RT Journal Article SR Electronic T1 PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2020-323395 DO 10.1136/gutjnl-2020-323395 A1 Jiang Li A1 Xi Liang A1 Jing Jiang A1 Lingling Yang A1 Jiaojiao Xin A1 Dongyan Shi A1 Yingyan Lu A1 Jun Li A1 Keke Ren A1 Hozeifa Mohamed Hassan A1 Jianing Zhang A1 Pengcheng Chen A1 Heng Yao A1 Jiaqi Li A1 Tianzhou Wu A1 Linfeng Jin A1 Ping Ye A1 Tan Li A1 Huafen Zhang A1 Suwan Sun A1 Beibei Guo A1 Xingping Zhou A1 Qun Cai A1 Jiaxian Chen A1 Xiaowei Xu A1 Jianrong Huang A1 Shaorui Hao A1 Jinqiu He A1 Shaojie Xin A1 Di Wang A1 Jonel Trebicka A1 Xin Chen A1 Jun Li A1 , YR 2021 UL http://gut.bmj.com/content/early/2021/10/18/gutjnl-2020-323395.abstract AB Objective Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.Methods Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).Results The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.Conclusions This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.Data, that is raw reads from RNA-seq experiments in fastq files, are available in a public, open access repository without restrictions on the use or distribution of the data. The Sequence Read Archive database project accession number for accessing the data produced for this study is PRJNA548207 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA548207/).