Project description:Heligmosomoides polygyrus is a natural intestinal parasite of mice which exerts wide ranging modulatory effects on the immune system. This experiment was designed to investigate its abillity to modify intestinal epithelial cells, which form part of its natural niche. We tested gene expression in vitro, in differentiating organoids of small intestinal origin, exposed to cytokines and the released products of the parasite, termed HpES.
Project description:Alcohol increases intestinal permeability to pro-inflammatory microbial products including endotoxin and this is a key step in alcohol-induced organ damage such as alcoholic liver disease. Elevated intestinal permeability is observed even after a period of sobriety. We sought to investigate mechanisms contributing to long-term effects of alcohol on intestinal permeability by testing the hypothesis that alcohol affects intestinal stem cells using ex vivo organoids generated from jejunum and colon from chronic alcohol fed mice.
Project description:IL-17 and IL-17R signaling in the intestinal epithelium regulate the intestinal microbiome. Given the reported links between intestinal dysbiosis, bacterial translocation, and liver disease, we hypothesized that intestinal IL-17R signaling plays a critical role in mitigating hepatic inflammation. To test this, we studied intestinal epithelial-specific IL-17RA deficient mice in a model of concanavalin A hepatitis. Absence of enteric IL-17RA signaling exacerbated hepatitis and hepatocyte cell death. These mice exhibited commensal dysbiosis, increased intestinal and liver Il18, and increased liver translocation of bacterial products, specifically CpG DNA. Mechanistically, CpG DNA induced hepatic IL-18, increasing IFNγ and FasL in hepatic T-cells to drive inflammation. Thus, intestinal IL-17R regulates translocation of TLR9 ligands and constrains susceptibility to hepatitis. These data connect enteric Th17 signaling and the microbiome in hepatitis, with broader implications on the effects of impaired intestinal immunity and subsequent release of microbial products seen in other extra-intestinal pathologies.
Project description:Microbial consortia consist of a multitude of prokaryotic and eukaryotic microorganisms. Their interaction is critical for the functioning of ecosystems. Until now, there is limited knowledge about the communication signals determining the interaction between bacteria and fungi and how they influence microbial consortia. Here, we discovered that bacterial low molecular weight arginine-derived polyketides trigger the production of distinct natural products in fungi. These compounds are produced by actinomycetes found on all continents except Antarctica and are characterized by an arginine-derived positively charged group linked to a linear or cyclic polyene moiety. Producer bacteria can be readily isolated from soil as well as fungi that decode the signal and respond with the biosynthesis of natural products. Both arginine-derived polyketides and the compounds produced by fungi in response shape microbial interactions.
Project description:We used single cell RNA sequencing to analyze the diversity of intestinal cells under conventional conditions and the effect of an acute, natural Vibrio cholerae infection on the intestinal transcriptome.
Project description:Excessive fructose consumption causes fatty liver disease and steatohepatitis, conditions that elevate liver cancer risk. Although fructose was documented to cause metabolic abnormalities and microbial dysbiosis, whether and how it triggers liver tumorigenesis was unknown. We now describe a mouse model in which fructose acts as a carcinogen, giving rise to intestinal dysbiosis and translocation of inflammation-evoking microbial products that reach the liver via the portal circulation. These inflammatory stimuli initiate hepatocellular carcinogenesis. Genetic enhancement of epithelial barrier integrity and microbiota depletion with broad spectrum antibiotics prevent fructose-induced steatosis and liver cancer.
Project description:To characterize the effect of microbiota on global gene expression in the distal small intestine during postnatal gut development we employed mouse models with experimental colonization by intestinal microbiota. Using microarray analysis to assess global gene expression in ileal mucosa at the critical stage of intestinal development /maturation associated with weaning, and asking how expression is affected by microbial colonization In the study presented here, preweaned and postweaned GF, SPF mouse small intestinal total RNAs were used. Also, 3-week-old gnotobiotic mouse as well as GF mouse small intestinal RNAs were used.
