Metabolic dysfunction–associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.

The liver and intestine engage in bidirectional communication due to their anatomical connection and the immunologic, metabolic, and hormonal interactions between them. Anatomically, the splanchnic venous intestinal outflow connects to the liver’s portal venous inflow. Portal venous blood contains nutrients, toxins, reabsorbed bile acids, and microbial and antimicrobial products. In the opposing direction, the liver produces bile, which enters the duodenum at the ampulla of Vater and contains emulsifying bile acids, trace elements, immune factors, and other lipids and metabolites. The biologic life cycle of bile acids requires intestinal microbiota for deconjugation, and conversely, bile acids exert often toxic effects on intestinal microbiota (8). Physiologically, the liver and gut are also connected via shared hormones. For example, cholecystokinin is produced by enteroendocrine cells to elicit bile production from the liver; fibroblast growth factor-19 (FGF-19) is produced in the intestine and regulates hepatic bile acid synthesis (9); and insulin-like growth factor, produced by the liver, helps maintain intestinal epithelial integrity (10).

This highly regulated enterohepatic circulation is fortified by the intestinal barrier that limits paracellular leakage of intestinal lumen substances directly into the systemic circulation or prevents lumen contents from reaching high concentrations in the portal circulation. The intestinal barrier has several components: epithelial cells, overlying mucous layers (a superficial, thick outer mucous layer and an inner, thin, unstirred layer), electrostatic microvilli, and intercalating proteins that create the apical junctional complex between adjacent epithelial cells (Figure 1). Working in concert with intestinal epithelial cells to fortify the barrier are Paneth cells, which secrete defensins and other antimicrobials, and the lamina propria, which is located beneath the epithelial cell basement membrane and has a role in innate and acquired immunity (11, 12).

Figure 1

Gut barrier dysfunction in MASLD. The intestinal epithelial barrier provides the main line of defense against translocation of gut microbiota. The barrier includes epithelial cell microvilli, an outer and inner mucous layer, and tight junction proteins located between adjacent epithelial cells. The figure compares (A) a normal intestinal epithelial barrier with diverse gut microbiome to (B) an impaired intestinal epithelial barrier as observed in MASLD with subsequent translocation of bacterial products, metabolites, and viable bacteria.

From apical to basal distribution, there are three domains that comprise the apical junctional complex: the zonula occludens (ZO), zonula adherens, and desmosome. While the intestinal barrier and the apical junctional complex within the barrier are structurally complex, investigators often use the integrity of the ZO region, or “tight junction,” or urinary recovery of orally administered molecules whose size should preclude intestinal epithelial paracellular passage as proxies for permeability (11).

While most research on intestinal barrier function in MASLD has involved the role of the epithelial cell tight junction, less studied is the role of the gut vascular barrier (GVB). Akin to the blood-brain barrier, this microvasculature barrier provides an additional guard against translocation of bacteria and potentially hepatotoxic molecules. The GVB derives from intestinal blood endothelial cells. Like intestinal epithelial cells, they also have a tight junction and associated tight junction and adherens junction proteins. The gut endothelial cells are surrounded by enteric glial cells and pericytes organized to form a vascular unit (13). Understanding these intricate, highly regulated interfaces between the gut and the liver is crucial to comprehending how disruptions to this barrier contribute to the gut microbiome’s influence on MASLD pathogenesis.

Studies on humans with MASLD indicate a compromised intestinal barrier. A metaanalysis of 14 studies involving adult and pediatric MASLD patients diagnosed via liver biopsy or ultrasound showed increased intestinal permeability, measured by urinary recovery of orally administered sugars or ZO levels, compared with healthy controls (14). Preclinical studies in mice have suggested that the reduction in intestinal integrity precedes hepatic injury in MASLD, as disruption of the intestinal epithelial barrier and the GVB occurs before hepatic steatosis develops (15). The increase in intestinal permeability and the ensuing liver injury in MASLD are recognized to be due to nutrient and microbial effects on the gut epithelium, microbial translocation, and immune dysregulation.

Nutrient effects on the intestinal barrier. Several nutrients have been linked to impairing the intestinal epithelial barrier (16). Fructose is particularly relevant to MASLD pathogenesis due to its association with MASLD risk in humans when consumed in excess (17). Experimental studies in mice and in vitro reported mixed results regarding fructose’s impact on the intestinal epithelial barrier. One study indicated that glucose, not fructose, damages the barrier (18), while others suggested that fructose severely impairs barrier integrity, possibly by direct effects on tight junction proteins (19–21). Although no studies have specifically examined fructose’s effect on barrier function in MASLD patients, fructose, unlike glucose, was associated with a compromised barrier in healthy adults (22), but did not cause the same injury in a recent small, double-blind crossover pilot study of ten individuals with obesity (23). In short, excess carbohydrate consumption can significantly disrupt the intestinal barrier and should be avoided (24).

Lipids also affect the intestinal epithelial barrier. Polyunsaturated fats generally protect the intestinal barrier, (25) whereas multiple experimental models show that dietary saturated and n-6 polyunsaturated fatty acids can harm the intestinal epithelial barrier. For example, in an enterocyte in vitro model, treatment with the saturated fatty acids palmitate (C16:0) and stearate (C18:0) increased epithelial permeability, as measured by transepithelial electrical resistance (26). Compared with mice fed a low-fat diet, mice fed diets high in saturated fat or n-6 polyunsaturated fat had higher colonic permeability (27). Cholesterol oxidation products such as oxysterols also injure the intestinal barrier through a reduction of tight junction proteins (28).

Microbes affect intestinal barrier, translocation, and immune dysregulation. Gut dysbiosis is the imbalance between beneficial and harmful gut microorganisms. In patients with MASLD, dysbiosis can result from increased intestinal microbial load, reduced microbial diversity, and/or a dominance of pathogenic microbes. These pathogenic microbes can decrease expression of tight junction and GVB junction proteins (15), secrete proteases to degrade these proteins (29), trigger local intestinal inflammation (30), and damage or invade the protective mucosal layer (31).

Disruption of the intestinal epithelial and vascular barrier leads to the translocation of gut microbiota and gut microbial components from the intestinal lumen into the systemic and portal circulations (Figure 1). Bacterial wall products such as lipopolysaccharide (LPS, endotoxin) enter the bloodstream, triggering steatotic and inflammatory responses within the liver. LPS, a pathogen-associated molecular pattern (PAMP), is recognized by the TLR4 receptor on hepatic Kupffer cells, integral to the innate immune response. This recognition activates myeloid differentiation factor 88 (MyD88) and interferon regulatory factor 3 (IRF3), initiating a proinflammatory cascade that results in TNF-α secretion (32). The subsequent liver disease progression from steatosis to steatohepatitis and fibrosis involves Nod-like receptor protein 3 (NLRP3) inflammasome activation and the liver’s production of damage-associated molecular patterns (DAMPs). These processes activate caspase 1, proinflammatory cytokines such as IL-1β, and Kupffer cells, which in turn stimulate hepatic stellate cells’ fibrogenic response (Figure 2). Translocated bacteria can also exert hepatic injury in MASLD through the production of microbial metabolites (discussed in more detail below). Indeed, we have shown that metabolite signatures (versus bacterial taxonomic stratification themselves) may be better able to distinguish noncirrhotic MASH from healthy human controls (33).

Figure 2

Microbial products and metabolites influence fibrogenic responses in the liver. PAMPs (such as LPS) and microbial metabolites (e.g., SCFAs, ethanol, bile acids) that translocate to circulation from the gut enter the liver via the portal vein. LPS stimulates a proinflammatory and ultimately fibrogenic cascade via Kupffer cells, which are liver-resident macrophages. Gut dysbiosis alters production of microbial metabolites, and these irregularities are associated with a variety of adverse effects in hepatocytes, including inflammatory processes that exacerbate fibrogenesis.

In addition to the hepatic immune effects of microbial translocation, translocation also results in adipose tissue inflammation, in part through LPS signaling. LPS targets the aforementioned TLR4 inflammatory signaling in adipocytes, promotes the inflammatory M1 macrophage transition, and prompts programmed adipocyte cell death through the activation of caspase signaling (34–36). The resultant effects on adipokine dysregulation that impair both glucose and lipid homeostasis are, in turn, likely to contribute to MASLD pathogenesis.

Viable microbes that escape the intestinal lumen encounter an additional line of surveillance by the intestinal immune system in the lamina propria and in the mesenteric lymph nodes (37). The exact route of translocation through the epithelial barrier is unclear, but may involve endocytosis or transcytosis (38). Full immune escape is possible, however, as demonstrated by the clinical syndrome of spontaneous bacterial peritonitis where translocated bacteria infect sterile ascitic fluid in patients with cirrhosis and portal hypertension (37). Additionally, there are reports of possible immune escape of viable microbes into the liver itself. Patients with MASH had increased bacterial DNA levels of the class Gammaproteobacteria, family Pseudomonadaceae, and order Pseudomonadales in the liver, while the family Lachnospiraceae was reduced (39). In another study of 26 human liver biopsies, 16s rRNA sequencing identified bacterial species in the liver with a predominance of Proteobacteria and a relative lower abundance of Firmicutes (40). 16s rRNA sequencing was also performed in livers of 82 patients with varying degrees of fibrosis and it was found that the liver bacteria comprised mostly Proteobacteria (41). Bacteria have also been observed in mouse livers, although at significantly lower abundance than in the intestines. Isolated bacteria were successfully cultured and visualized using 16S FISH and transmission electron microscopy, which showed bacteria in hepatic sinusoids and being engulfed by resident Kupffer cells (40). Validation of these studies in humans is challenged by the difficulty of obtaining sterile liver biopsy tissue and reliance on 16s rRNA sequencing, a surrogate measure of bacterial burden. Once validated, however, these studies would shift the paradigm of the liver being a sterile organ (42) and help provide a direct link between intestinal barrier disruption and subsequent liver inflammation in MASLD.

In humans with MASLD, there is evidence that microbial translocation and subsequent immune dysregulation occur. Plasma LPS levels, as a surrogate maker for increased intestinal permeability, are significantly elevated in MASH patients compared with patients with MASLD, as are hepatic TLR4 mRNA levels. A similar, albeit nonstatistically significant trend, is observed with MyD88 hepatic mRNA levels (43). Recently, in biopsy-proven MASH patients, researchers observed higher serum LPS and hepatocyte LPS compared with controls. These levels correlated with serum ZO, an aforementioned marker of increased gut permeability. There were also higher amounts of TLR4⁺ macrophages in MASH patients as compared with control and patients with only steatosis; and these levels correlated with serum LPS (44). Finally, hepatic NLRP3 levels are increased in MASH patients compared with early stage MASLD patients (45).

These mechanisms collectively lead to gut dysbiosis, compromised intestinal barriers, and liver injury in MASLD. Below, we will examine the specific bacterial, viral, and fungal organisms and metabolites involved in human MASLD pathogenesis.

Bacterial microbiome. Small intestinal bacterial overgrowth (SIBO) is a quantitative increase in bacteria in the small intestine. It can be assessed by direct culturing of small intestinal contents or different breath tests. Experimental SIBO can lead to liver injury and inflammation even in the absence of a direct liver toxin. SIBO is prevalent in patients with MASLD, and up to 35% of patients show SIBO (46). SIBO is more prevalent in patients with MASH cirrhosis (47.1%) compared with patients with MASLD (47). Escherichia coli and Staphylococcus aureus were the most commonly cultured bacterial organisms from small bowel aspirates (47).

Numerous studies have assessed the bacterial composition in patients with MASLD and MASH. However, many of these studies have small sample sizes, lack validation cohorts, fail to control for metabolic comorbidities, or do not carefully characterize liver disease activity. Additionally, results from sequencing studies are influenced by factors such as DNA extraction methods, the use of different sequencing regions, sequencing depth, and methods of analysis. Consequently, there is considerable heterogeneity in the reported changes in the bacterial gut microbiota in patients with MASLD.

Reduced bacterial diversity has been consistently reported in multiple studies in patients with MASLD as compared with healthy controls (48, 49). Using a longitudinal cohort of 867 subjects from China with MASLD and 679 controls, an increased abundance of the fecal microbiota phylum Fusobacteria and family Veillonellaceae were associated with increased MASLD risk, whereas families Rikenellaceae and Barnesiellaceae, and strain Bifidobacterium adolescentis were associated with a lower presence of MASLD as assessed by 16S rRNA gene sequencing (50). Some of these changes can be used to monitor response to treatment. For example, the abundance of bile-acid–sensitive Veillonella increases in patients responding to an FGF-19–mediated suppression of bile acid synthesis (51).

A metaanalysis of 54 studies with 8,894 subjects showed reduced prevalence of antiinflammatory microbes (family, Ruminococcaceae; genera, Alistipes, Blautia, and Faecalibacterium) and higher abundance of potentially inflammatory microbes (family, Fusobacteriaceae and Enterococcaceae; family, Escherichia and Granulicatella) in patients with MASLD (49). Another metaanalysis and systematic review of 28 published studies (3,566 subjects with confirmed MASLD) confirmed reduced Shannon diversity and a decrease in the relative abundance of short chain fatty acid–producing (SCFA-producing) bacteria such as Ruminococcus, Faecalibacterium, and Coprococcus. This review also showed an increase in Escherichia in individuals with MASLD (52). These results were overall confirmed in a metaanalysis including 577 patients with MASLD and 688 controls (53). The relative abundance of Escherichia, Prevotella, and Streptococcus was increased, while Coprococcus, Faecalibacterium, and Ruminococcus were decreased (53, 54).

Beyond distinguishing patients with MASLD and controls, several studies characterized fecal microbiota features in patients with progressive MASLD and those developing fibrosis. There is a stepwise increase of E. coli and a stepwise decrease of Eubacterium rectale, Eubacterium eligens, Facelibacterium prausnitzii, and Dorea longicatena as patients progress from MASLD steatosis to MASLD with mild fibrosis (F1/2/3) and eventually to MASLD cirrhosis (F4) as assessed by metagenomic sequencing (55, 56). Interestingly, using 16S rRNA gene sequencing, Ruminococcaceae decrease and Veillonellaceae increase as fibrosis became more severe in nonobese, but not obese patients with MASLD (57). Using culturomics, four bacterial strains (Enterococcus faecium, Streptococcus oralis, Escherichia coli, and Klebsiella pneumoniae) were isolated from children with MASLD and shown to have a lipogenic effect in HepG2 cells. A larger cohort analysis (n = 161) using metagenomic sequencing confirmed that these identified bacterial strains were stepwise enriched from obese to MASLD and MASH children (58). Taken together, the transition from a healthy to a steatotic liver is associated with SIBO, a decrease of beneficial bacteria, and an increase of pathobionts in feces.

Mycobiome. Beyond bacteria, the fungal microbiota has been characterized in patients with MASLD. Similar to the bacterial microbiota, fungal diversity is also decreased in fecal samples of MASLD subjects (n = 21) as compared with controls (n = 20) (59). Saccharomyces cerevisiae and Schizosaccharomyces pombe were more abundant in feces of the healthy group, while higher proportions of Mucor ambiguous were found in feces and saliva of subjects with MASLD (59). Patients with MASH or advanced fibrosis had a distinct fecal mycobiome as compared with simple steatosis or minimal fibrosis, which was characterized by increased C. albicans, Babjeviella inositovora, Mucor sp., unknown Hanseniaspora, unknown Pleosporales, and Pichia barkeri (60). Notably, these changes were observed in nonobese patients with MASLD for which risk factors are not well understood. The importance of the mycobiome in MASLD pathogenesis was further highlighted in a microbiota-humanized mouse model. In this model, oral antifungal treatment with amphotericin B reduced steatohepatitis and liver fibrosis induced by a Western diet (60). However, the mechanism by which fungi contribute to MASLD remains unknown. Patients with MASLD and advanced liver fibrosis had higher systemic anti–C. albicans IgG levels than controls or patients with minimal fibrosis (60), indicating that fungi or their products could translocate from the gut to the liver through a compromised gut barrier.

Virome. In a study of fecal viromes from patients with MASLD and controls, histologic markers of MASLD severity were associated with reduced viral diversity and a lower proportion of bacteriophages (phages) compared with other intestinal viruses (61). Specific gut viral taxa, such as Lactococcus phages, were decreased in patients with advanced fibrosis (61). Interestingly, consumption of low to moderate amounts of alcohol in MASLD patients accounted for differences in the intestinal viromes. For example, viral diversity of the alcohol-consuming MASLD population was similar to those of patients with alcohol use disorder and significantly higher than the non–alcohol-consuming MASLD population or controls (62). Mechanistic studies are needed to investigate a potential causal role of gut virome changes in disease progression.

A summary of the above microbiome changes is depicted in Figure 3.

Figure 3

Changes in the gut microbiota associated with MASLD. Patients with steatosis exhibit alterations in their gut bacterial, fungal, and viral microbiomes. As the disease progresses towards fibrosis and cirrhosis, further microbiota changes are observed.

The gut microbiota play an important role in the development and progression of MASLD by influencing the host’s metabolic environment. Gut microbes produce or metabolize a variety of metabolites, such as ethanol, SCFAs, and bile acids, which can affect liver function and overall metabolic health. Alterations in the composition and activity of the gut microbiota can lead to dysregulated production of these microbial-derived metabolites, contributing to inflammation, insulin resistance, lipid accumulation in the liver, and hepatic fibrosis. Understanding these interactions offers potential therapeutic targets for MASLD (Figure 4).

Figure 4

Influence of gut microbial metabolites on MASLD. A dysbiotic gut microbiota produces less beneficial metabolites such as the SCFA acetate, or tryptophan metabolites indole-3-propionic acid (IPA) and indole-3-acetic (IAA), which stabilize the gut barrier during health. On the other hand, ethanol as a fermentation byproduct of bacteria and fungi causes triglyceride accumulation and death of hepatocytes, resulting in inflammation and fibrosis. Patients with MASLD have an increased bacterial metabolism of primary to unconjugated secondary bile acids in the gut, which are hepatotoxic and cause disease progression and HCC. It might also result in increased bile acid synthesis by hepatocytes.

Ethanol. Ethanol is a fermentation byproduct of bacteria and fungi, naturally produced in the human body. It is typically metabolized by enzymes in the intestinal epithelial cells or after being absorbed into the bloodstream and transported to the liver via the portal vein (63). Disruptions in gut homeostasis can lead to elevated ethanol production by intestinal microbes. Studies indicate that patients with MASH exhibit higher levels of peripheral blood alcohol, with even higher concentrations found in the portal vein, especially as liver disease severity increases (64–66). In extreme cases, excessive microbial ethanol production can overwhelm the liver’s metabolic capacity, leading to high blood alcohol levels and a rare condition known as autobrewery syndrome (67). Research involving the transplantation of stool from a MASH patient with ethanol-producing Klebsiella pneumoniae into mice has demonstrated that this can cause steatohepatitis, a process that can be mitigated by using phages targeted against the ethanol-producing bacteria (68). Other intestinal bacteria also produce ethanol and contribute to liver inflammation (69). This evidence underscores a causal link between ethanol-producing bacteria and the development of steatohepatitis.

Bile acids. Bile acids, primary metabolites synthesized by hepatocytes from cholesterol, play essential roles in food digestion within the small bowel and are reabsorbed in the terminal ileum. Beyond digestion, bile acids interact with receptors like Farnesoid X receptors (FXR) and TGR5, profoundly influencing glucose and lipid metabolism and regulating their own synthesis through the secretion of FGF-19 in the terminal ileum. Bile acids also modulate the gut microbiota and are metabolized by these microbes in turn. Thus, disturbances in any of the factors that change bile acids can have profound effects on metabolic diseases. Bile acid homeostasis is disturbed in patients with MASLD. There is heterogeneity in results reporting changes in bile acid associated with MASLD, which may result from different analytical methods, small sample size, and confounding factors such as medications, age, BMI, and sex (33, 70).

Although serum bile acid levels do not significantly differ in patients with MASLD compared with controls, several studies found serum bile acids associated with greater liver disease severity in patients with MASLD. Secondary unconjugated bile acids, particularly lithocholic acid species, were increased in patients with mild and significant fibrosis in a Chinese cohort of patients with MASLD (n = 550) (71). Similar results were found in a Hispanic cohort (n = 390), where total and primary conjugated bile acids were higher in subjects with fibrosis, with high lithocholic acid levels strongly associated with advanced fibrosis (72). Additionally, Caussy et al. noted an increase in total bile acids and primary-conjugated bile-acid proportion with increasing liver fibrosis stage in patients with MASLD (n = 312) (73). Plasma bile acids, FGF19, or de novo bile acid synthesis (measured as serum C4 levels) did not correlate with fibrosis stage within a noncirrhotic cohort of patients with MASH after adjusting for BMI and age (n = 279) (33) demonstrating the role metabolic risk factor confounding may have on the interpretation of MASLD microbiome studies.

Increased systemic levels of secondary bile acids such as deoxycholic acid and lithocholic acid may exert direct hepatotoxic effects, potentially contributing to liver damage (74). These hydrophobic bile acids are particularly effective in activating the TGR5 receptor (75), which may lead to decreased activity of FXR and subsequent increase of de novo bile acid synthesis as described in patients with MASH compared with healthy controls (76). The therapeutic potential of restoring this pathway is supported by the successful use of the semisynthetic FXR agonist obeticholic acid, which has antifibrotic effects in patients with MASH (77). Additionally, microbial-derived deoxycholate has been implicated in the pathogenesis of HCC, underscoring the complex role of gut microbiota in liver disease (78, 79).

Recently, new amino acid or amine-conjugated bile acids (bile acid amidates) have been identified (80, 81). One of these bile acids is 3-succinylated cholic acid, which is synthesized by Bacteroides uniformis and was found to be lower in stool from patients with MASLD compared with controls. Supplementation of this lumen-restricted 3-succinylated cholic acid alleviated steatohepatitis by expanding the population of Akkermansia muciniphila in mice (82). Other secondary bile acids induce Tregs, either directly or by stimulating dendritic cells, which inhibit Th17 cells in the intestine (83–85). It will be interesting to investigate whether these secondary bile acids suppress intestinal inflammation in patients with MASLD, which is closely linked to intestinal barrier dysfunction (86).

SCFAs and branched-chain fatty acids. SCFAs are key microbial fermentation products of nondigestible proteins and fibers, which play crucial roles in immune regulation and maintaining gut barrier integrity. Several SCFA-producing bacteria are depleted in the microbiota of patients with MASLD. Consequently, plasma levels of acetate are generally lower in MASLD patients (n = 100) compared with healthy controls (n = 50), while other SCFAs like propionate are elevated and linked to liver fibrosis (87). Propionate, in particular, is associated with increased fibrosis and may also contribute to insulin resistance in humans (87, 88). Conversely, acetate produced by Bifidobacterium pseudolongum protects against diet-induced steatohepatitis and MASH-associated HCC by stabilizing the gut barrier and exerting a direct antiproliferative effect on liver cells (89). Several other metabolites are also produced as fermentation products of proteins such as branched-chain fatty acids (BCFA), which include iso-butyric acid and iso-valeric acid. The production of BCFAs is impacted by diet quality, and fecal BCFA levels have been correlated with less consumption of dietary insoluble fiber (90). Patients with MASLD and MASH have higher total BCFAs in the liver as compared with controls. Total hepatic BCFAs correlated with disease severity in patients with MASLD (91). Further research is needed to determine whether hepatic BCFAs originate from the microbiota and whether they play a role in the pathogenesis of MASLD.

Other microbial metabolites affecting MASLD. Other microbial-derived metabolites have also been implicated in the pathogenesis of MASLD. MASLD patients have higher circulating levels of the microbial metabolite trimethylamine N-oxide (TMAO) as compared with controls (92). TMAO promotes lipid accumulation in cultured cells (93). Serum phenylacetate was associated with steatosis in women with obesity, and phenylacetate promoted hepatic triglyceride accumulation in mice (94).

On the other hand, other metabolites produced by the gut microbiota might be beneficial for MASLD. Pentadecanoic acid produced by Parabacteroides distasonis is protective against diet-induced steatohepatitis in mice (95). Fecal levels of the tryptophan metabolites indole-3-propionic acid and indole-3-acetic acid were lower in patients with MASLD compared with healthy controls. Indole-3-propionic acid and indole-3-acetic acid administration ameliorated diet-induced steatohepatitis in mice by stabilizing the gut barrier and through direct effects on the liver (96, 97).

In the current era of gut-microbiome discovery in MASLD, efforts are underway to translate findings on gut microbial and metabolite changes into patient care (98). Still, clinical trials evaluating microbiome-based therapies in MASLD are limited but are, fortunately, increasing in number. Recent studies suggest that validated interventions such as nutrition, exercise, and bariatric surgery favorably impact the microbiome, which may contribute to the efficacy in MASLD. Emerging research explores targeted microbiome-based therapies using prebiotic, probiotic, and postbiotic approaches to improve treatment outcomes (99–101) (Table 1).

Table 1

Targeted microbiome-based therapies

Standard of care. The current standard of care in MASLD includes dietary and exercise recommendations and medications. Of the diets, the Mediterranean-style diet is often recommended (1). This diet increases microbial diversity in part due to bioactive components like fiber, polyphenols, unsaturated fatty acids, and fermentation products (102–105). These bioactives, directly and via conversion to active metabolites, support microbial and mitochondrial health, potentially reducing hepatic fat, inflammation, and fibrosis (106). Additionally, the Mediterranean diet is low in red meat, sugar, salt, additives, saturated fat, and choline, which may further benefit microbial diversity and function (92, 107–110). Interestingly, vitamin E, regular exercise, and even bariatric surgery have been shown to improve microbial diversity (111–113), a mechanism that warrants further exploration.

While there is only one FDA-approved medication for MASLD for patients with at least moderate fibrosis (114), many patients have been prescribed metformin or statins to manage concomitant insulin resistance/diabetes or hyperlipidemia, respectively. Metformin and statins have important but seemingly opposing effects on the gut microbiome. Statins may, in fact, worsen glucose homeostasis through disruptions of the gut microbiome (115), while metformin’s effects on the gut microbiome improve glucose homeostasis. In a randomized, double-blind trial involving treatment-naive type 2 diabetes patients and controls, metformin modified the gut microbiota, and transplanting feces from metformin-treated individuals into germ-free mice improved glucose control without affecting body weight or fat mass (116). These studies demonstrate that there can be multiple factors that impact the gut microbiome in MASLD.

Prebiotics and food. Prebiotics, like lactulose and the bioactive fibers and polyphenols in plant-based foods, promote the growth of beneficial bacteria and their metabolites, potentially improving liver health in MASLD patients (117–119). For example, a randomized controlled trial (RCT) evaluating 27 adults consuming a high-fiber roll twice daily for two months showed a significant reduction in liver steatosis by FibroScan, accompanied by significant changes in microbial metabolites (120). In another RCT, 19 adults taking the prebiotic fiber inulin versus the carbohydrate maltodextrin for 12 weeks saw an increase in Bifidobacterium without significant changes in liver fat or function tests (121). The variability in outcomes may relate to specific fiber types, baseline diets, and subject characteristics. Clinical intervention studies with polyphenols favorably impact the microbiome (122, 123), though their evaluation in MASLD is still limited.

Probiotics and bacteria. Probiotics, live bacterial products (LBPs), and fecal microbiota transplantation (FMT) are live bacterial interventions being evaluated for MASLD treatment (124–126). Probiotic trials are heterogeneous, typically using combinations of Lactobacillus and Bifidobacterium. A metaanalysis of 27 studies, including a 12-week RCT of 68 subjects with MASLD, found improvements in liver steatosis, though liver function tests did not improve (127, 128). Recent RCTs with various probiotics, such as lactic acid bacteria combinations and Bacillus coagulans, have shown mixed results (129, 130). FMT studies for MASLD are limited to three small RCTs, with varying effects on liver fat and function (131). LBPs, such as those recently approved for Clostridium difficile infection, offer the potential benefits of a defined therapeutic microbial consortium, although no trials have been reported to date (132, 133).

Postbiotics and Metabolites. Postbiotics, beneficial metabolites produced by gut bacteria (e.g., butyrate, modified polyphenols) or by fermenting foods (e.g., lactic acid, acetate, modified polyphenols), may improve gut health and reduce liver fat, inflammation, and fibrosis (134). A recent trial of 50 subjects randomized to butyrate, vitamin D3, and zinc versus placebo showed a significant improvement in steatosis by the fatty liver index and steatosis index, an effect seen previously in animal model studies for MASLD (135). Modified polyphenols such as urolithin A have only been evaluated in animal models to date, where they have demonstrated a decrease in steatohepatitis (136). Fermented foods have not been evaluated for MASLD, but a recent RCT showed they can significantly increase microbial diversity and decrease systemic inflammation (137).

While research on microbiome-targeting therapies for MASLD is still in its early stages, some findings suggest these interventions may complement standard care. Investigating individual components like dietary bioactives, microbial species, and metabolites may yield valuable insights, underscoring the importance of whole-food diets and leading to new targeted therapies. Postbiotics and fermented foods, which may bypass the need for a healthy microbiome by directly supplying beneficial metabolites, remain particularly underexplored and hold promise as potential new treatments for MASLD. Further research into the small intestine microbiome and metabolites with newly available tools may also provide new therapeutic avenues (138).

Gut dysbiosis is pivotal in MASLD pathogenesis, with microbial imbalance being associated with both the onset and progression of liver disease. Understanding these associations supports the development of microbial-based therapies to restore gut balance. Further research is needed to refine these therapies for personalized treatment of steatosis, inflammation, and fibrosis in MASLD. This includes investigating xenobiotic metabolism to predict therapy responders and nonresponders.

This study was supported in part by services provided by NIH grants P30 DK120515 (BS) and by R01 AA026302 (RMC). The new MASLD nomenclature has been substituted for prior studies on NAFLD given the disease concordance.

Address correspondence to: Rotonya M. Carr, Department of Medicine, University of Washington, 1959 NE Pacific St., Box 356424, Seattle, Washington, 98195, USA. Email: rmcarr@uw.edu.

Conflict of interest: BS has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, and Takeda. BS is a founder of Nterica Bio. BS’s institution UCSD has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, Intercept, NGM Biopharmaceuticals, Prodigy Biotech, and Synlogic Operating Company. CJD consults for Supergut, One Bio, and Oobli. RMC consults for Intercept Pharmaceuticals and Novo Nordisk and receives grant funding from Merck Co.

Copyright: © 2025, Schnabl et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2025;135(7):e186423. https://doi.org/10.1172/JCI186423.

1. Rinella ME, et al. AASLD Practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835.
   View this article via: PubMed CrossRef Google Scholar
2. Rinella ME, et al. Reply: A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;79(3):E93–E94.
   View this article via: PubMed Google Scholar
3. Scorletti E, Carr RM. A new perspective on NAFLD: focusing on lipid droplets. J Hepatol. 2022;76(4):934–945.
   View this article via: PubMed CrossRef Google Scholar
4. Rinella ME, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966–1986.
   View this article via: CrossRef PubMed Google Scholar
5. Dempsey JL, et al. Mechanisms of lipid droplet accumulation in steatotic liver diseases. Semin Liver Dis. 2023;43(4):367–382.
   View this article via: PubMed Google Scholar
6. Walters KE, Martiny JBH. Alpha-, beta-, and gamma-diversity of bacteria varies across habitats. PLoS One. 2020;15(9):e0233872.
   View this article via: CrossRef PubMed Google Scholar
7. Friedman ES, et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid. Gastroenterology. 2018;155(6):1741–1752.
   View this article via: CrossRef PubMed Google Scholar
8. Stellaard F, Lutjohann D. Dynamics of the enterohepatic circulation of bile acids in healthy humans. Am J Physiol Gastrointest Liver Physiol. 2021;321(1):G55–G66.
   View this article via: PubMed Google Scholar
9. Carr RM, Reid AE. FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr Atheroscler Rep. 2015;17(4):500.
   View this article via: PubMed CrossRef Google Scholar
10. Chen K, et al. Insulin-like growth factor-I prevents gut atrophy and maintains intestinal integrity in septic rats. JPEN J Parenter Enteral Nutr. 1995;19(2):119–124.
    View this article via: CrossRef PubMed Google Scholar
11. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516–1526.
    View this article via: PubMed CrossRef Google Scholar
12. Bennett KM, et al. Epithelial microvilli establish an electrostatic barrier to microbial adhesion. Infect Immun. 2014;82(7):2860–2871.
    View this article via: PubMed CrossRef Google Scholar
13. Spadoni I, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015;350(6262):830–834.
    View this article via: CrossRef PubMed Google Scholar
14. De Munck TJI, et al. Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta-analysis. Liver Int. 2020;40(12):2906–2916.
    View this article via: PubMed CrossRef Google Scholar
15. Mouries J, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol. 2019;71(6):1216–1228.
    View this article via: CrossRef PubMed Google Scholar
16. Khoshbin K, Camilleri M. Effects of dietary components on intestinal permeability in health and disease. Am J Physiol Gastrointest Liver Physiol. 2020;319(5):G589–G608.
    View this article via: PubMed Google Scholar
17. Abdelmalek MF, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(6):1961–1971.
    View this article via: PubMed Google Scholar
18. Zhang X, et al. Glucose but not fructose alters the intestinal paracellular permeability in association with gut inflammation and dysbiosis in mice. Front Immunol. 2021;12:742584.
    View this article via: CrossRef PubMed Google Scholar
19. Volynets V, et al. Intestinal barrier function and the gut microbiome are differentially affected in mice fed a western-style diet or drinking water supplemented with fructose. J Nutr. 2017;147(5):770–780.
    View this article via: PubMed CrossRef Google Scholar
20. Spruss A, et al. Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function. Lab Invest. 2012;92(7):1020–1032.
    View this article via: CrossRef PubMed Google Scholar
21. Cho YE, et al. Fructose promotes leaky gut, endotoxemia, and liver fibrosis through ethanol-inducible cytochrome P450-2E1-mediated oxidative and nitrative stress. Hepatology. 2021;73(6):2180–2195.
    View this article via: PubMed CrossRef Google Scholar
22. Nier A, et al. Short-term isocaloric intake of a fructose- but not glucose-rich diet affects bacterial endotoxin concentrations and markers of metabolic health in normal weight healthy subjects. Mol Nutr Food Res. 2019;63(6):e1800868.
    View this article via: PubMed Google Scholar
23. Aleman JO, et al. Excess dietary fructose does not alter gut microbiota or permeability in humans: a pilot randomized controlled study. J Clin Transl Sci. 2021;5(1):e143.
    View this article via: PubMed CrossRef Google Scholar
24. Zhao S, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. 2020;579(7800):586–591.
    View this article via: CrossRef PubMed Google Scholar
25. Jiang WG, et al. Regulation of tight junction permeability and occludin expression by polyunsaturated fatty acids. Biochem Biophys Res Commun. 1998;244(2):414–420.
    View this article via: CrossRef PubMed Google Scholar
26. Guerbette T, et al. Saturated fatty acids differently affect mitochondrial function and the intestinal epithelial barrier depending on their chain length in the in vitro model of IPEC-J2 enterocytes. Front Cell Dev Biol. 2024;12:1266842.
    View this article via: PubMed CrossRef Google Scholar
27. Devkota S, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10^–/– mice. Nature. 2012;487(7405):104–108.
    View this article via: CrossRef PubMed Google Scholar
28. Deiana M, et al. Derangement of intestinal epithelial cell monolayer by dietary cholesterol oxidation products. Free Radic Biol Med. 2017;113:539–550.
    View this article via: PubMed CrossRef Google Scholar
29. Caminero A, et al. The emerging roles of bacterial proteases in intestinal diseases. Gut Microbes. 2023;15(1):2181922.
    View this article via: CrossRef PubMed Google Scholar
30. Jiang W, et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep. 2015;5:8096.
    View this article via: PubMed CrossRef Google Scholar
31. Sicard JF, et al. Interactions of intestinal bacteria with components of the intestinal mucus. Front Cell Infect Microbiol. 2017;7:387.
    View this article via: CrossRef PubMed Google Scholar
32. Spruss A, et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009;50(4):1094–1104.
    View this article via: PubMed CrossRef Google Scholar
33. Carr RM, et al. An integrated analysis of fecal microbiome and metabolomic features distinguish non-cirrhotic NASH from healthy control populations. Hepatology. 2023;78(6):1843–1857.
    View this article via: CrossRef PubMed Google Scholar
34. Wu J, et al. Metabolism-inflammasome crosstalk shapes innate and adaptive immunity. Cell Chem Biol. 2024;31(5):884–903.
    View this article via: CrossRef PubMed Google Scholar
35. Thomas D, Apovian C. Macrophage functions in lean and obese adipose tissue. Metabolism. 2017;72:120–143.
    View this article via: CrossRef PubMed Google Scholar
36. Ghanim H, et al. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care. 2009;32(12):2281–2287.
    View this article via: PubMed Google Scholar
37. Cirera I, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34(1):32–37.
    View this article via: PubMed Google Scholar
38. Yu LC, et al. Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis. Am J Physiol Gastrointest Liver Physiol. 2014;307(8):G824–G835.
    View this article via: CrossRef PubMed Google Scholar
39. Sookoian S, et al. Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease. Gut. 2020;69(8):1483–1491.
    View this article via: CrossRef PubMed Google Scholar
40. Leinwand JC, et al. Intrahepatic microbes govern liver immunity by programming NKT cells. J Clin Invest. 2022;132(8):e151725.
    View this article via: JCI PubMed Google Scholar
41. Champion C, et al. Human liver microbiota modeling strategy at the early onset of fibrosis. BMC Microbiol. 2023;23(1):34.
    View this article via: CrossRef PubMed Google Scholar
42. Michan-Dona A, et al. Are there any completely sterile organs or tissues in the human body? Is there any sacred place? Microb Biotechnol. 2024;17(3):e14442.
    View this article via: PubMed CrossRef Google Scholar
43. Sharifnia T, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol. 2015;309(4):G270–G278.
    View this article via: CrossRef PubMed Google Scholar
44. Carpino G, et al. Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology. 2020;72(2):470–485.
    View this article via: PubMed CrossRef Google Scholar
45. Wree A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59(3):898–910.
    View this article via: CrossRef PubMed Google Scholar
46. Gudan A, et al. The prevalence of small intestinal bacterial overgrowth in patients with non-alcoholic liver diseases: NAFLD, NASH, fibrosis, cirrhosis-a systematic review, meta-analysis and meta-regression. Nutrients. 2022;14(24):5261.
    View this article via: CrossRef PubMed Google Scholar
47. Gkolfakis P, et al. Prevalence of small intestinal bacterial overgrowth syndrome in patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: a cross-sectional study. Microorganisms. 2023;11(3):723.
    View this article via: PubMed CrossRef Google Scholar
48. Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21(11):719–733.
    View this article via: PubMed CrossRef Google Scholar
49. Su X, et al. Composition of gut microbiota and non-alcoholic fatty liver disease: a systematic review and meta-analysis. Obes Rev. 2024;25(1):e13646.
    View this article via: CrossRef PubMed Google Scholar
50. Zeng F, et al. Gut microbiome features and metabolites in non-alcoholic fatty liver disease among community-dwelling middle-aged and older adults. BMC Med. 2024;22(1):104.
    View this article via: PubMed CrossRef Google Scholar
51. Loomba R, et al. The commensal microbe veillonella as a marker for response to an FGF19 analog in NASH. Hepatology. 2021;73(1):126–143.
    View this article via: CrossRef PubMed Google Scholar
52. Cai W, et al. Changes in the intestinal microbiota of individuals with non-alcoholic fatty liver disease based on sequencing: an updated systematic review and meta-analysis. PLoS One. 2024;19(3):e0299946.
    View this article via: CrossRef PubMed Google Scholar
53. Li F, et al. Compositional alterations of gut microbiota in nonalcoholic fatty liver disease patients: a systematic review and meta-analysis. Lipids Health Dis. 2021;20(1):22.
    View this article via: CrossRef PubMed Google Scholar
54. Iino C, et al. Significant decrease in Faecalibacterium among gut microbiota in nonalcoholic fatty liver disease: a large BMI- and sex-matched population study. Hepatol Int. 2019;13(6):748–756.
    View this article via: CrossRef PubMed Google Scholar
55. Oh TG, et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab. 2020;32(5):878–888.
    View this article via: CrossRef PubMed Google Scholar
56. Loomba R, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017;25(5):1054–1062.
    View this article via: CrossRef PubMed Google Scholar
57. Lee G, et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat Commun. 2020;11(1):4982.
    View this article via: CrossRef PubMed Google Scholar
58. Wei J, et al. Identification of commensal gut bacterial strains with lipogenic effects contributing to NAFLD in children. iScience. 2024;27(2):108861.
    View this article via: PubMed CrossRef Google Scholar
59. Niu C, et al. Mapping the human oral and gut fungal microbiota in patients with metabolic dysfunction-associated fatty liver disease. Front Cell Infect Microbiol. 2023;13:1157368.
    View this article via: CrossRef PubMed Google Scholar
60. Demir M, et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol. 2022;76(4):788–799.
    View this article via: CrossRef PubMed Google Scholar
61. Lang S, et al. Intestinal virome signature associated with severity of nonalcoholic fatty liver disease. Gastroenterology. 2020;159(5):1839–1852.
    View this article via: PubMed CrossRef Google Scholar
62. Hsu CL, et al. Any alcohol use in NAFLD patients is associated with significant changes to the intestinal virome. Hepatology. 2023;77(6):2073–2083.
    View this article via: CrossRef PubMed Google Scholar
63. Meijnikman AS, et al. Endogenous ethanol production in health and disease. Nat Rev Gastroenterol Hepatol. 2024;21(8):556–571.
    View this article via: CrossRef PubMed Google Scholar
64. Meijnikman AS, et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nat Med. 2022;28(10):2100–2106.
    View this article via: PubMed CrossRef Google Scholar
65. Engstler AJ, et al. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease. Gut. 2016;65(9):1564–1571.
    View this article via: CrossRef PubMed Google Scholar
66. Zhu L, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57(2):601–609.
    View this article via: CrossRef PubMed Google Scholar
67. Yuan J, et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 2019;30(4):675–688.
    View this article via: CrossRef PubMed Google Scholar
68. Gan L, et al. Bacteriophage targeting microbiota alleviates non-alcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae. Nat Commun. 2023;14(1):3215.
    View this article via: CrossRef PubMed Google Scholar
69. Purohit A, et al. Collinsella aerofaciens linked with increased ethanol production and liver inflammation contribute to the pathophysiology of NAFLD. iScience. 2024;27(2):108764.
    View this article via: PubMed CrossRef Google Scholar
70. Fitzinger J, et al. Gender-specific bile acid profiles in non-alcoholic fatty liver disease. Nutrients. 2024;16(2):250.
    View this article via: CrossRef PubMed Google Scholar
71. Liu AN, et al. Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2023;57(8):872–885.
    View this article via: CrossRef PubMed Google Scholar
72. Kwan SY, et al. Bile acid changes associated with liver fibrosis and steatosis in the Mexican-American population of South Texas. Hepatol Commun. 2020;4(4):555–568.
    View this article via: CrossRef PubMed Google Scholar
73. Caussy C, et al. Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD. Aliment Pharmacol Ther. 2019;49(2):183–193.
    View this article via: CrossRef PubMed Google Scholar
74. Wang Q, et al. Hepatoprotective effects of glycyrrhetinic acid on lithocholic acid-induced cholestatic liver injury through choleretic and anti-inflammatory mechanisms. Front Pharmacol. 2022;13:881231.
    View this article via: PubMed CrossRef Google Scholar
75. Thomas C, et al. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7(8):678–693.
    View this article via: CrossRef PubMed Google Scholar
76. Mouzaki M, et al. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS One. 2016;11(5):e0151829.
    View this article via: CrossRef PubMed Google Scholar
77. Neuschwander-Tetri BA, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965.
    View this article via: PubMed Google Scholar
78. Yoshimoto S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101.
    View this article via: CrossRef PubMed Google Scholar
79. Ma C, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391):eaan5931.
    View this article via: CrossRef PubMed Google Scholar
80. Gentry EC, et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature. 2024;626(7998):419–426.
    View this article via: CrossRef PubMed Google Scholar
81. Mohanty I, et al. The underappreciated diversity of bile acid modifications. Cell. 2024;187(7):1801–1818.
    View this article via: CrossRef PubMed Google Scholar
82. Nie Q, et al. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway. Cell. 2024;187(11):2717–2734.
    View this article via: PubMed CrossRef Google Scholar
83. Campbell C, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020;581(7809):475–479.
    View this article via: CrossRef PubMed Google Scholar
84. Song X, et al. Microbial bile acid metabolites modulate gut RORγ⁺ regulatory T cell homeostasis. Nature. 2020;577(7790):410–415.
    View this article via: CrossRef PubMed Google Scholar
85. Hang S, et al. Bile acid metabolites control T_H17 and T_reg cell differentiation. Nature. 2019;576(7785):143–148.
    View this article via: PubMed CrossRef Google Scholar
86. Rahman K, et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151(4):733–746.
    View this article via: CrossRef PubMed Google Scholar
87. Thing M, et al. Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease. BMC Gastroenterol. 2024;24(1):43.
    View this article via: CrossRef PubMed Google Scholar
88. Tirosh A, et al. The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans. Sci Transl Med. 2019;11(489):eaav0120.
    View this article via: CrossRef PubMed Google Scholar
89. Song Q, et al. Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma. J Hepatol. 2023;79(6):1352–1365.
    View this article via: PubMed CrossRef Google Scholar
90. Rios-Covian D, et al. An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: associated dietary and anthropometric factors. Front Microbiol. 2020;11:973.
    View this article via: CrossRef PubMed Google Scholar
91. Martinez-Montoro JI, et al. Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case-control study. Obesity (Silver Spring). 2023;31(4):1064–1074.
    View this article via: CrossRef PubMed Google Scholar
92. Theofilis P, et al. Trimethylamine N-oxide levels in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Metabolites. 2022;12(12):1243.
    View this article via: CrossRef PubMed Google Scholar
93. Nian F, et al. Gut microbiota metabolite TMAO promoted lipid deposition and fibrosis process via KRT17 in fatty liver cells in vitro. Biochem Biophys Res Commun. 2023;669:134–142.
    View this article via: PubMed CrossRef Google Scholar
94. Hoyles L, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018;24(7):1070–1080.
    View this article via: CrossRef PubMed Google Scholar
95. Wei W, et al. Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid. Nat Microbiol. 2023;8(8):1534–1548.
    View this article via: CrossRef PubMed Google Scholar
96. Min BH, et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes. 2024;16(1):2307568.
    View this article via: CrossRef PubMed Google Scholar
97. Ding Y, et al. Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice. Elife. 2024;12:RP87458.
    View this article via: CrossRef PubMed Google Scholar
98. Rodriguez J, et al. State of the art and the future of microbiome-based biomarkers: a multidisciplinary Delphi consensus. Lancet Microbe. 2024;6(2):100948.
    View this article via: CrossRef PubMed Google Scholar
99. Vallianou NG, et al. NAFLD/MASLD and the gut-liver axis: from pathogenesis to treatment options. Metabolites. 2024;14(7):366.
    View this article via: PubMed CrossRef Google Scholar
100. Pan Y, et al. Efficacy of probiotics, prebiotics, and synbiotics on liver enzymes, lipid profiles, and inflammation in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. BMC Gastroenterol. 2024;24(1):283.
     View this article via: CrossRef PubMed Google Scholar
101. Koning M, et al. Targeting nonalcoholic fatty liver disease via gut microbiome-centered therapies. Gut Microbes. 2023;15(1):2226922.
     View this article via: CrossRef PubMed Google Scholar
102. Merra G, et al. Influence of mediterranean diet on human gut microbiota. Nutrients. 2020;13(1):7.
     View this article via: CrossRef PubMed Google Scholar
103. Vazquez-Cuesta S, et al. Impact of the mediterranean diet on the gut microbiome of a well-defined cohort of healthy individuals. Nutrients. 2024;16(6):793.
     View this article via: CrossRef PubMed Google Scholar
104. Montemayor S, et al. Dietary patterns, foods, and nutrients to ameliorate non-alcoholic fatty liver disease: a scoping review. Nutrients. 2023;15(18):3987.
     View this article via: PubMed CrossRef Google Scholar
105. Anania C, et al. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol. 2018;24(19):2083–2094.
     View this article via: CrossRef PubMed Google Scholar
106. Oh KK, et al. The identification of metabolites from gut microbiota in NAFLD via network pharmacology. Sci Rep. 2023;13(1):724.
     View this article via: CrossRef PubMed Google Scholar
107. Henney AE, et al. Ultra-processed food intake is associated with non-alcoholic fatty liver disease in adults: a systematic review and meta-analysis. Nutrients. 2023;15(10):2266.
     View this article via: CrossRef PubMed Google Scholar
108. Hashemian M, et al. Red meat consumption and risk of nonalcoholic fatty liver disease in a population with low meat consumption: The Golestan Cohort Study. Am J Gastroenterol. 2021;116(8):1667–1675.
     View this article via: PubMed CrossRef Google Scholar
109. Shojaei-Zarghani S, et al. Sodium in relation with nonalcoholic fatty liver disease: a systematic review and meta-analysis of observational studies. Food Sci Nutr. 2022;10(5):1579–1591.
     View this article via: CrossRef PubMed Google Scholar
110. Fagunwa O, et al. The Human gut and dietary salt: the Bacteroides/Prevotella ratio as a potential marker of sodium intake and beyond. Nutrients. 2024;16(7):942.
     View this article via: CrossRef PubMed Google Scholar
111. Pham VT, et al. Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome- a pilot study. Gut Microbes. 2021;13(1):1–20.
     View this article via: PubMed Google Scholar
112. Boytar AN, et al. The effect of exercise prescription on the human gut microbiota and comparison between clinical and apparently healthy populations: a systematic review. Nutrients. 2023;15(6):1534.
     View this article via: CrossRef PubMed Google Scholar
113. Hamamah S, et al. Influence of bariatric surgery on gut microbiota composition and its implication on brain and peripheral targets. Nutrients. 2024;16(7):1071.
     View this article via: CrossRef PubMed Google Scholar
114. Chen VL, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2024;81(1):312–320.
     View this article via: CrossRef PubMed Google Scholar
115. She J, et al. Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner. Cell Metab. 2024;36(2):408–421.
     View this article via: CrossRef PubMed Google Scholar
116. Wu H, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850–858.
     View this article via: CrossRef PubMed Google Scholar
117. Zhu Y, et al. Dietary fiber intake and non-alcoholic fatty liver disease: The mediating role of obesity. Front Public Health. 2022;10:1038435.
     View this article via: PubMed CrossRef Google Scholar
118. Rahimlou M, et al. Polyphenol consumption and Nonalcoholic fatty liver disease risk in adults. Sci Rep. 2024;14(1):6752.
     View this article via: CrossRef PubMed Google Scholar
119. Odenwald MA, et al. Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease. Nat Microbiol. 2023;8(11):2033–2049.
     View this article via: CrossRef PubMed Google Scholar
120. Stachowska E, et al. Precision nutrition in NAFLD: effects of a high-fiber intervention on the serum metabolome of NAFD patients-a pilot study. Nutrients. 2022;14(24):5355.
     View this article via: CrossRef PubMed Google Scholar
121. Reshef N, et al. Prebiotic treatment in patients with Nonalcoholic fatty liver disease (NAFLD)-a randomized pilot trial. Nutrients. 2024;16(11):1571.
     View this article via: CrossRef PubMed Google Scholar
122. Plamada D, Vodnar DC. Polyphenols-gut microbiota interrelationship: a transition to a new generation of prebiotics. Nutrients. 2021;14(1):137.
     View this article via: PubMed CrossRef Google Scholar
123. Yang K, et al. Efficacy and safety of dietary polyphenol supplementation in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. Front Immunol. 2022;13:949746.
     View this article via: CrossRef PubMed Google Scholar
124. Hill C, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–514.
     View this article via: CrossRef PubMed Google Scholar
125. Cordaillat-Simmons M, et al. Live biotherapeutic products: the importance of a defined regulatory framework. Exp Mol Med. 2020;52(9):1397–1406.
     View this article via: CrossRef PubMed Google Scholar
126. Gupta S, et al. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol. 2016;9(2):229–239.
     View this article via: PubMed Google Scholar
127. Zhou X, et al. Efficacy of probiotics on nonalcoholic fatty liver disease: a meta-analysis. Medicine (Baltimore). 2023;102(4):e32734.
     View this article via: CrossRef PubMed Google Scholar
128. Ahn SB, et al. Randomized, double-blind, placebo-controlled study of a multispecies probiotic mixture in nonalcoholic fatty liver disease. Sci Rep. 2019;9(1):5688.
     View this article via: PubMed CrossRef Google Scholar
129. Silva-Sperb AS, et al. Probiotic supplementation for 24 weeks in patients with non-alcoholic steatohepatitis: the PROBILIVER randomized clinical trial. Front Nutr. 2024;11:1362694.
     View this article via: CrossRef PubMed Google Scholar
130. Hsieh RH, et al. Bacillus coagulans TCI711 supplementation improved nonalcoholic fatty liver by modulating gut microbiota: a randomized, placebo-controlled, clinical trial. Curr Dev Nutr. 2024;8(3):102083.
     View this article via: CrossRef PubMed Google Scholar
131. Qiu XX, et al. Fecal microbiota transplantation for treatment of non-alcoholic fatty liver disease: mechanism, clinical evidence, and prospect. World J Gastroenterol. 2024;30(8):833–842.
     View this article via: CrossRef PubMed Google Scholar
132. Quaranta G, et al. “Bacterial Consortium”: a potential evolution of fecal microbiota transplantation for the treatment of Clostridioides difficile infection. Biomed Res Int. 2022;2022:5787373.
     View this article via: PubMed CrossRef Google Scholar
133. Nagarakanti S, Orenstein R. Treating Clostridioides difficile: could microbiota-based live biotherapeutic products provide the answer? Infect Drug Resist. 2023;16:3137–3143.
     View this article via: CrossRef PubMed Google Scholar
134. Vinderola G, et al. The concept of postbiotics. Foods. 2022;11(8):1077.
     View this article via: CrossRef PubMed Google Scholar
135. Fogacci F, et al. Effect of supplementation of a butyrate-based formula in individuals with liver steatosis and metabolic syndrome: a randomized double-blind placebo-controlled clinical trial. Nutrients. 2024;16(15):2454.
     View this article via: CrossRef PubMed Google Scholar
136. Zhang C, et al. Ellagitannins-derived intestinal microbial metabolite urolithin a ameliorates fructose-driven hepatosteatosis by suppressing hepatic lipid metabolic reprogramming and inducing lipophagy. J Agric Food Chem. 2023;71(9):3967–3980.
     View this article via: PubMed CrossRef Google Scholar
137. Wastyk HC, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137–4153.
     View this article via: CrossRef PubMed Google Scholar
138. Shalon D, et al. Profiling the human intestinal environment under physiological conditions. Nature. 2023;617(7961):581–591.
     View this article via: CrossRef PubMed Google Scholar