Project ID iCASE2023_03

ThemeCM-HD

Co Supervisor 1A Faculty of Life Sciences & Medicine School of Immunology & Microbial Sciences Roger Williams Institute of HepatologWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine School of Immunology & Microbial Sciences Department of Liver SciencesWebsite

Therapeutic Targeting of Intestinal Cell Death in Cirrhosis – Opportunities for Translation

Scientific basis: Breakdown of the gut barrier in cirrhosis leads to ‘translocation’ of bacterial products from the gut to systemic circulation, leading to complications and death. The only current treatment for bacterial translocation is long-term of administration of antibiotics to decrease gut bacterial burden. However, this approach leads to antimicrobial resistance and toxicity. Novel treatments for gut barrier dysfunction in cirrhosis are urgently needed.

The intestinal epithelium maintains the integrity of the gut barrier. Intestinal cell death has previously been shown to contribute to gut permeability in models of sepsis. Key observations from our group, demonstrate:

Intestinal epithelial cell death is significantly increased in patients with cirrhosis, and in rodent models of cirrhosis, compared to healthy controls

Intestinal permeability can be reliably measured in vitro using ‘mini-gut’ organoids

The cell death inhibitor, Dimethyl fumarate (DMF), significantly improves cell death and inflammatory pathway activation in vitro

Aims/Questions:

In patients with cirrhosis, what is the mechanism of intestinal cell death?

Is pro-inflammatory cell death increased in intestinal organoids derived from cirrhotic mice, compared to control? If so, does this lead to altered intestinal permeability?

Is DMF effective in inhibiting intestinal cell death, and improving intestinal permeability in intestinal organoids and rodent models of cirrhosis?

Techniques and skills provided: intestinal organoid and permeability studies, in vivo models of liver disease, introduction to bioinformatic analyses, drug development, intellectual property and commercial interactions.

One representative publication from each co-supervisor:

Junqueira C, Crespo Â, Ranjbar S, de Lacerda LB, Lewandrowski M, Ingber J, Parry B, Ravid S, Clark S, Schrimpf MR, Ho F, Beakes C, Margolin J, Russell N, Kays K, Boucau J, Das Adhikari U, Vora SM, Leger V, Gehrke L, Henderson LA, Janssen E, Kwon D, Sander C, Abraham J, Goldberg MB, Wu H, Mehta G, Bell S, Goldfeld AE, Filbin MR, Lieberman J. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature. 2022 Jun;606(7914):576-584.

Patel VC*, Lee S*, McPhail M, Da Silva K, Guilly S, Zamalloa A, Witherden E, Støy S, Manakkat Vijay GK, Pons N, Galleron N, Huang X, Gencer S, Coen M, Tranah TH, Wendon JA, Bruce K, Le Chatelier E, Ehrlich SD, Edwards LA, Shoaie S, Shawcross DL. Rifaximin reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial. J Hepatol. 2022 Feb;76(2):332-342.