Project Details
Projekt
Immune modulation by metagenomic DNA from the gastrointestinal microbiota of newborn infants
Applicant
Professor Dr. Wolfgang Florian Fricke
Subject Area
Parasitology and Biology of Tropical Infectious Disease Pathogens
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 316130265
Disturbed interactions between the gastrointestinal microbiota and the host immune system, commonly referred to as dysbiosis, have been associated with a diverse set of diseases, including for example inflammatory bowel disease, antibiotic-associated diarrhea and obesity. Control over gastrointestinal immune responses is especially important in newborn infants that are in the process of establishing their microbiota, as they need to avoid excessive inflammation in response to transient colonization with potential pathogenic bacteria. In spite of growing evidence for a functional role of the gastrointestinal microbiota for dysbiosis, it has been difficult to identify parameters that would clearly define dysbiosis on the microbiota level. The human host can detect microbes via innate immune receptors such as TLR9 from the group of Toll-like receptors. TLR9 recognizes specific short oligomers of microbial DNA and is involved both in the pro-inflammatory activation and anti-inflammatory modulation of host immune responses. Fecal microbiota characterization by metagenomic sequence analysis to quantify TLR9-stimulating and TLR9-regulating sequence motifs, in combination with TLR9-dependent experimental immune assays, is attractive to study the dynamics of host-microbe interactions, as it has the potential to identify sequence-based diagnostic biomarkers for gastrointestinal dysbiosis.Our preliminary data indicate that the newborn infant fecal microbiota has a reduced capacity to induce TLR9-dependent immune activation, compared to that of adults, as well as an altered metagenomic sequence composition with respect to the relative abundances of known TLR9-binding sequence motifs. We therefore propose to use the newborn fecal microbiota as a model to study DNA-dependent host-microbe immune interactions. Correspondingly, the aims of this proposal are to assemble a cross-sectional cohort of infants and adults and to measure and compare immune responses to fecal metagenomic DNA in vitro (Objective I), to perform metagenomic sequencing on the samples, calculate relative abundances of immunostimulatory and immunoregulatory TLR9-binding oligomers, respectively, and to develop predictive models for metagenomic sequence-based immune activation (Objective II), and to measure the effects of gastrointestinal immune stimulation with fecal metagenomic DNA in a germfree mouse model, as well as the ability of newborn fecal metagenomic DNA to attenuate inflammation in a murine model of chemically induced colitis (Objective III).
DFG Programme
Priority Programmes
