Focus on the gut-liver axis: semisynthetic bile acid has anti-inflammatory effects on the gut

A research team from the Medical University of Vienna has made further progress in the treatment of intestinal inflammation. A study shows that the semi-synthetic bile acid NorUDCA inhibits in the intestine the formation of pro-inflammatory T helper 17 cells (TH17) and at the same time promotes the generation of anti-inflammatory regulatory T cells. This could be a promising new therapeutic option for patients with TH17-mediated intestinal diseases. The results were recently published in the journal Gut.

NorUDCA (24-nor-ursodeoxycholic acid) is a chemically modified bile acid that has already shown promising results in the treatment of liver diseases such as primary sclerosing cholangitis (PSC) and is being tested in clinical studies. As PSC is often associated and potentially causally linked with chronic inflammatory bowel disease, a MedUni Vienna research team, jointly led by Michael Trauner (Clinical Division of Gastroenterology and Hepatology) and Wilfried Ellmeier (Institute of Immunology), has now investigated the effect of NorUDCA on the intestinal immune system. It was shown that NorUDCA not only inhibits pro-inflammatory TH17 cells, but also favors their conversion into regulatory T cells (Tregs).

Various mouse models that mimic intestinal inflammation were used to investigate the effect of NorUDCA. These included a model in which certain immune cells (CD4+ T cells) were transferred into immunocompromised mice to analyze the role of TH17 cells. Another mouse model used human immune cells from PSC patients to transfer the results to humans. State-of-the-art analytical methods such as multicolour flow cytometry, RNA sequencing and metabolic analyses using mass spectrometry helped to uncover the mechanisms behind the anti-inflammatory effects of NorUDCA. The results in the models show that NorUDCA also has an effect on human immune cells. Ci Ashley Zhu, senior postdoc and first author of the study: "We were able to confirm the anti-inflammatory effect of NorUDCA not only in mouse models, but also in a humanised mouse model with cells from PSC patients, which indicates that this effect could also work in the human intestine." This study provided new mechanistic insights into the signaling action of bile acids in the gut-liver axis.

Wilfried Ellmeier explains: "The results of our study provide new insights into the regulation and modulation of TH17 cells and show how metabolic processes in immune cells can be specifically influenced by NorUDCA in order to treat T-cell-mediated inflammatory diseases. The result of this research is the outcome of a successful collaboration between basic immunological research and clinical gastroenterology and hepatology at MedUni Vienna."

Michael Trauner adds: "The fact that NorUDCA has a significant immunomodulatory effect not only in the liver, but also in the intestine, could lead to the development of new therapies for inflammatory bowel diseases such as ulcerative colitis or Crohn's disease in the future, in addition to its importance for the treatment of PSC. The preclinical data also indicate that these immunomodulatory processes could even influence neuroinflammatory processes in the brain, i.e. outside the gut-liver axis."

The research, which was initiated during a retreat of the Immunology Research Cluster of the Medical University of Vienna, was supported by funding from the Austrian Science Fund (FWF).