Bacterial Membrane Vesicle as modulators of Liver Inflammation and Fibrosis in PSC-IBD
Background
In the context of PSC-IBD, the gut microbiota, including pathobionts like Klebsiella pneumoniae and Proteus mirabilis, actively shapes disease's initiation and progression, highlighting its significance in this multifactorial disorder. Interestingly, increasing evidence indicates bacterial extracellular vesicles (BEVs) as intriguing and novel contributors to the pathogenesis of various immune-mediated diseases such as PSC-IBD, necessitating further investigation.
Methods
Preclinical mouse models in addition to ductal organoids (human and murine) were used characterize the impact of tryptophan metabolisms and bacterial outer membrane vesicle (OMVs) to promote liver fibrosis. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n=22), PSC-IBD (n=45) and control individuals (n=27) was performed to detect OMVs in the systemic circulation and liver.
Results
Utilizing ductal organoids, we were able to identified pro-inflammatory and fibrogenic effects of OMVs to signaling pathways reliant on TLR4 and NLRP3-GSDMD. This pro-inflammatory capacity of OMVs could be further demonstrated in macrophages and hepatic stellate cells. Moreover, administration of OMVs derived from gut pathobionts to Mdr2-/- mice markedly exacerbated liver inflammation and fibrosis, underscoring the detrimental impact of these vesicles. In a translational effort, we substantiated the presence of OMVs in both systemic circulation and hepatic tissues of individuals with severe fibrosis from a PSC-IBD patient cohort. Translocation of OMVs triggers innate immune responses culminating in the secretion of pro-inflammatory factors and promotes fibrosis.
Conclusion
Identifying OMVs as a critical environmental factor interacting with other disease determinants highlights promising avenues for fibrosis therapy for PSC-IBD patients.
Keywords
bacterial extracellular vesicle, hepatic inflammation, PSC-IBD, inflammasome
Authors
Iris Stolzer1 (Corresponding Author: iris.stolzer[at]uk-erlangen[dot]de ), Heidrun Dorner1, Jochen Mattner2,3, Sofia Leistl1, Lisa-Maria Edrich1, Raphael Schwendner1, Miguel Gonzalez Acera1, Miriam Düll1, Claus Hellerbrand4, Gregor Fuhrmann5, Ute Distler6, Stefan Tenzer6, Philipp Arnold7, Raja Atreya1,3,8, Peter Dietrich1,5, Stefan Wirtz1,3,8, Andreas E. Kremer1,8,9, Markus F. Neurath1,3,8, Claudia Günther1,3,8