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Lena Holm

Gastro-intestinal protection mechanisms studied in vivo

The gastro-intestinal (GI) mucosal barrier, i.e. the mucus layer, the tight epithelium, the blood flow and the immune system, are crucial in separating the inside of our bodies from the high acidity in the stomach and the enormous amount of bacteria residing in the colonic lumen. Our primary goals are to investigate protection mechanisms against the hazardous agents in the gastro-intestinal lumen. The mucosal barrier is studied in rats and mice (germ free or genetically modified) in a unique GI model developed in our laboratory, allowing direct access to the mucosa with intravital microscopy. Using this model we measure mucus thickness and accumulation rate with microelectrodes, and have demonstrated that the adherent gastricand colonic mucus gel in vivo can be divided in two layers, afirmly and aloosely adherent layer (Fig 1). The firmly adherent mucus layer acts as a barrier towards hydrochloric acid in the stomach and luminal bacteria in the colon. After DSS induced colitis this protective barrier is destroyed allowing bacterial translocation into the tissue.

 

Fig 1. The mucus layers in different parts of the GI tract.

 

We have shown that dietary nitrate induces potent protection against NSAID induced upper GI inflammation. Bacteria in the oral cavity reduce nitrate to nitrite, which is further reduced to nitric oxide, NO, in the acidic stomach. NO strengthen the mucosal barrier by increasing mucus thickness and blood flow. Ongoing studies indicate protection by dietary nitrate even further down in the intestine where luminal NO is not increased and the mechanisms behind this protection is now being investigated.
The influence of probiotics on mucus dynamics, bacterial composition, inflammatory variables and epithelial tight junctions are studied to elucidate the mechanisms behind their protective effects. We have recently shown that pretreatment with probiotics (L. reuteri) prevent dextran sodiumsulphate (DSS) induced colitis in rats and mice. Up regulation of P-selectin in the colonic venules wasprevented by probiotic therapy, and in vivo fluorescence microscopy confirmed these results by showing decreased leukocyte rolling and adhesion to endothelial cells, as well as decreased platelet-endothelial cell interactions (Fig 2 and 3).


Fig 2. Leukocyte rolling
in colonic mucosal venules.

 

Fig 3. Transient platelet-endothelial interaction in vivo.

Our current research focus on the interplay between the commensal bacteria and the colonic mucosal barrier in health and during inflammation (IBD). The studies also involve the interplay between the microbiota, visceral fat and the metabolic syndrome.

 

Dissertations 2007 - 2011:

Joel Petersson (2008)
Olof Schreiber (2010)


For further information about this research group please contact
Professor Lena Holm: Lena.Holm@mcb.uu.se

Grants:

Collaborators

within the Department of Medical Cell Biology:

  • Mia Phillipson,
  • Stellan Sandler.

outside the Department of Medical Cell Biology:

  • Håkan Björne (Karolinska Institute, Stockholm),
  • Johan Dicksved (Uppsala University),
  • Lars Engstrand (Karolinska Institute, Stockholm),
  • Gunnar C Hansson (Göteborg University),
  • Per Hellström (Uppsala University),
  • Nathalie Juge (Norwich Research Park, Norwich, UK),
  • Mats Lindblad (Karolinska Institute, Stockholm),
  • Jon Lundberg (Karolinska Institute, Stockholm) ,
  • Margareta Nyman (Lund University),
  • Michael Perry (University of New South Wales, Sydney, Australia),
  • Stefan Roos (Swedish University of Agricultural Sciences (SLU), Uppsala),
  • Eddie Weitzberg (Karolinska Institute, Stockholm),