The influence of host genetics on liver microbiome composition in patients with NAFLD
Carlos Jose Pirola,
Adrian Salatino,
Maria Florencia Quintanilla,
Gustavo Osvaldo Castaño,
Martin Garaycoechea,
Silvia Sookoian
Affiliations
Carlos Jose Pirola
University of Buenos Aires, School of Medicine, Institute of Medical Research A Lanari, Ciudad Autónoma de Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute for Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Ciudad Autónoma de Buenos Aires, Argentina; Corresponding authors at: Instituto de Investigaciones Médicas, IDIM-CONICET, Combatientes de Malvinas 3150, CABA-1427, Argentina.
Adrian Salatino
University of Buenos Aires, School of Medicine, Institute of Medical Research A Lanari, Ciudad Autónoma de Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute for Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Ciudad Autónoma de Buenos Aires, Argentina
Maria Florencia Quintanilla
University of Buenos Aires, School of Medicine, Institute of Medical Research A Lanari, Ciudad Autónoma de Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute for Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Ciudad Autónoma de Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute for Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Ciudad Autónoma de Buenos Aires, Argentina
Gustavo Osvaldo Castaño
Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
Martin Garaycoechea
Department of Surgery and CEMET, Hospital de Alta Complejidad en Red “El Cruce”, Florencio Varela, Buenos Aires, Argentina
Silvia Sookoian
University of Buenos Aires, School of Medicine, Institute of Medical Research A Lanari, Ciudad Autónoma de Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute for Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Ciudad Autónoma de Buenos Aires, Argentina; Corresponding authors at: Instituto de Investigaciones Médicas, IDIM-CONICET, Combatientes de Malvinas 3150, CABA-1427, Argentina.
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.
