Microbial regulation of PPARgamma : nuclear receptor networks important for colonic homeostasis
Author: Aronsson, Linda
Date: 2008-06-13
Location: Föreläsningssalen (E525) vid institutionen för mikrobiologi, tumör och cellbiologi, Theorells väg 1, Karolinksa Institutet
Time: 09.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
View/ Open:
thesis.pdf (584.6Kb)
Abstract
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.
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.
List of papers:
I. Lundin A, Bok CM, Aronsson L, Björkholm B, Gustafsson JA, Pott S, Arulampalam V, Hibberd M, Rafter J, Pettersson S (2008). "Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine." Cell Microbiol 10(5): 1093-103. Epub 2007 Dec 17
Pubmed
II. Are A, Aronsson L, Wang S, Greicius G, Lee YK, Gustafsson JA, Pettersson S, Arulampalam V (2008). "Enterococcus faecalis from newborn babies regulate endogenous PPARgamma activity and IL-10 levels in colonic epithelial cells." Proc Natl Acad Sci U S A 105(6): 1943-8. Epub 2008 Jan 30
Pubmed
III. Aronsson L, Huang Y, Parini P, Gustafsson J-Å, Pettersson S, Arulampalam V, Rafter J (2008). "Lactobacilli targets fat storage by activating fasting induced adipose factor (FIAF)." PLoS Biology (Submitted)
I. Lundin A, Bok CM, Aronsson L, Björkholm B, Gustafsson JA, Pott S, Arulampalam V, Hibberd M, Rafter J, Pettersson S (2008). "Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine." Cell Microbiol 10(5): 1093-103. Epub 2007 Dec 17
Pubmed
II. Are A, Aronsson L, Wang S, Greicius G, Lee YK, Gustafsson JA, Pettersson S, Arulampalam V (2008). "Enterococcus faecalis from newborn babies regulate endogenous PPARgamma activity and IL-10 levels in colonic epithelial cells." Proc Natl Acad Sci U S A 105(6): 1943-8. Epub 2008 Jan 30
Pubmed
III. Aronsson L, Huang Y, Parini P, Gustafsson J-Å, Pettersson S, Arulampalam V, Rafter J (2008). "Lactobacilli targets fat storage by activating fasting induced adipose factor (FIAF)." PLoS Biology (Submitted)
Issue date: 2008-05-23
Rights:
Publication year: 2008
ISBN: 978-91-7409-048-2
Statistics
Total Visits
Views | |
---|---|
Microbial ...(legacy) | 640 |
Microbial ... | 101 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Microbial ... | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 343 |
thesis.pdf | 118 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 326 |
China | 64 |
Sweden | 62 |
Germany | 61 |
South Korea | 15 |
Finland | 12 |
United Kingdom | 9 |
Russia | 9 |
Ireland | 7 |
Denmark | 6 |
Top cities views
Views | |
---|---|
Sunnyvale | 26 |
Romeo | 24 |
Beijing | 22 |
Kiez | 18 |
Seoul | 14 |
Nürnberg | 11 |
Dublin | 7 |
London | 7 |
Shenzhen | 7 |
University Park | 7 |