Differential blood transcriptome modules predict response to corticosteroid therapy in alcoholic hepatitis

Shvetank Sharma; Sukriti Baweja; Jaswinder S Maras; Saggere M Shasthry; Richard Moreau; Shiv K Sarin

doi:10.1016/j.jhepr.2021.100283

Differential blood transcriptome modules predict response to corticosteroid therapy in alcoholic hepatitis

JHEP Rep. 2021 Mar 24;3(3):100283. doi: 10.1016/j.jhepr.2021.100283. eCollection 2021 Jun.

Authors

Shvetank Sharma¹, Sukriti Baweja¹, Jaswinder S Maras¹, Saggere M Shasthry², Richard Moreau^{3

4}, Shiv K Sarin²

Affiliations

¹ Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
² Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
³ Centre de Recherche sur l'Inflammation (CRI), INSERM, Université de Paris, Paris, France.
⁴ Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.

Abstract

Background & aims: In patients with severe alcoholic hepatitis (SAH), little is known about the profile of peripheral blood mononuclear cells (PBMCs) at baseline and during corticosteroid therapy, among those who can be treated successfully with steroids (steroid-responders [R] and those who cannot (steroid-non-responders [NR]); 2 groups with different outcomes.

Methods: We performed RNA-seq analysis in PBMCs from 32 patients with definite SAH, at baseline and after 7 days of corticosteroids. The data were sorted into R and NR (n = 16, each group) using the Lille model and 346 blood transcription modules (BTMs) were identified. BTMs are predefined modules of highly co-expressed PBMC genes, which can determine specific immune cell types and cellular functions. The activity of each BTM was taken as the mean value of its member genes.

Results: At baseline, 345 BTMs had higher activity (i.e. were upregulated) in NR relative to R. The 100 most upregulated BTMs in NR, included several modules related to lymphoid lineage (T, B, and natural killer [NK] cells), modules for cell division and mitochondrial respiratory electron transport chain (ETC, relating to energy production), but only a few modules of myeloid cells. Correlation studies of BTM activities found features of significantly greater activation/proliferation and differentiation for T and B cells in NR relative to R. After 7 days of corticosteroids, NR had no significant changes in BTM activities relative to baseline, whereas R had downregulation of BTMs related to innate and adaptive immunity.

Conclusions: At baseline and during corticosteroid therapy, increased activity in the PBMCs of gene modules related to activation/proliferation and differentiation of T and B cells, NK cells, and mitochondrial ETC, is a hallmark of SAH patients who are steroid-non-responders.

Lay summary: Patients with severe alcoholic hepatitis receive steroid therapy as the main line of treatment; however, this treatment is ineffective in some patients. This only becomes apparent after 7 days of steroid therapy. We have developed an approach where it can be estimated if a patient is going to respond or not to steroid therapy using the gene expression information of blood cells. This method will allow clinicians to assess the response of patients to steroids earlier, and will help them in adopting alternate strategies if the treatment is found to be ineffective in a particular patient.

Keywords: Alcoholic liver disease; BTM, blood transcription module; CTP score, Child-Turcott-Pugh score; DEGs, differentially expressed genes; ETC, electron transport chain; Glucocorticoid receptor; MDF, Maddrey’s discriminant function; MELD, model for end-stage liver disease; NK cells, natural killer cells; NR, non-responders; NR3C1; NR3C1, nuclear receptor subfamily 3 group c gene member 1; OxPhos, oxidative phosphorylation; PBMCs, peripheral blood mononuclear cells; R, responders; RNA-seq, RNA sequencing; SAH, severe alcoholic hepatitis; Steroid; Transcriptome.