The Integrated “Multiomics” Landscape at Peak Injury and Resolution From Alcohol‐Associated Liver Disease

Abstract

Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wildtype mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD. (Hepatology Communications 2021;0:1-28).A ccording to the National Institutes on Alcohol Abuse and Alcoholism, about 88,000 people (62,000 men and 26,000 women) die from alcohol use disorders annually, making alcohol the third leading preventable cause of death in the United States. Overall, alcohol causes more than 5% of the global disease burden worldwide.

Advancements in the Alcohol-Associated Liver Disease Model

“…Furthermore, the species, gender, age, and environment of the animals may have an impact on the construction of the model [ 10 , 142 , 221 ]. More obvious damage can be obtained using the same conditions via choosing animals that are more sensitive to alcohol (such as elderly and female rats) to build a model [ 221 , 222 ].…”

“…Furthermore, the species, gender, age, and environment of the animals may have an impact on the construction of the model [ 10 , 142 , 221 ]. More obvious damage can be obtained using the same conditions via choosing animals that are more sensitive to alcohol (such as elderly and female rats) to build a model [ 221 , 222 ]. Interestingly, some changes, such as increased room temperature, can significantly reduce mortality as well as the extent of liver damage in the rodents being greatly reduced [ 10 , 112 ].…”

Ablation of secreted phosphoprotein‐1 in hepatocytes increases fatty acid oxidation and ameliorates alcohol‐associated liver disease

“…Details on general methodology, such as immunohistochemistry (IHC) of SPP1, hematoxylin and eosin (H&E) staining, measurement of liver TGs, serum alanine aminotransferase (ALT) activity, and serum alcohol concentration, total RNA extraction, and qPCR analysis, are described in previous publications (Arriazu et al., 2017; Cubero & Nieto, 2012; Das et al., 2022; Embgenbroich & Burgdorf, 2018; Ge, Antoine, et al., 2014; Ge, Leung, et al., 2014; Nieto, 2006). Primer sequences are listed in Table S1.…”

Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function

“…DNA was isolated from fecal samples using the DNeasy power soil kit (Qiagen, Germantown, MD). 55 Sequencing of 16S rRNA was performed at the Argonne National Laboratory (Lemont, IL) using an Illumina micro MiSeq platform. 56 , 57 The V4 region of the 16S rRNA gene was amplified using specific barcodes and primer sequences listed in Table 2 .…”