Microbiota-induced morphogenetic adaption of the small intestinal architecture

• Applicant: Professor Dr. Christoph Ralf Reinhardt
• Subject Area: Gastroenterology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259005283

The enteric microbiota has been identified as an environmental factor that strongly impacts renewal and differentiation processes and profoundly shapes the architecture of its intestinal habitat. While the influence of the enteric microbiota on the architecture of the small intestine is well-recognized, the role of pattern recognition receptors in adaptive remodelling processes of the intestine is unresolved and it remains enigmatic, which morphogenic signaling pathways are specifically regulated by this gut resident microbial ecosystem. Small intestinal development and morphology are tightly controlled by defined morphogen gradients, which include Hedgehog and TGF-beta/Bone Morphogenetic Protein signaling in the small intestinal villus structures that are nerved by an intricate capillary network, supporting absorption of nutrients for systemic distribution. Inactivation of Hedgehog signaling directly augments expression of BMPs, which have been demonstrated essential for intestinal villus patterning and intestinal morphogenesis. To resolve these fundamental questions, the proposed project takes advantage of gnotobiotic mouse technology, a tool to explore effects of the gut microbiota on small intestinal morphogenesis. Specialized germ-free Toll-like receptor (Tlr) 2- and 4-deficient mouse lines will enable us to analyse microbiota-induced pattern recognition pathways that are linked to morphogenetic pathways, promoting changes in the intestinal architecture and villus patterning. We will colonize germ-free mice with minimal bacterial consortia and individual gut microbes, as well as with E. coli mutants that lack specific Toll-like receptor-activating ligands to elucidate the role of defined pattern recognition signals and individual colonizers on microbiota-induced morphogenetic adaption and renewal of the small intestine. Combined with in-depth morphometric analyses, we will elucidate which morphogenetic pathways are influenced by colonization with defined gut microbes. Furthermore, we will test the effects of defined diets on the morphogenetic adaption and renewal of the small intestine.Collectively, this project will reveal how gut microbiota influence the architecture and renewal of their intestinal habitat and how this is influenced depending on diet. The results will contribute to understand the role of the microbiota in the regulation of pathways that were linked to the development of intestinal cancers.

• DFG Programme: Research Grants