Sven Pettersson Group
Project Groups with the Sven Pettersson Group
Regulation of gut homeostasis
Biological functions are initiated through the elicitation and receipt of signals: mechanical, chemical or biological. The manner in which the cell receives, relays and interprets a particular signal leads to the emergence of the relevant biological response(s). In many instances these signaling pathways direct the appropriate response leading to normal biological functions. However, when the integrity of the correct signal is breached, the outcome is likely detrimental to the cell and the organism. The task of maintaining this integrity is made more difficult since these pathways often operate as multiple signaling networks, enhancing and canceling a whole series of common modulators.
Our group is trying to understand how transcription factors (TF) receive information from signaling molecules that enables them to activate genes. TFs are important whenever there is a need to adapt the organism to environmental changes. In the gastrointestinal (GI) tract this can be exemplified by food intake and alterations of the gut flora.
Our model system is the alimentary tract. The aim of our studies is to comprehend the genetic and epigenetic events that determine and regulate the function(s) of the epithelial lining (a tissue critical in host responses), in interacting with the microflora, but also following triggering of inflammation as well as repair and remodeling of damaged tissue.
Our group joined MTC in late 2001. Being localized in the G-house, we have the opportunity to work in a great laboratory space full of light and work friendly setting. In addition to myself, one junior group-leader, Velmurugesan Arulampalam, PhD (Gesan), helps out to effectively organize the daily activities of the group. Gesan (a molecular biologist with interests in signal transduction) is focused on the signaling processes that regulate gut homeostasis, in particular the nuclear receptor PPARg and the transcription factor NF-kB. A recent member of our team, PhD Britta Björkholm, will be responsible for the functional genomic approach to understand how microbes contribute to and tune normal gut homeostasis (cellular microbiology).
Our studies involve experiments in cell lines and more complex experiments in mice, either under specific-pathogen-free (SPF) conditions, or kept under germ-free conditions at the core facility of Cellular Microbiology. The use of antisense and siRNA technology, together with transgenic mice expressing the adenoviral receptor on all cells enable us to study gene function in non-transformed cells and in whole organisms. Additionally, we have inhibited expression of one of the subcomponents of NF-kB (p65) by the use of phosphorothioated antisense oligonucleotides in a pilot clinical trial to treat patients with inflammatory bowel disease (IBD). The results demonstrate that abrogation of p65 activity has a dramatic effect on the chronic inflammation in these patients. We have also initiated a functional genomic approach of molecular profiling of colonic cells obtained from rodents and humans in collaboration with Index Pharmaceuticals and KTH, Sweden, and the Genome Institute of Singapore (GIS). Our focus is on chronic inflammatory disorders in the gut and in the skin. As endpoints we aim to identify critical gene products that could be used for diagnosis and prognosis for IBD, as well as to identify novel genes intimately linked to chronic inflammation, cell growth and differentiation. An additional major task for the group is to develop basic gene expression profiles from tissues like gut and liver from germ-free mice and compare these with profiles obtained from SPF mice.
Work on the Nuclear receptor PPARg
PPARg is a nuclear receptor that not only controls the expression of a large number of genes involved in metabolism, but can also inhibit inflammation. PPARg is expressed at high levels in the colonic mucosa, which is the part of the GI tract containing the highest numbers of luminal bacteria. This anti-inflammatory role suggests that bacteria could regulate the expression of PPARg in the colon and recent work from our group has shown that not only can bacteria regulate the expression of PPARg, but also that a major regulator of PPARg appears to be the TLR4 receptor. Thus, gut homeostasis depends in part on the ability to recognize and respond to bacteria in the appropriate way, by means of modulating gene expression of cells constantly exposed to microorganisms in the lumen of the gut. A major focus of our research is to understand the interaction of signaling pathways between TLR4-PPARg and control of NF-kB activity. As of January 2003 we are a part of the SSF sponsored Strategic Centre for Receptor Biology and Signal Transduction studies, with Professor Klas Kärre as its director.
Core facility for Germ Free Research
Frida Tjärnberg , Johanna Aspsäter, Evelina Edén
Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model.
Carcinogenesis 2016 May;37(5):491-9
Helicobacter pylori and gut microbiota modulate energy homeostasis prior to inducing histopathological changes in mice.
Gut Microbes 2016 ;7(1):48-53
Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.
Sci Rep 2016 ;6():20127
The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system.
Gut Microbes 2015 ;6(6):398-403
An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth.
Sci Transl Med 2015 Apr;7(281):281ra44
Microbiota Controls the Homeostasis of Glial Cells in the Gut Lamina Propria
Panagiotis S. Kabouridis, Reena Lasrado, Sarah McCallum, Song Hui Chng, Hugo J. Snippert, Hans Clevers, Sven Pettersson, Vassilis Pachnis
Neuron. January 08, 2015. DOI: http://dx.doi.org/10.1016/j.neuron.2014.12.037
The gut microbiota influences blood-brain barrier permeability in mice
Viorica Braniste, Maha Al-Asmakh, Czeslawa Kowal, Farhana Anuar, Afrouz Abbaspour, Miklós Tóth, Agata Korecka, Nadja Bakocevic, Ng Lai Guan, Parag Kundu, Balázs Gulyás, Christer Halldin, Kjell Hultenby, Harriet Nilsson, Hans Hebert, Bruce T. Volpe, Betty Diamond, Sven Pettersson
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009759
Immunology: Mammalian watchdog targets bacteria.
Nature 2014 Aug;512(7515):377-8
The gut microbiota and developmental programming of the testis in mice.
PLoS ONE 2014 ;9(8):e103809
Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway.
PLoS Pathog. 2014 Jan;10(1):e1003887
ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways.
Am. J. Physiol. Gastrointest. Liver Physiol. 2013 Jun;304(11):G1025-37
Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice.
Oncogene 2014 Jan;33(3):369-77
Enterococcus faecalis: a biological marker predicting the emergence of necrotizing enterocolitis.
Acta Paediatr. 2012 Nov;101(11):1112-3
Gut microbial communities modulating brain development and function.
Gut Microbes ;3(4):366-73
Therapeutic modulation of microbiota-host metabolic interactions.
Sci Transl Med 2012 Jun;4(137):137rv6
Host-gut microbiota metabolic interactions.
Science 2012 Jun;336(6086):1262-7
Lipocalin 2 performs contrasting, location-dependent roles in APCmin tumor initiation and progression.
Oncogene 2013 Mar;32(10):1233-9
Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice.
Carcinogenesis 2012 Jun;33(6):1231-8
Normal gut microbiota modulates brain development and behavior.
Proc. Natl. Acad. Sci. U.S.A. 2011 Feb;108(7):3047-52
Analysis of 39 Crohn's disease risk loci in Swedish inflammatory bowel disease patients.
Inflamm. Bowel Dis. 2010 Jun;16(6):907-9
Genome-wide association identifies multiple ulcerative colitis susceptibility loci.
Nat. Genet. 2010 Apr;42(4):332-7
SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer.
Mol. Cancer Ther. 2010 Mar;9(3):642-52
|Afrouz Abbaspour||PhD student, Graduate Student|
|Terri Phua||Graduate Student|
|Velmurugesan Arulampalam||Senior researcher|
Biomedical Scientist Annika Samuelsson
PhD student Sebastian Pott
PhD student Agata Korecka