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Host-microbiota interactions across the gut immune system: lessons from early onset inflammatory bowel diseases and from gnotobiotic mice

Final Report Summary - IMMUNOBIOTA (Host-microbiota interactions across the gut immune system:lessons from early onset inflammatory bowel diseases and from gnotobiotic mice)

The project Immunobiota had two main objectives. The first was to identify human pathways indispensable to build an efficient gut barrier through the genetic dissection of intestinal monogenic disorders. A cohort of 550 children with severe chronic diarrhea of very early onset was built and explored. A causal gene defect was identified in 30% of the patients and in 45 distinct genes including 5 genes which had not been previously implicated in intestinal diseases. One participates in the defense of the gut barrier against the microbiota; three control inflammatory signals induced by the microbiota; one is necessary for the differentiation of the gut epithelium. Besides providing important insight into the respective role of different genes and pathways in the regulation of intestinal immune responses, this project has allowed to implement diagnostic strategy and tools that are instrumental to guide therapy and improve long term prognosis of very severe diseases.
The second objective aimed at characterizing a very unique intestinal symbiont called Segmented filamentous bacterium (SFB) and the nature of its interactions with its host. Demonstration of the crucial role of SFB in the development of gut lymphoid tissues supports its key role in the post-natal maturation of gut adaptive immune responses against microbiota. Demonstration that SFB lifecycle can be recapitulated in vitro exclusively upon direct contact with epithelial cells, explains how this bacterium can fulfill its auxtrophic needs and clarifies why this bacterium develops after attaching to the ileal mucosa, its natural niche. Implementing a methodology to shave SFB surface has allowed to identify among several molecules, flagellins which may allow SFB intracellular offsprings to swim within the mucus and reach their epithelial niche.