Microscopy image* of colon with senescent cells stained red, tight junction protein Occludin stained in green and nuclei in blue. Image by Gemma Beasy and Naiara Beraza, QIB Advanced Microscopy Facility

Researchers have shown that certain drugs that target senescent liver cells may aggravate the progression of cholestatic liver disease by also affecting cells in the gut lining.

Research from the Quadram Institute, Norfolk and Norwich University Hospital and University of East Anglia suggests that the use of these drugs should be carefully considered because of this interconnection between the gut and liver.

Cellular senescence is a normal process whereby cells damaged by stress are prevented from replicating themselves. This senescence has important roles in tissue repair, preventing tumours and development. However, persistent, unchecked senescence can have detrimental effects, and has been implicated in liver disease.

Drugs that target senescent cells could be useful in limiting the severity of the effects of liver disease. But these senolytic drugs could also affect senescence in other organs, including the gut.

Understanding senescence in the cells that line the gut is especially important as cholestatic liver disease is associated with an overgrowth of gut bacteria and changers in its composition, as well as disruption of gut lining as a barrier preventing bacteria leaking beyond the gut. The precise mechanisms linking these changes and the gut-liver axis aren’t known.

To better understand what role cell senescence plays in this Dr Naiara Beraza and colleagues from the Quadram Institute, the Norfolk and Norwich University Hospital and University of East Anglia studied intestinal senescence during cholestatic liver disease using a combination of samples from patients with the condition and mouse models of this liver disease. The research was supported by the Biotechnology and Biological Sciences Research Council, part of UKRI.

The study, published in the Journal of Hepatology Reports, showed that in both humans and mice, cholestatic liver disease induces senescence in important cells lining the gut.

Their experiments showed that senescence is triggered by the increased presence of bacteria associated with the disease. This provides a mechanism where senescence regulates the body’s response to try to repair itself and preserve the integrity of the gut lining as a barrier.

Senolytic drugs that systematically block senescence could therefore prove to be detrimental to this process in the gut. The team’s experiments backed this up; eliminating senescent cells caused the intestinal barrier to become more leaky, and aggravated liver damage.

“Our results suggest that using senolytic drugs to counter cholestatic liver disease may cause detrimental side-effects by increasing intestinal leakiness, which exacerbates the progression of the disease” said Dr Naiara Beraza from the Quadram Institute.

“The use of these drugs needs to be carefully considered, taking in their wider effects across the gut-liver access, before they can be translated into clinical practice.”

Approaches that target specific cells or organs may avoid these problems, but information from this study linking the gut microbes to senescence also opens up opportunities to modulate the microbiome as a way of alleviating damage from cholestatic liver disease.

Reference: Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression, Mar Moreno-Gonzalez, Katherine Hampton, Paula Ruiz, Gemma Beasy, Falk SP. Nagies, Aimee Parker, James Lazenby, Caitlin Bone, Ane Alava-Arteaga, Meha Patel, Charlotte Hellmich, Pablo Luri-Martin, Ece Silan, Mark Philo, David Baker, Simon M. Rushbrook, Falk Hildebrand, Stuart A. Rushworth, Naiara Beraza, JHEP Reports, Volume 6, Issue 10,DOI: 10.1016/j.jhepr.2024.101159

*Image is part of Fig 1.