5 research outputs found
Targeting the pregnane X receptor using microbial metabolite mimicry
The human PXR (pregnane X receptor), a master regulator of drug
metabolism, has essential roles in intestinal homeostasis and abrogating
inflammation. Existing PXR ligands have substantial offtarget
toxicity. Based on prior work that established microbial
(indole) metabolites as PXR ligands, we proposed microbial
metabolite mimicry as a novel strategy for drug discovery that
allows exploiting previously unexplored parts of chemical space.
Here, we report functionalized indole derivatives as first-in-class
non-cytotoxic PXR agonists as a proof of concept for microbial
metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere
6), binds directly to PXR protein in solution, induces PXRspecific
target gene expression in cells, human organoids, and
mice. FKK6 significantly represses pro-inflammatory cytokine
production cells and abrogates inflammation in mice expressing
the human PXR gene. The development of FKK6 demonstrates for
the first time that microbial metabolite mimicry is a viable strategy
for drug discovery and opens the door to underexploited
regions of chemical space
Increased Bacterial Translocation in Gluten-Sensitive Mice Is Independent of Small Intestinal Paracellular Permeability Defect
Review article: future research on coeliac disease - a position report from the European multistakeholder platform on coeliac disease (CDEUSSA).
BACKGROUND: CDEUSSA is a Specific Support Action project from the Sixth Framework Programme Priority of the European Union (EU). Its aim is to bring together basic and applied research in the area of coeliac disease (CD). This paper reviews the main issues that are a result of the CDEUSSA initiative.
AIM: To identify the major issues in need of investigation in the areas of clinical aspects, treatment, prevention and public health.
METHODS: Key stakeholders, representing a wide range of knowledge with crucial importance for CD research and practice, have participated in two workshops aimed at identifying and proposing to the EU, as high priority research, topics in the areas of clinical aspects, treatment, prevention and public health.
RESULTS: In public health, the overall goal should be to improve quality of life of the European population by implementing primary prevention strategies, early diagnosis and improved treatments for CD. New treatment strategies need to be developed. The option of primary prevention should be fully explored, which requires combined epidemiological, clinical and basic scientific research efforts. Such studies should also consider the importance of gene-environment interactions in the development of CD. Increased knowledge is needed on the natural history of CD. Diagnostic criteria need to be revised.
CONCLUSIONS: To achieve these goals, a collaboration of the stakeholders is fundamental, including research and patient organizations, as well as industries within both diagnostics and food production