Microbial regulation of PPARgamma : nuclear receptor networks important for colonic homeostasis

Sammanfattning: One of the central issues surrounding the physiology of good health is to uncover and understand the molecular networks responsible for its maintenance. The alimentary tract in particular, demands a properly sustained homeostatic control since it is constantly challenged by potentially harmful agents along with innocuous nutrients, with the burden of basic metabolic functions in its ward. The colon is thus a digestive and absorptive organ with life sustaining authority, and central to its great protective nature is its need to sense and use bacterial products. Our microflora is an organ in itself, representing a greatly efficient and stable bioreactor where dietary constituents are degraded for our benefit. An understanding of how the intestinal barrier senses and responds to bacterial products is critical to gaining insights into the pathogenesis of disease as well as the impact of bacterial metabolism on energy balance of the host. My work summarized in this thesis, highlights that development of the gastrointestinal tract is subject to regulation by colonizing microorganisms, and explores to what extent the microflora can tune its functions. These processes require crosstalk between commensal bacteria and host cells by way of signaling through for example Toll-like receptor pathways, activating transcription factors such as nuclear receptors. By comparing mRNA expression profiles of nuclear receptors and Toll-like receptors, I have identified a subset of these to be conditionally regulated by the gut microbiota. It would seem that the gut flora affects receptors intimately connected to innate immunity and metabolic control. Apart from transcriptional communication, bacteria can also converse through posttranslational effects. By altering phosphorylation status of the nuclear receptor PPARgamma much like a specific ligand would, commensal bacteria are able to skew cell fate into maturation and anti-inflammation, thus affecting overall homeostasis. This implies that the manner in which the crosstalk is carried out may be through secreted molecules which affect host cells. Except for the clues presented in this thesis, there still remains a paucity of information regarding bacterial influence on host physiology, and even less information on how this influence is mediated. The search for mediators for fine tuning of body homeostasis has recognized probiotics as potentially beneficial. In my work I have shown that nuclear receptors such as the PPARs, can be regulated by microflora both in expression and function. One of their target genes, fasting induced adipose factor (FIAF), has a potentially interesting role in obesity because of its actions as a lipoprotein lipase inhibitor. Certain probiotic strains are able to upregulate FIAF, possibly through PPARs, with the implication of regulatory effects on body fat storage. Although the purported health benefits attributed to bacteria are numerous, the precise molecular mechanisms governing the cross-talk within the intestinal ecosystem remain to be discovered. Research now points toward host microbe interactions being essential to several conditioning aspects of normal physiology. The work presented here adds to our understanding of the molecular basis for the complex and dynamic interactions between the microbiota and its host, and further underscores the huge potential in manipulation of the microbiota as a tool for sustained health.