The 'microbiome', the 'gut-liver-axis' and systemic immune priming

The ‘Microbiome, the ‘gut-liver-axis’ and systemic immune priming’.

This project aims to investigate the immunological mechanisms of acute-on-chronic liver failure, an area causing most morbidity and mortality in liver disease at present, with the aim to develop new research approaches and much needed new clinical treatments.

The relationship between the mucosal immune system with the human microbiota is a balanced, yet unchartered, interplay between defence, pathogenic and symbiotic factors. Genetic, dietary and environmental factors can compromise the composition of a healthy microbiota leading to microbial imbalance or dysbiosis. Intestinal dysbiosis results in gut barrier dysfunction and bacterial translocation, which modulates antigenic exposure, antigen presenting cell immunogenicity, and regulatory lymphocyte function in the gut. The liver is in constant exposure to gut-derived nutrient and microbial products; microbiota-dysbiosis influences liver immunopathology and is currently considered a key pathogenic cofactor in liver diseases, the mechanisms for this are unclear.

The intestinal microbiota has an immense impact on host physiology, metabolism and immunity. The major end products of bacterial fermentation are the short-chain fatty acids (SCFA). SCFA play an important role in regulating the integrity of the intestinal epithelial barrier. SCFA also condition intestinal epithelial cells to be more responsive to bacterial products. This function is important for controlling the dichotomy between host responses to pathogens, whilst tolerance to microbiota. Recently, SCFA have been found to modulate the aryl-hydrocarbon receptor (AhR) and it’s target genes in the liver and intestine. The AHR has emerged as a regulator of both innate and adaptive immunity in mucosal barriers. SCFA have been shown to promote regulatory T cell (Treg) induction and modulate the mTOR pathway and depending on the cytokine milieu, generate TH17, TH1 and IL-10+ T-cells. Further work is urgently needed in human models to determine the role of SCFA and the AHR in mucosal barrier integrity and liver immunology.

 

Contact Dr Lindsey Edwards:  l.edwards@researchinliver.or.uk

 

Key collaborators:

Professor Giovanni Lombardi KCL, Professor Richard Thompson KCL, Professor Graham Lord KCL, Dr Nick Powel KCL, Dr Simon Eaton UCL, Dr Julian Naglik KCL, Professor Bryan MacKenzie University of Cincinnati USA

 

Key publicatons:

Chronic Rejection of Cardiac Allografts is Associated with Increased Lymphatic Flow and Cellular Trafficking  Edwards, LA et al. Circulation. 2017; https://doi.org/10.1161/CIRCULATIONAHA.117.028533

Enterotoxin-producing staphylococci cause intestinal inflammation by a combination of direct epithelial cytopathy and superantigen-mediated T-cell activation. Edwards, LA et al,. Apr 2012: Inflammatory Bowel Diseases. 18, 4, p. 624-40

Characterization of a new mouse model of empyema and the mechanisms of pleural invasion by Streptococcus pneumoniae. Edwards, LA et al,. Feb 2012: American Journal of Respiratory Cell and Molecular Biology. 46, 2, p. 180-7

Aberrant response to commensal Bacteroides thetaiotaomicron in Crohn's disease: an ex vivo human organ culture study. Edwards, LA et al,. May 2011: Inflammatory Bowel Diseases. 17, 5, p. 1201-8

Bacterial-epithelial contact is a key determinant of host innate immune responses to enteropathogenic and enteroaggregative Escherichia coli. Edwards, LA et al,. 2011: PloS one. 6, 10, p. e27030

Delineation of the innate and adaptive T-cell immune outcome in the human host in response to Campylobacter jejuni infection. Edwards, LA et al,. Nov 2010: PloS one. 5, 11, p. e15398

Published by: Foundation for Liver Research

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