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1. Cross talk between the liver microbiome and epigenome in patients with metabolic dysfunction-associated steatotic liver diseaseResearch in context

Author

Carlos Jose Pirola, Adrian Salatino, Tomas Fernández Gianotti, Gustavo Osvaldo Castaño, Martin Garaycoechea, and Silvia Sookoian

Subjects
NAFLD, MASLD, Microbiota, Epigenetics, HDAC, HAT, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease), including its severe clinical forms, involves complex processes at all levels of biological organization. This study examined the potential link between the liver microbiome profile and epigenetic factors. Methods: Liver microbial DNA composition was analysed using high throughput 16S rRNA gene sequencing in 116 individuals, with 55% being female, across the spectrum of liver disease severity. Total activity of histone deacetylases (HDACs) and acetyltransferases (HATs) was assayed in nuclear extracts from fresh liver samples. In addition, we measured the global 5-hydroxymethylcytosine (5-hmC) levels of liver DNA. Findings: Patients with MASLD showed a 2.07-fold increase (p = 0.013) in liver total HAT activity. Moreover, a correlation was observed between liver total HAT activity and the score for histological steatosis (Spearman’s R = 0.60, p = 1.0E-3) and disease severity (R = 0.40, p = 2.0E-2). Liver HAT and HDAC activities also showed associations with the abundance of several liver bacterial DNAs. Additionally, liver global levels of 5-hmC showed negative correlation with the read number of Bacteroidetes (R = −0.62, p = 9.3E-4) and Gammaproteobacteria (R = −0.43, p = 3.2E-2), while it was positively correlated with the abundance of Acidobacteria (R = 0.42, p = 4.1E-2) and Actinobacteria (R = 0.47, p = 1.8E-2). Interpretation: The host liver epigenome, including the activity of enzymes involved in maintaining the balance between protein acetylation and deacetylation and the global DNA hydroxy-methylation status, may be the target of microbial signals. Funding: Agencia Nacional de Promoción Científica y Tecnológica, FonCyT.

Published
2024
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2. The influence of host genetics on liver microbiome composition in patients with NAFLD

Author

Carlos Jose Pirola, Adrian Salatino, Maria Florencia Quintanilla, Gustavo Osvaldo Castaño, Martin Garaycoechea, and Silvia Sookoian

Subjects
TM6SF2, transmembrane 6 superfamily member 2, Medicine (General), Genotype, HSD17B13, hydroxysteroid 17-beta dehydrogenase 13, Polymorphism, Single Nucleotide, MBOAT7, Membrane bound O-Acyltransferase domain containing 7, General Biochemistry, Genetics and Molecular Biology, TM6SF2, FGF21, Fibroblast growth factor 21, HSD17B13, MBOAT7, FGF21, R5-920, Non-alcoholic Fatty Liver Disease, RNA, Ribosomal, 16S, Genetics, Humans, Genetic Predisposition to Disease, PNPLA3, PNPLA3, patatin-like phospholipase domain containing 3, Microbiota, NASH, Membrane Proteins, Articles, Lipase, General Medicine, Liver, NAFL, nonalcoholic fatty liver, Medicine, Risk score, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis
Abstract

Summary Background Human body microbiotas are influenced by several factors, including the interaction of the host with the environment and dietary preferences. The role of host genetics in modulating the liver microbiota in the context of NAFLD remains unknown. To address this gap, we examined the interplay between the liver metataxonomic profile and host genetics. Methods We obtained 16S rRNA gene sequences from liver biopsies and genotypes by Taqman-assays in 116 individuals. We compared taxon abundance at the genus level across host genotypes using dominant models of inheritance. We focused the analysis on variants influencing the risk/ protection against NAFLD-histological severity (PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and HSD17B13-rs72613567) and a variant influencing macronutrient intake (FGF21-rs838133). We also explored the variants' combined effect via a polygenic risk score (PRS). Findings We identified at least 18 bacterial taxa associated with variants in the selected loci. Members of the Gammaproteobacteria class were significantly enriched in carriers of the rs738409 and rs58542926 risk-alleles, including Enterobacter (fold change [FC]=6.2) and Pseudoalteromonas (FC=2) genera, respectively. Lawsonella (1.6-FC), Prevotella_9 (FC=1.5), and Staphylococcus (FC=1.3) genera were enriched in rs838133-minor allele carriers, which is linked to sugar consumption and carbohydrate intake. Tyzzerella abundance (FC=2.64) exhibited the strongest association (p = 0.0019) with high PRS values (>4 risk alleles). The percentage of genus-level taxa variation explained by the PRS was ∼7.4%, independently of liver steatosis score and obesity. Interpretation We provided evidence that genetic variation may influence the liver microbial DNA composition. These observations may represent potentially actionable mechanisms of disease., Graphical abstract Image, graphical abstract

Published
2022

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