Gut microbiota and metabolic biomarkers in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), a replacement of the nomenclature employed for NAFLD, is the most prevalent chronic liver disease worldwide. Despite its high global prevalence, NAFLD is often under-recognized due to the absence of reliable noninvasive biomarkers for diagnosis and staging. Growing evidence suggests that the gut microbiome plays a significant role in the occurrence and progression of NAFLD by causing immune dysregulation and metabolic alterations due to gut dysbiosis. The rapid advancement of sequencing tools and metabolomics has enabled the identification of alterations in microbiome signatures and gut microbiota-derived metabolite profiles in numerous clinical studies related to NAFLD. Overall, these studies have shown a decrease in α-diversity and changes in gut microbiota abundance, characterized by increased levels of Escherichia and Prevotella, and decreased levels of Akkermansia muciniphila and Faecalibacterium in patients with NAFLD. Furthermore, bile acids, short-chain fatty acids, trimethylamine N-oxide, and tryptophan metabolites are believed to be closely associated with the onset and progression of NAFLD. In this review, we provide novel insights into the vital role of gut microbiome in the pathogenesis of NAFLD. Specifically, we summarize the major classes of gut microbiota and metabolic biomarkers in NAFLD, thereby highlighting the links between specific bacterial species and certain gut microbiota-derived metabolites in patients with NAFLD.

FIGURE 1

Specific mechanisms of gut microbiota-derived in NAFLD progression. In this figure, the arrows reflect hypothetical relationships, not direct causal links between the pathological mechanisms and NAFLD. The gut-liver axis is an anatomically and functionally closely related structure that allows bidirectional interaction between the gut microbiome and the liver. Here, we only focus on the unidirectional roles that gut microbiota-derived components exert on the liver in NAFLD. Under gut dysbiosis conditions, gut microbiota-derived components translocate into the liver. PAMPs, including LPS, PGN, and microbial DNA, activate the innate immune system and trigger chronic low-grade inflammation by binding to pattern recognition receptors (PPRs), such as TLRs and NLRs. BAs, acting as signaling molecules, on the one hand, could bring about effects of suppressed lipogenesis, reduced gluconeogenesis, and increased insulin sensitivity by activating nuclear receptors; on the other hand, BAs bind to G protein-coupled bile acid receptors in adipose tissue and play a role in maintaining energy metabolic homeostasis. TMA is converted in the liver to TMAO, the latter binds to endoplasmic reticulum stress enzymes and further induces apoptosis and inflammation. SCFAs could inhibit the expression of pro-inflammatory factors and maintain low levels of inflammation. Indoles can not only induce the upregulation of PFKFB3, thereby suppressing the inflammatory response, but also reduce the expression of numerous lipogenesis-related genes, such as Srebf1, ACCA1, PPARγ, etc. In addition, both indoles and SCFAs contribute to restraining the entry of LPS into the circulation and the liver by strengthening the intestinal barrier. The processes that promote NAFLD progression are represented in green arrows and lines, and the ones that hamper NAFLD progression are represented in yellow. Abbreviations: ACCA1, acetyl-CoA carboxylase1; BA, Bile acid; FXR, farnesoid X receptor; IFN, interferon; LPS, lipopolysaccharide; NLR, nod-like receptors; PAMP, pathogen-associated molecular patterns; PGN, peptidoglycan; PPARγ, peroxisome proliferator-activated receptors; SCFA, short-chain fatty acids; Srebf1, sterol regulatory element-binding protein1; TGR5, bile acid G protein-coupled receptor 5; TLR, toll-like receptors; TMA, Trimethylamine; TMAO, trimethylamine oxide.

FIGURE 2

Common methods for microbial identification.