Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host-microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow-up cohort, where 22 subjects with varying degree of HS are characterized.

Gut microbiota–mitochondrial inter-talk in non-alcoholic fatty liver disease

“…For example, Campylobacter concisus and Porphyromonas endodontalis negatively regulated the expression of CXCL9 and LIF-R, respectively, and Veillonella atypica positively regulated the expression of CD244. Based on these data, we can infer that these inflammation-related proteins are responsible for enhancing antigen presentation to lymphocytes, which break the liver immune tolerance and stimulate both cellular and humoral immune responses in NAFLD ( 4 , 39 ). In addition, some species of bacteria, including Bacteroides caecimuris , Bacteroides xylanisolvens , and Clostridium bolteae , were able to regulate the levels of IL-10+ Tregs and CD8+ T-cells in patients with NAFLD-HCC, suggesting that these bacteria participate in the modulation of adaptive immunity ( 39 ).…”

“…Meantime, the abundance of Enterobacteriaceae , Streptococcus , and Gallibacterium was enhanced in patients with NAFLD-cirrhosis, while Faecalibacterium prausnitzii , Catenibacterium , Rikenellaceae , Mogibacterium , and Peptostreptococcaceae were only identified in healthy participants. The composition of the gut microbiome also significantly differed with different severities of HS ( 4 ). The abundance of Bacteroidetes , Proteobacteria , Lentisphaerae , and Firmicutes was largely decreased in patients with mild steatosis.…”

“…Metabolites in the circumstance system were also altered, following the changes in the gut microbiota, which highlighted the etiological mechanisms of NAFLD. Data are available describing specific metabolite signatures related to the different stages of NAFLD ( 4 ). Furthermore, gut bacterial metabolites participate in maintaining homeostasis and affect the development of NAFLD through the gut microbiota–liver axis ( Table 2 ).…”

“…Non-alcoholic fatty liver disease (NAFLD) is a progressive disease initiated by an increase in hepatic lipid content, which may progress to various chronic liver diseases such as hepatic steatosis (HS), steatohepatitis, cirrhosis, and NAFLD-related hepatocellular carcinoma (HCC) (1)(2)(3). Due to its close relationship with metabolic dysfunction, NAFLD has been defined as metabolic dysfunction-associated fatty liver disease (MAFLD) (4). The prevalence of NAFLD is increasing at an alarming rate worldwide, severely affecting 20-30% of North American adults, 80% of individuals 10.3389/fnut.2022.934113 with obesity, and most patients with type 2 diabetes (T2D) (5).…”

Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease

“…Additionally, a reanalysis of a metabolomics study that focused on youth non-alcoholic fatty liver disease revealed an association between the serum 5-AVAB level and hepatic steatosis [72,73]. Similarly, the 5-AVAB plasma level has been associated with metabolic dysfunction-associated fatty liver disease and, rather interestingly, a di-methylated form of 5-AVAB was claimed to be an important predictor for metabolic dysfunction-associated fatty liver [74].…”