Regulatory T cells improve gut barrier integrity through preserving colonic short-chain fatty acid levels in cirrhotic mice

The intestinal epithelial barrier is not just a static physical barrier but rather interacts continuously with the gut microbiome and immune cells. An intact intestinal barrier protects the host against invasion of microorganisms and toxins whereas at the same time it allows absorption of essential fluids and nutrients.

The pathophysiology of cirrhosis is associated with a dysfunctional intestinal barrier, which facilitates translocation of pathogens or their products and other noxious invasions to the bloodstream. Although the inflammatory response to these episodes in cirrhosis is modulated by an interleukin (IL)-10-mediated mechanism, the underlying mechanisms by which IL-10 producing regulatory T cells (Tregs) improve gut barrier integrity in cirrhosis is unknown.

In a recent study of our research group we have demonstrated that Tregs restrict permeability to bacterial antigen translocation through preserving the levels of short-chain fatty acids in experimental cirrhosis.

After 16 weeks-induced cirrhosis through carbon tetrachloride, we assessed gut barrier markers and intestinal T helper lymphocytes crucial in gut homeostasis in mice that cannot produce mature B and T cells and wild-type mice (controls).

Mice without the capacity to produce mature B and T lymphocytes showed an increased gut permeability to orally administered lipopolysaccharide (LPS) and higher rates of bacterial DNA translocation in mesenteric lymph nodes, when compared with control mice.

By contrast, the inoculation of naïve T cells and Treg cells from wild-type animals into immunodeficient mice led to a reduction in gut permeability to LPS and restored tight junction protein expression -including zonula occludens (ZO-1), occludin, claudin 1 and claudin 2- in colonic tissue. Naïve T cells alone were not able to reduce gut permeability to LPS, which highlights the crucial role of Tregs on gut barrier integrity.

Besides this, the coinjection of naïve T and Treg cells also limited the proinflammatory Th1 and Th17 responses in mice challenged with Escherichia coli.

We then went one step further and studied whether colonic microbiota-derived short-chain fatty acids (SCFAs) may contribute in T cells protective role on gut barrier integrity. E. coli administration led to a reduction in both colonic SCFAs levels and their receptors. However, naïve T and Tregs transfer to immunodeficient mice allowed to preserve SCFA colonic levels and reestablish the expression of SCFA receptors involved in keeping inflammatory response at bay.

On the whole, our experimental findings show that gut microbiota-derived SCFAs are relevant players contributing to the role of Tregs in maintaining gut barrier integrity and reduced permeability secondary to cirrhosis in mice.

 

 

Reference:

Juanola O, Piñero P, Gómez-Hurtado I, et al. Regulatory T cells restrict permeability to bacterial antigen translocation and preserve short-chain fatty acids in experimental cirrhosis. Hepatology Communications. 2018; 0(0):1-14. doi: 10.1002/hep4.1268.

Oriol Juanola & Rubén Francés
Oriol Juanola & Rubén Francés
Oriol Juanola is a PhD. student of the Hepatic and Intestinal Immunobiology Group at Miguel Hernández University (Alicante, Spain). The group is interested in molecular and cellular aspects around the immune system that are responsible for the surveillance, response and regulation of homeostasis with our gut microbiota in the so-called "gut-liver axis", a central element in different metabolic pathologies within the scope of the gastroenterology and hepatology. The translation of these aspects, addressed from different methodological perspectives, to the clinical field is also relevant for the Group in order to improve the diagnosis, treatment and/or prognosis of these diseases. Rubén Francés is professor of Immunology and Head of the Hepatic and Intestinal Immunobiology Group at Miguel Hernández University and the Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD).