Liver tissue microbiota in nonalcoholic liver disease: a change in the paradigm of host-bacterial interactions

Abstract

Nonalcoholic fatty liver disease (NAFLD) pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors, the genetic variance of the nuclear and mitochondrial genome, associated phenotypic traits, and the yet not fully explored interactions with epigenetic and other environmental factors, including the microbiome. Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD, the precise mechanisms that explain the variability of the histological phenotypes are not fully understood. Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis (NASH) provided clues on the role of the fecal microbiome in the disease pathogenesis. Nevertheless, the composition of the gut microbiota does not fully explain tissuespecific mechanisms associated with the degree of disease severity, including liver inflammation, ballooning of hepatocytes, and fibrosis. The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein. Therefore, not only microbes would become entrapped in the complex liver anatomy but, more importantly, bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response. Hence, the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a "gut-centric" to a "liver-centric" approach. Here, we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH. Besides, we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.

Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem

“…Indeed, anatomically, the liver is a true receptacle for bacteria and derived products, filtering them from incoming blood through the hepatic artery and the portal vein. In a recent review [ 30 ], studies performed specifically in young people with MAFLD showed an increase in Prevotella copri , Proteabacteria and Escherichia species. Bacteria-derived products such as bacterial RNA and DNA can also induce host inflammatory responses by activating the innate immune defense system such as the inflammasome.…”

Human blood vessel microbiota in healthy adults based on common femoral arteries of brain-dead multi-organ donors

“…In the case of visceral tissues previously considered sterile, it has been repeatedly shown that they contain microbial genetic material ( Aagaard et al, 2014 ; Ghaemi et al., 2021 ; Sookoian and Pirola, 2021 ). Indeed, hereby we could detect these from healthy arterial wall.…”

“…Traditionally, most of the internal organs and blood are considered sterile. However, recent evidence has challenged this dogma by molecular-based detection of microorganisms in different tissues of healthy and non-healthy individuals ( Paisse et al., 2016 ; Mansour et al., 2020 ; Molina et al., 2021 ; Sookoian and Pirola, 2021 ). Moreover, some authors could identify biologically relevant living microorganisms in these “sterile” regions ( Clifford and Hoffman, 2015 ; Potgieter et al., 2015 ; Moreno et al., 2016 ).…”

The gut barrier and chronic diseases

“…Patients with NAFLD and NASH are also more likely to have increased intestinal permeability via disruption of tight junction proteins that occurs after initial hepatic injury [35]. Interestingly, intestinal permeability through direct exposure of endotoxemia from lipopolysaccharide of gram negative microbes has also been suggested as playing role in the pathogenesis of NASH [36].…”