E. coli is a main pathogenic bacterium causing high lipopolysaccharide (LPS) content in patients with fatty liver [25]. The overgrowth of E. coli may boost gut permeability and LPS levels in the portal vein, thus activating inflammasomes and causing liver damage [16]. Some E. coli strains can ferment carbohydrates to produce ethanol and raise the blood ethanol levels [26]. Endogenous ethanol could induce oxidative stress and mitochondrial dysfunction in liver cells, worsening fatty liver [27]. Shen et al. [28] demonstrated an increased abundance of intestinal Enterobacteriaceae in MASLD patients with severe fat deposition and fibrosis. Importantly, translocation of E. coli exacerbated hepatic steatosis, inflammation, and fibrosis in MASLD mice [28]. E. coli has a bidirectional causal relationship with MASLD. The metabolic disorders accompanying MASLD, such as obesity and insulin resistance, may alter GM composition and cause E. coli proliferation, creating a vicious cycle. Given the strain heterogeneity of E. coli (commensal vs pathogenic), its diverse effects on the liver need further strain-specific research [29]. Iannone et al. [30] found that aldafermin-expressing E. coli Nissle 1917 combined with dietary changes could improve epididymal visceral adipose tissue (eVAT) histology, and alleviate liver steatosis and other MASLD-related pathological conditions by improving liver metabolism through eVAT-liver interactions. Thus, therapeutic intervention targeting E. coli may be a promising candidate for MASLD therapy.

Some Ruminococcus species, such as R. gnavus [31], R. bromii [32], and R. albus [33], could break down gut mucus, damage the mucous layer, and increase the risk of leaky gut, which promote the translocation of endotoxins like LPS and further lead to liver inflammation [34]. Moreover, certain Ruminococcus-derived metabolites may activate the TLR4 pathway, worsening insulin resistance and hepatic fat deposition [35]. On the other hand, species like R. bromii could ferment dietary fibers to produce SCFAs, thereby improving insulin sensitivity and inhibiting liver fat production [36]. The role of Ruminococcus and related molecules in MASLD is largely correlative, yet some experiments hint at potential causal mechanisms. It has been shown that transplanting GM enriched in Ruminococcus from MASLD patients into germ-free mice would induce liver steatosis and inflammation [37]. Also, clinical studies indicate a positive correlation between Ruminococcus abundance and liver fibrosis severity in MASLD patients [38].

Prevotella, a prominent genus within the Bacteroidetes phylum, exhibits context-dependent roles in human health. While recognized as a commensal bacterium contributing to polysaccharide degradation and SCFA metabolism that is critical for maintaining glucose homeostasis, certain strains display pathogenic potential linked to chronic inflammatory disorders [39]. This transition from commensal to pathobiont is driven by dysbiosis-induced upregulation of virulence factors, which disrupts immune tolerance and shifts host-microbe equilibrium [40]. Prevotella also showed inconsistent results in the progression of MASLD. Yuan et al. [39] have demonstrated that Prevotella plays a unique role in carbohydrate metabolism. It can also produce higher levels of LPS, which stimulate inflammation and promote the development of MASLD [41, 42]. Clinical studies indicate that Prevotella copri is significantly enriched in MASLD patients and positively correlates with liver fat and plasma/serum alanine aminotransferase (ALT) [16]. Animal experiments show that transferring GM from mice with inflammasome defects (Asc or IL-18 knockout) to wild-type mice aggravates NASH induced by a methionine-choline-deficient diet. This is seen as increased liver steatosis, inflammation, and elevated liver enzymes when Prevotella-rich microbiota is present [43]. Thus, Prevotella has a pro-disease association with MASLD. However, some research reveals a protective role in high dietary fiber intake individuals, wherein Prevotella is more abundant and liver fat is lower, which may result from its propionate production improving metabolism [44]. Michail et al. [45] found that children with MASLD have more Prevotella, whereas opposite results were obtained in adult studies. These discrepancies suggest that Prevotella’s impact on MASLD is modulated by age, metabolic context, and strain-specific functional differences. Regarding Prevotella-targeted therapies, potential strategies include antibiotics that directly combat Prevotella and prebiotics/probiotics (e.g., dietary fiber supplements) to modulate GM. Additionally, lifestyle changes and traditional medications are mentioned, though their relevance is relatively low [46].

Faecalibacterium, a member of the Firmicutes phylum, is a strictly anaerobic, oxygen-sensitive, gram-positive bacterium. As a major butyrate producer, it strengthens the intestinal barrier by inhibiting translocation of endotoxins to the liver, thereby reducing systemic inflammation and hepatic injury [47]. Additionally, it enhances insulin sensitivity via AMPK pathway activation, decreases hepatic lipid accumulation [48], and suppresses pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) [49]. Wang et al. [50] showed that oral administration of either live F. prausnitzii or its extracellular vesicles significantly reduced the severity of fibrosis induced by repeated administration of DSS in mice. Butyrate-producing bacteria such as F. prausnitzii could reduce bacterial translocation and stimulate mucin secretion, thus maintaining intestinal integrity [51]. MASLD patients frequently exhibit reduced GM diversity and diminished Faecalibacterium abundance, positioning this bacterium or its derivatives as promising therapeutic agents for MASLD-associated intestinal pathologies [52]. FMT from healthy donors is often used to introduce beneficial bacteria like Faecalibacterium into MASLD patients’ gut [53]. Also, postbiotics derived from Faecalibacterium species, such as cell wall components, exopolysaccharides and SCFAs, exert anti-inflammatory, antioxidant, immunomodulatory, and gut barrier enhancing effects, thus indirectly improving MASLD [54]. However, further research is required to establish optimal dosing regimens, administration routes, and mechanistic pathways to maximize its therapeutic potential.

Emerging evidence highlights that GM is a pivotal modulator in the pathogenesis and advancement of MASLD [55]. This microbial consortium exerts direct regulatory effects on host physiology through multiple interconnected mechanisms: (1) compromising intestinal epithelial integrity through tight junction disruption [56]; (2) triggering systemic inflammation via pathogen-associated molecular pattern translocation [57]; (3) intensifying redox imbalance through reactive oxygen species (ROS) generation [58]; and (4) modifying bile acid enterohepatic circulation [59].

Besides the direct regulation of GM on the gut-liver axis, several GM metabolites have been identified as key mediators of microbial influence on hepatic metabolism and function. While beneficial compounds like SCFAs alleviate the symptom of MASLD via sustaining lipid metabolism homeostasis and strengthening the gut barrier, harmful byproducts, such as endogenous ethanol and TAMO, promote MASLD progression through stimulating oxidative stress and inflammatory reactions (Figure 2).

Dietary intervention remains the cornerstone therapy for MASLD, necessitating research into gut-liver axis optimization through microbial modulation. Current evidence highlights prebiotics and probiotics as key targets, demonstrating their therapeutic potential in reshaping GM and mitigating MASLD progression [84] (Figure 3a).

FMT is a therapeutic approach that involves transplanting fecal microbial communities from healthy donors into a patient’s intestinal tract to reconstruct gut microbial ecology, thereby restoring gut dysbiosis and alleviating associated disorders [115]. FMT represents a cutting-edge therapeutic modality for MASLD [116], involving the transfer of processed donor microbiota to reconstitute GM homeostasis. Mechanistically grounded in the gut-liver axis theory, this approach targets the dysregulated interplay between intestinal microbiota and hepatic metabolic pathways. Preclinical studies demonstrate that FMT significantly ameliorates MASLD pathology, primarily mediated through correction of gut dysbiosis [117] (Figure 3b). Zhou et al. [118] reported reduced hepatic lipid accumulation and inflammatory markers in MASLD model mice following FMT. A multi-omics investigation further elucidated FMT’s multi-target mechanisms, revealing its capacity to reshape GM profiles (e.g., increased Faecalibacterium prausnitzii and Blautia wexlerae abundance), modulate plasma metabolites including PAC and PAG, and normalize hepatic DNA methylation patterns [119]. Clinically, a systematic review and meta-analysis confirmed FMT’s safety and efficacy, showing significant improvement in NAFLD-associated metabolic parameters without severe adverse events [117]. However, given the multifactorial pathogenesis of MASLD involving the interplay of metabolic pathways and GM, FMT may induce profound alterations in microbial composition, yet its long-term consequences remain poorly characterized, necessitating longitudinal studies to comprehensively evaluate its risk-benefit profile [120] (Table 2).

TCM, a holistic medical system rooted in syndrome differentiation and natural herbal formulations, modulates host physiology through multi-target and multi-pathway mechanisms. It emphasizes systemic regulation and syndrome differentiation-guided therapeutics, formulating individualized treatment protocols based on patients’ clinical manifestations and constitutional characteristics [121]. In the context of MASLD, TCM primarily targets the remodeling of GM via tripartite regimens, such as microbial restructuring and metabolic improvement, intestinal barrier restoration and hepatoprotection, and anti-inflammatory reprogramming (Figure 3c and Table 2). For example, berberine restores the Firmicutes/Bacteroidetes ratio, enriches Bifidobacterium, and ameliorates serum transaminases (ALT/AST) and lipid profiles (reduced TG, LDL-C) in HFD mice [122]. Chaihu Shugan powder (CSP) upregulates FXR/PPARγ expression, reduces intestinal permeability and LPS translocation, thereby alleviating hepatic steatosis, inflammation, and fibrosis in NAFLD rats [123, 124]. TCM formulations suppress TLR4/NF-κB signaling, downregulate TNF-α, IL-1β, and LPS levels, thereby attenuating hepatic inflammation [125]. TCM’s synergistic multi-target effects via the gut-liver axis significantly improve MASLD-related metabolic dysregulation and inflammation, with components like Berberine validated by randomized controlled trials [122]. However, the complexity of TCM’s “multi-component, multi-target” mechanisms necessitates advanced omics technologies (e.g., metabolomics, metagenomics) for deeper mechanistic insights, while standardization of herbal formulations remains critical to ensure efficacy consistency and clinical reproducibility.

Notably, statins also demonstrate pleiotropic therapeutic effects in MASLD through GM modulation. As HMG-CoA reductase inhibitors, their mechanisms include: (1) ‌Microbial restructuring and lipid homeostasis‌: Statins enhance colonization of SCFA-producing genera (Faecalibacterium and Bacteroides), which regulate hepatic lipid metabolism via GPCRs, reducing lipotoxicity. Concurrently, suppression of Clostridium reduces secondary bile acid synthesis, mitigating bile acid-induced hepatocyte injury and cholestatic stress in MASLD [126, 127]. (2) ‌Cholesterol metabolism regulation‌: By enriching Lactobacillus, statins promote intestinal cholesterol excretion and alleviate microbiota-mediated inhibition of the FXR/PXR pathway on CYP7A1. This restores cholesterol 7α-hydroxylase activity, accelerating cholesterol-to-bile acid conversion and reducing hepatic cholesterol accumulation, a key driver of MASLD progression [128, 129]. (3) ‌Gut barrier restoration‌: Statins upregulate mucin-degrading Akkermansia, which enhances TJP expression (e.g., Occludin, Zonula occludens-1) and reduces LPS translocation. This alleviates hepatic inflammation by suppressing TLR4/NF-κB signaling, a critical pathway in MASLD-related hepatocyte injury [130] (Figure 3C and Table 2). These mechanisms collectively target MASLD hallmarks, lipotoxicity, inflammation, and gut barrier dysfunction, highlighting statins’ multi-modal therapeutic potential.

MASLD pathogenesis is mechanistically linked to gut dysbiosis, with alcohol-hyperproducing Klebsiella pneumoniae (HiAlcKpn) identified as a key microbial driver through its portal vein-mediated ethanol delivery that directly induces hepatocyte steatosis and lipid dysregulation [131]. Bacteriophage therapy emerges as a precision antimicrobial strategy, leveraging taxon-specific lysis to selectively eradicate pathobionts like HiAlcKpn while preserving commensal microbiota integrity [132]. Preclinical validation demonstrates that HiAlcKpn-targeted bacteriophages attenuate steatohepatitis via multi-omics remodeling, such as normalizing hepatic transcriptomic profiles (downregulating lipogenic PPARγ/SCD1), reducing pro-inflammatory cytokines (IL-6, TNF-α), and restoring lipid/carbohydrate metabolic flux [131] (Figure 3d). Human-relevant efficacy is further supported by FMT studies where Enterococcus faecalis-specific phages significantly reduced serum ALT levels and hepatic steatosis in humanized mice [133]. Bacteriophages therapy, as a novel microbiome-targeted intervention, remains insufficiently validated for long-term safety. The precision elimination of specific bacterial taxa by phages may induce gut microbial dysbiosis, potentially disrupting host-microbiota metabolic crosstalk and exerting multifaceted impacts on MASLD progression. This necessitates longitudinal studies to delineate its clinical risk-benefit equilibrium [134] (Table 2).