This discovery demonstrates the importance of a better knowledge of the therapeutic potential of lipopeptides produced by the intestinal microbiota. The overall objective of our project is to study the involvement of bacterial lipid compounds in IBS. We will determine the genetic background of mucosa associated-bacteria in IBS patients. Then, our study will identify and quantify lipid molecules produced by E. coli isolated from the mucosa of IBS patients. The correlation between these two parameters (bacterial strain and lipid compounds) and clinical data of IBS patients should allow us to characterized patients relative to their bacterial carriage and to evaluate the potential use of lipid dosage as a prognostic and/or diagnosis marker in IBS. We will characterize secondly the metabolism pathway of these lipids by bacteria. Genetic manipulation of bacteria isolated from patients will help us to determine the involvement of bacterial lipid compounds in IBS symptoms. In the last part of our project, we will determine the impact of these lipid compounds on the cells involved in the pathogenicity of IBS. Then, in vivo, in animals, we will quantify the impact of these compounds on intestinal homeostasis. This project based on the complementarity of the different partners should allow a better characterization of this highly deleterious syndrome and to propose new therapeutic approaches.