Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.

Keywords: FATTY LIVER; GENE EXPRESSION; INTESTINAL MICROBIOLOGY.

Figure 1. Risk factors in MASLD and the intricate interplay between gut microbiome, microbial metabolites, and host genetics and epigenetics. MASLD is a multifactorial disease which associates with host genetics, epigenetics, gut microbiome and gut-derived metabolites. More importantly, these risk factors may influence one another in the course of MASLD development and progression. The altered gut microbial abundance impacts their metabolite production and thus affecting lipid metabolism, inflammatory response and gut barrier function. The gut microbiome also influences host epigenetics at a transcription level, while host genetics shape the composition and function of the gut microbial community. The results of these various factors eventually lead to hepatic lipid accumulation, persisted inflammation and progression to MASLD-HCC. The microbiota-gene interaction may provide novel therapeutic strategies in MASLD and MASLD-HCC treatments. BAs, bile acids; BCAAs, branched-chain amino acids; DNMT, DNA methyltransferase; GCRK, glucokinase regulatory protein; HDACs, histone deacetylases; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; lncRNA, long non-coding RNA; LPS, lipopolysaccharide; m6A, n6-methyladenine; MASH, metabolic dysfunction-associated steatohepatitis; MASLD-HCC, metabolic dysfunction-associated steatotic liver disease (MASLD)-associated hepatocellular carcinoma; MBOAT7, membrane-bound O-acyltransferase 7; METTL3, methyltransferase 3; miRNA, microRNA; NF-κB, nuclear factor kappa B; NOD2, nucleotide-binding oligomerization domain 2; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPARγ, peroxisome proliferator-activated receptor gamma; SCFAs, short-chain fatty acids; TCA, tricarboxylic acid; TG, triglyceride; TLR, Toll-like receptor; TM6SF2, transmembrane 6 superfamily member 2; YTHDF1, YTH N6-methyladenosine RNA binding protein F1.

Figure 2. Gut microbiota and microbial metabolites modulate host epigenetics in MASLD. Gut microbiome and their derived metabolites are closely linked with host epigenetic modifications, influencing DNA methylation, histone modification and RNA regulation. Gut dysbiosis may promote DNA methylation and DNMT activity in genes associated with lipid metabolism, insulin resistance and stem cell proliferation. SCFAs are well-known histone deacetylase inhibitors and regulate transcription in anti-inflammatory genes. Dysbiosis also favour specific miRNA activity in promoting MASH and MASLD-HCC. Moreover, gut microbiota and metabolites may regulate m6A modification in MASLD and HCC prevention which require further investigation. ACC1, acetyl-CoA carboxylase 1; APOA4, apolipoprotein A4; DNMT, DNA methyltransferase; FABP4, fatty acid binding protein 4; HNF4, hepatocyte nuclear factor 4; IL-6, interleukin 6; LPS, lipopolysaccharide; MASH, metabolic dysfunction-associated steatohepatitis; MASLD-HCC, metabolic dysfunction-associated steatotic liver disease (MASLD)-associated hepatocellular carcinoma; METTLE3, methyltransferase 3; miRNA, microRNA; m6A, n6-methyladenine; PEDF, pigment-epithelium-derived factor; PPARα, peroxisome proliferator-activated receptor-alpha; SCD1, stearoyl-CoA desaturase 1; SCFAs, short-chain fatty acids; Snhg9, small nucleolar RNA host gene 9; SOX13, Sex-determining Region Y-box transcription factor 13; TNF-α, tumour necrosis factor-alpha; TMBIM1, transmembrane BAX inhibitor motif containing 1; TLR4, Toll-like receptor 4; YTHDF1, YTH N6-methyladenosine RNA binding protein F1; ZFP57, zinc finger protein 57.

Figure 3. Development of personalised gut microbiota-based therapy targeting host genetics and epigenetics. Recent studies have unravelled the effects of host genetics and epigenetics in shaping the composition and metabolic production of the gut microbiota. Identification of the host genotype-associated gut dysbiosis allows development of personalised gut microbiota-based therapies. Preclinical studies and randomised clinical trials (ClinicalTrials.gov ID labelled in brackets) are currently ongoing in investigating the therapeutic effects of probiotics, postbiotics, antimicrobials, genetically modified bacteria, FMT and bacteriophage in MASLD. FVT, faecal virome transplantation; GDCA, glycodeoxycholic acid; GLP-1, glucagon-like peptide 1; KO, knock out; MASLD, metabolic dysfunction-associated steatotic liver disease; TDCA, taurodeoxycholic acid; WT, wild type; UDCA, ursodeoxycholic acid.

Figure 4. Recent advances in clinical application and future research directions in MASLD in relation to gut microbiome and genes. (a) There is currently no consistent evidence of a single microbial signature that can be applied universally to distinguish or determine the stage of simple steatosis, MASH or HCC. Potential confounding impact of metabolic variables might also influence the detection of microbial signatures. Larger cohorts comprising various population groups, detailed information pertaining to diet composition and extensive control groups are essential in developing diagnostic/prognostic markers and new therapeutic targets. (b) Conducting larger cohorts to explore the effect of the host genome on the liver, gut and intestinal microbiome is important to understand the impact of host genetics on MASLD and HCC gut microbial composition and, more importantly, to aid in the development of personalised medicine. (c) It is crucial to comprehend the gene-environment interaction to understand whether gut microbiome is primarily influenced by host phylogenetics or shared environments, or if both factors have a co-regulatory effect in the development of MASLD. (d) Randomised clinical trials have demonstrated the promising therapeutic effects of untargeted gut microbiota modulation by probiotics, antimicrobials and FMT in patients with MASLD. In the future, there should be more focus on modulating the gut microbiota in a targeted manner via probiotics, postbiotics (metabolites), genetically engineered microbiota and bacteriophages. (e) The collection of preclinical research has revealed the role of gut metabolites in mediating the modification of host epigenetics. A comprehensive understanding of the underlying mechanisms could offer valuable insights into potential clinical applications. (f) While resmetirom is the sole FDA-approved drug for treating MASH-fibrosis, its mechanism remains unclear. As the gut microbiome-epigenetic interplay plays a vital role in MASLD, exploring resmetirom’s potential impact on gut microbiome and epigenetic modifications could shed light on its efficacy in mitigating MASLD. FDA, Food and Drug Administration; FMT, faecal microbiota transplantation; MASLD, metabolic dysfunction-associated steatotic liver disease; T2DM, type 2 diabetes mellitus.