Relationship Between Hepatic Gene Expression, Intestinal Microbiota, and Inferred Functional Metagenomic Analysis in NAFLD

Abstract

INTRODUCTION: We previously reported a lower fecal abundance of Ruminococcus spp., Faecalibacterium prausnitzii, and Coprococcus spp. in nonalcoholic fatty liver disease (NAFLD). In this article, we assess the associations between hepatic gene expression, the specific taxa, and bacterial pathways. METHODS: The relationships between hepatic genes that were differentially expressed in patients with NAFLD vs healthy controls (HC) and the abundance of these specific taxa were studied. Inferred functional metagenomic analysis using Piphillin was also performed to investigate associations with bacterial pathways. RESULTS: Fifteen patients with NAFLD and 6 HC participated. Of 728 hepatic genes examined, 176 correlated with the abundance of Ruminococcus spp., 138 with F. prausnitzii, and 92 with Coprococcus spp. For Ruminococcus spp., genes were enriched in gene ontology (GO) terms related to apoptotic process, response to external and cytokine stimuli, and regulation of signaling. Several genes related to the Kyoto Encyclopedia of Genes and Genomes pathway insulin resistance were correlated with F. prausnitzii. The hepatic genes associated with F. prausnitzii were enriched in GO terms related to cellular response to different stimuli, apoptotic process, and regulation of metabolic pathways. For Coprococcus spp., only the GO term response to external stimulus was enriched. There was a distinct pattern of associations between hepatic genes and bacterial taxa in NAFLD vs HC. For bacterial pathways, 65 and 18 hepatic genes correlated with bacterial metabolic functions in NAFLD and HC, respectively. DISCUSSION: Hepatic gene expression related to insulin resistance, inflammation, external stimuli, and apoptosis correlated with bacterial taxa. Patients with NAFLD showed a higher presence of bacterial pathways associated with lipid metabolism.

Characterization of gut dominant microbiota in obese patients with nonalcoholic fatty liver disease

“…Desulfovibro is growing whereas Clostridia is declining in the obese population, and Bacteroidetes may increase or decrease (Liu et al, 2017;Wang and Hooper, 2019;Vieira-Silva et al, 2020). Escherichia, Dorea, and Peptoniphilus significantly increased in NAFLD, but Bacteroides (Cheng et al, 2022), F. prausnitzii (Pettinelli et al, 2022), Eubacterium and Prevotella (Del Chierico et al, 2017;Hoyles et al, 2018) significantly decreased. Similarly, F. prausnitzii was significantly lower in obesity with NAFLD than in simple obesity.…”

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

“…Several studies have shown that Patients with NAFLD have the remarkable gut dysbiosis, in which the relative abundances of Proteus and Enterobacter bacteria were increased while and Ruminococcus and Lactobacillus were decreased ( Loomba et al., 2019 ; Oh et al., 2020 ). As simple steatosis progresses to advanced liver fibrosis, the number of Gram-negative bacteria was increases, especially Proteus bacteria ( Caussy et al., 2018 ; Pettinelli et al., 2022 ). Fecal BAs may reflect alterations in two bile acid metabolic pathways: “glycine, serine, and threonine metabolism” and “taurine and hypotaurine metabolism.” Escherichia , Bilophila and Rhodobacter involved in BAs-mediating taurine and glycine metabolism were significantly increased in the faeces of NASH patients ( Jiao et al., 2018 ).…”

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

“…Short-chain fatty acids are a primary type of bacterial metabolite produced by bacterial fermentation of otherwise indigestible fibers in the colon (46). Many previous studies have illustrated the role of aberrant levels of SCFAs in NAFLD progression (39,40,(47)(48)(49)(50). SCFAs can disrupt the functioning of the intestinal barrier impairing the translocation of LPS and increasing the level of liver endotoxemia to promote the pathogenesis of NAFLD (50).…”

“…For example, F. prausnitzii can produce SCFAs to induce apoptosis by regulating mitochondrial death, reactive 10.3389/fnut.2022.934113 oxygen species (ROS), and the caspase pathway during the progression of NAFLD to NASH (55). SCFA levels were also positively dependent on Peptococcus and Romboutsia and negatively dependent on Ruminiclostridiun-6 and Muribaculum (40). SCFAs and these bacteria were found to positively regulate the levels of TC, leptin, and body weight in female participants.…”

“…Previous studies have suggested that Cidea, CD36, and GPAT3 are involved in the lipid metabolism pathway that drives the occurrence of HS ( 26 ). Third, F. prausnitzii can also regulate genes related to other pathways, such as IRS-1/2, IL-6, SOCS3, LEPR, and steroid response element binding protein-α (SREBP-α), to prevent the development of NAFLD ( 40 ). In addition, F. prausnitzii regulates the immune response by mediating the expression of PRKCZ, STAT3, and IRS2.…”