Keeping the gut barrier intact - The thin line between cell survival and cell death

3 September 2014
​Researchers at VIB and Ghent University have unraveled the crucial role of a protein (RIPK1) in keeping the gut epithelium intact. The epithelium of the gut plays a critical role in the human body as it allows absorption of nutrients and functions as a barrier to protect our body from intestinal bacteria. Keeping of this epithelium intact therefore requires tight control, which is ensured by a subtle balance between cell renewal, cell survival and cell death. RIPK1 is a protein that fulfills a dual role as regulator of cell death and cell survival. In many pathological conditions, the pro-death function of RIPK1 is predominant. Nozomi Takahashi and Peter Vandenabeele (VIB/UGent) found that , under normal conditions, RIPK1 is essential to protect gut epithelial cells from excessive cell death, and thereby ensures the barrier function of this organ from bacterial infiltration. Targeting RIPK1’s functions may therefore open new doors for the therapeutic control of diseases that are characterized by gut inflammation and local barrier loss, such as Crohn’s disease.

Nozomi Takahashi (VIB/UGent): “The right balance between cell survival and cell death is crucial in life. Too much cell death results in inappropriate functioning of an organism while too little cell death may promote cancer development. Our gut consists of a single layer of epithelial cells that separates our body from the billions of bacteria that live in our gut. The survival of epithelial cells is crucial for this barrier function that prevents bacteria from penetrating the body and causing inflammation.”

Peter Vandenabeele (VIB/UGent): “In collaboration with colleagues in Belgium, US and Germany, we found that RIPK1 plays a crucial role in protecting the gut epithelium. Under normal conditions, RIPK1 protects epithelial cells from death, which may also be the case in other cell types of the body. This contrasts with the predominant pro-death function of this protein in a growing number of disease conditions. The big remaining question is how this protein can exert such opposing functions.”

A potential new therapeutic strategy: stabilizing the pro-survival function of RIPK1
Stabilizing the pro-survival function of RIPK1 may be helpful in treating intestinal inflammatory diseases in which the barrier function is reduced, such as in Crohn’s disease. The platform function of RIPK1 actively suppresses cell death and keeps our gut barrier intact. When the platform function is disrupted, the epithelial cells of the gut die massively by apoptosis, a particular cell death program. This cell death results in permeability of the gut to bacteria, which initiates a vicious cycle of inflammation-driven cell death.

The research was published in the top magazine Nature.
Nature, September 4, 2014.

RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
Nozomi Takahashi, Lars Vereecke, Mathieu J. M. Bertrand, Linde Duprez, Scott B. Berger, Tatyana Divert, Amanda Gonçalves, Mozes Sze, Barbara Gilbert, Stephanie Kourula, Vera Goossens, Sylvie Lefebvre, Claudia Günther, Christoph Becker, John Bertin, Peter J. Gough,Wim Declercq, Geert van Loo and Peter Vandenabeele

Gut organoids grown out of stem cells of the mice lacking RIPK in the gut (lower panels) or not (upper panels) at early (left panels) or late time point (right panels) showing the dying cells stained with a red dye.
(c) VIB

Peter Vandenabeele & Nozomi Takahashi
(c) VIB - 2014