Phd in SENSORINEURAL PLASTICITY

Thesis title: Pediatric Chronic Intestinal Pseudo-obstruction (PIPO): Interplay between enteric nervous system, mucosa-associated microbiota and the serotoninergic pathway

Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory functions. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent 5HT- receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely undetermined. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in pediatric CIPO (PIPO). To this purpose, biopsies of the colon, ileum and duodenum have been collected from 9 PIPO patients, and 9 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16S, on an Illumina Miseq platform. The expression of genes implicated in 5HT pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR. Correlation analysis were performed to highlight connections between MAM, the expression of serotoninergic pathway genes, and clinical parameters in PIPO patients. Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. This is the first study in PIPO patients where it has been demonstrated the presence of a specific MAM associated to underlying pathology and of an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.