Duodenal CD8+ T resident memory cell apoptosis contributes to gut barrier dysfunction and microbial translocation in early alcohol-associated liver disease in humans.

Maccioni, Luca;Loriot, Axelle;Dewulf, Joseph;Bommer, Guido;Starkel, Peter;et.al.
(2022) Alimentary Pharmacology and Therapeutics — Vol. 56, n° 6, p. 1055-1070 (2022)

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(en) BACKGROUND: Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol-associated liver disease (ALD) remain unknown. AIM: To explore the links between intestinal T cells, microbial translocation and ALD METHODS: Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non-alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18-M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC-MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS-sorted cells. Mechanisms for T-cell alterations were assessed in vitro. RESULTS: Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose-dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short-term abstinence did not reverse TRM cell death in patients with ALD. CONCLUSIONS: Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.
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Maccioni, L., Loriot, A., Dewulf, J., Bommer, G., Horsmans, Y., Lanthier, N., Leclercq, I., Schnabl, B., & Starkel, P. (2022). Duodenal CD8+ T resident memory cell apoptosis contributes to gut barrier dysfunction and microbial translocation in early alcohol-associated liver disease in humans. Alimentary Pharmacology and Therapeutics, 56(6), 1055-1070. https://doi.org/10.1111/apt.17177 (Original work published 2022)