# These authors share the senior authorship.

Ernesto Saenz , Nathally Espinosa Montagut , Baohong Wang , Christoph Stein-Thöringer , Kaicen Wang , Honglei Weng , Matthias Ebert , Kai Markus Schneider , Lanjuan Li , Andreas Teufel

Engineering ›› 2024, Vol. 40 ›› Issue (9) : 55 -66.

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Engineering ›› 2024, Vol. 40 ›› Issue (9) :55 -66. DOI: 10.1016/j.eng.2024.03.019
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Abstract

The prevalence of metabolic-dysfunction-associated steatotic liver disease (MASLD) is alarmingly high; it is estimated to affect up to a quarter of the global population, making it the most common liver disorder worldwide. MASLD is characterized by excessive hepatic fat accumulation and is commonly associated with comorbidities such as obesity, dyslipidemia, and insulin resistance; however, it can also manifest in lean individuals. Therefore, it is crucial to develop effective therapies for this complex condition. Currently, there are no approved medications for MASLD treatment, so there is a pressing need to investigate alternative approaches. Extensive research has characterized MASLD as a multifaceted disease, frequently linked to metabolic disorders that stem from dietary habits. Evidence suggests that changes in the gut microbiome play a fundamental role in the development and progression of MASLD from simple steatosis to steatohepatitis and even hepatocellular carcinoma (HCC). In this review, we critically examine the literature on the emerging field of gut-microbiota-based therapies for MASLD and metabolic-dysfunction-associated steatohepatitis (MASH), including interventions such as fecal microbiota transplantation (FMT), probiotics, prebiotics, short-chain fatty acids, antibiotics, metabolic pathway targeting, and immune checkpoint kinase blockade.

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Keywords

Microbiome / Fecal microbiota transplantation / Metabolic-dysfunction-associated steatotic liver disease / Fatty liver

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Ernesto Saenz, Nathally Espinosa Montagut, Baohong Wang, Christoph Stein-Thöringer, Kaicen Wang, Honglei Weng, Matthias Ebert, Kai Markus Schneider, Lanjuan Li, Andreas Teufel. # These authors share the senior authorship.. Engineering, 2024, 40(9): 55-66 DOI:10.1016/j.eng.2024.03.019

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1. Introduction

The global prevalence of metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is estimated to be as high as 25% [1]. Just recently, the novel nomenclature “MASLD” was endorsed by an international expert consensus to replace “non-alcoholic fatty liver disease,” in order to more accurately capture the multifaceted origins—genetic, metabolic, and environmental—of hepatic steatosis [2]. The disease is closely linked to increasing obesity in many countries. However, up to 20% of all MASLD cases are considered to be lean, indicating the need for a more complex pathophysiology than just being overweight [3]. China is one of the regions with the highest projection of a prevalence increase to 29.1% by 2030. In European countries, MASLD prevalence may increase to 14.0%-29.5% during the same period [4]. Overall, MASLD has become a global epidemic.

In its initial state, the pathophysiology is characterized by simple steatosis (fat accumulation in > 5% of hepatocytes), from which it can progress to metabolic-dysfunction-associated steatohepatitis (MASH) and end-stage liver disease including advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [5]. Given the high and increasing prevalence of the disease, MASLD-related cirrhosis has become a leading cause of liver cancer globally [6], [7] and the primary cause of liver transplantation [8]. It accounts for 10%-38% of all HCC cases. Notably, HCC development has also been reported to be significantly increased in noncirrhotic MASH [9].

Furthermore, the chronic inflammation derived from steatohepatitis leads to a variety of accompanying heath issues such as cardiovascular comorbidities [10], metabolic syndrome [11], osteoporosis [12], diabetes mellitus [13], and chronic kidney disease [14].

Therefore, it is imperative to promote the development of therapies; yet, no medication has been approved for its treatment thus far [15]. A growing number of studies have defined MASLD as a multifaceted disease associated with nutrition-related metabolic disorders [16]. However, the gut microbiome and the gut-liver axis have been repeatedly suggested to be centrally involved in the development of MASLD and in the progression from simple steatosis to steatohepatitis and even HCC [17], [18]. Since gut-derivate metabolites such as 3-(4-hydroxyphenyl)lactate [19], acetaldehyde [20], and trimethylamine-N-oxide (TMAO) can influence the development of fibrosis [21] through the M1 polarization of Kupffer cells, as well as the development of other hepatic lesions through the modulation of peripheral immune cells [22], major efforts are currently being undertaken in clinical research to determine how to effectively target the microbiome in order to prevent and treat MASLD.

1.1. The microbiome in liver disease

A microbiome is the entirety of a whole range of different microorganisms, including bacteria, archaea, viruses, and fungi, colonizing the body’s surfaces. The gut harbors one of the body’s most complex microbiomes, which is made up largely of bacteria—particularly of the five main bacterial phyla, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Verrucomicrobia—with each serving different functions in specific gut niches [23]. In addition to bacteria, the gut microbiome includes archaea, fungi, viruses, and bacteriophages. Among the total quantity of microorganisms found in the gastrointestinal tract, less than 1% corresponds to fungi. However, due to their large size and biomass in comparison with bacteria, the relative metabolic impact of fungi is probably much higher [24], [25], [26], [27]. Different microorganisms within the microbiome interact with each other and play active roles in human physiology. The microbiome is located at the interface between the host and the environment, where it acts as a metabolically active organ and a point of integration for environmental influences into host physiology [28]. It supports various functions such as digestion, immune system education, and vitamin biosynthesis, and is able to rapidly adapt to changing environments [29]. In general, an unfavorable microbiome, which is characterized by reduced diversity and an expansion of pathobionts, can result in an altered microbial metabolism, impaired intestinal barrier function, and the translocation of microbial components from the gut to the liver. The microbiome’s high plasticity and central role in the pathophysiology of MASLD make it a promising target for combating MASH [30].

1.2. Intestinal barrier function and bacterial translocation

Several bacterial species have been found to contribute to MASLD development, including Bacteroides fragilis, Escherichia coli, and Helicobacter pylori. Unfavorable changes in gut microbiota composition promote intestinal barrier impairment and increased translocation of microbe-associated molecular patterns (MAMPs) such as lipopolysaccharides (LPSs) [31]. Several MASLD-associated bacteria can produce LPSs, which activate Toll-like receptors (TLRs) on liver cells and promote inflammation [32], [33]. On the other hand, beneficial bacteria, such as Akkermansia muciniphila (A. muciniphila) and Bifidobacterium, can produce short-chain fatty acids (SCFAs) that have anti-inflammatory properties, can improve intestinal barrier function, and can protect against MASLD development [34], [35], [36].

The progression of MASLD to MASH is characterized by the infiltration of immune cells into the liver, leading to inflammation and fibrosis. The gut microbiome can affect immune cell activation and infiltration through the production of pro-inflammatory cytokines, which can activate TLRs on immune cells and promote inflammation [37]. Changes in gut microbiome composition have been associated with alterations in TLR signaling and immune cell activation, leading to the development of MASH [37], [38]. For example, studies have shown that increased levels of LPSs in the blood are related to the severity of MASH [39]. The gut microbiome can also affect the activation of hepatic stellate cells (HSCs), which are responsible for the deposition of extracellular matrix proteins and the development of fibrosis in the liver [40], [41]. Moreover, LPSs from the outer membrane of Gram-negative bacteria can activate TLR4 and stimulate the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 [42]. Furthermore, dysbiosis of the gut microbiome can lead to an increase in the ratio of Firmicutes to Bacteroidetes, which is also associated with an increase in TNF-α and IL-6 levels in the liver [43].

1.3. Microbial bile acid (BA) metabolism in MASLD

Dysbiosis of the gut microbiome may alter the composition of BAs and promote the production of secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are toxic to liver cells and can promote the development of liver cancer [44]. Studies have shown that DCA can activate the farnesoid X receptor (FXR) and promote the proliferation of liver cancer cells [45]. Furthermore, LCA can activate the pregnane X receptor (PXR) and induce the expression of genes involved in tumor growth and metastasis [46]. Moreover, obesity-related alterations in gut microbiota can lead to increased levels of DCA. This secondary BA has been shown to induce a senescence-associated secretory phenotype (SASP) in HSCs. This SASP phenotype promotes HCC development through the secretion of inflammatory and tumor-promoting factors. Importantly, blocking DCA production via microbiota modulation was found to effectively prevent HCC development in obese mice, suggesting a critical role for the DCA-SASP axis in obesity-associated HCC [17].

The gut microbiota also contributes to a significant proportion of circulating metabolites [47]. Dysbiosis can promote the production of TMAO, a metabolite of choline, which has been shown to promote the development of liver cancer by inducing angiogenesis and inflammation [48].

1.4. Emerging roles of the mycobiome and virome in MASLD

Several fungal species have been identified in the gut of MASLD patients, including Candida albicans (C. albicans) and Saccharomyces cerevisiae. These fungi can produce harmful metabolites, such as ethanol and acetaldehyde, that can damage liver cells and promote inflammation [49], [50]. C. albicans, a commensal fungus in the gut, was found to be enriched in MASLD patients compared with healthy controls. C. albicans can promote intestinal inflammation and induce the production of pro-inflammatory cytokines, such as IL-17 and IL-22, which can contribute to the development of liver fibrosis and HCC [51]. In addition, Aspergillus can interact with hepatocytes and induce oxidative stress and inflammation, leading to liver damage [50]. Penicillium can cause gut dysbiosis and induce mitochondrial dysfunction, leading to oxidative stress and liver damage [52]. In contrast, beneficial fungi, such as Saccharomyces boulardii (S. boulardii), can modulate the gut microbiota composition and reduce intestinal inflammation, which may have a protective effect against MASLD [53], [54].

Lastly, it must be recognized that intestinal viruses make up a major part of the gut population. Most are bacteriophages, meaning that they can specifically infect specific bacterial communities. Recently, many studies have reported an association between certain phage abundances and diverse metabolic alterations [55], [56], [57], [58]. For example, Yang et al. [57] showed through shotgun metagenomic sequencing that the high presence of the Mimiviridae family in the gut microbiome of obese individuals might be associated with obesity and diabetes. Human adenovirus infection has been identified as a significant risk factor for the progression of MASLD by reducing leptin expression and thereby increasing food intake, as well as by increasing glucose uptake through the activation of lipogenic and pro-inflammatory pathways, leading to chronic inflammation and altered fat metabolism [55].

2. Microbiome treatments for fatty liver disease

2.1. Fecal microbiota transplantation

Several studies have reported on the metabolic effect of fecal microbiota transplantation (FMT) in patients with metabolic syndrome [59], [60], [61], [62]. Since a close link between metabolic syndrome and MASLD has repeatedly been established [63], modification of the fecal microbiome as a potentially common cause is being extensively discussed as a therapeutic option for MASLD. In general, it has been shown that FMT can ameliorate gut permeability, which is observed in autoimmune diseases, metabolic syndrome, and MASLD (Fig. 1) [64], [65], [66].

However, the clinical impact of FMT on MASLD remains to be established. FMT has only been explored in small feasibility trials to determine its therapeutic potential to modify the gut microbiome composition in MASLD patients. Vrieze et al. [59] demonstrated that patients with metabolic syndrome demonstrated significant improvements in insulin sensitivity after six weeks of receiving FMT from lean donors; moreover, their abundance of Roseburia intestinalis was 2.5-fold higher, and their butyrate production increased. As a microbial metabolite, butyrate triggers key mechanisms in liver injury, and its decreased levels are linked to poor outcomes [67]. Similarly, Witjes et al. [61] demonstrated that allogenic FMT from lean and vegan donors to patients with fatty liver disease changed the intestinal microbiota composition, leading to beneficial changes in plasma metabolites and markers of MASLD. De Groot et al. [60] studied the impact of FMT on metabolic syndrome donors who either received bariatric surgery or not (control) and were able to demonstrate a decrease in insulin sensitivity, faster intestinal transit time, and a decrease in inflammatory markers; there were also changes in several intestinal microbiota.

However, other pilot trials have challenged the hypothesis of microbiota transplantation being effective in MASLD. A randomized clinical trial administering allogenic FMT to 15 patients with MASLD and comparing them with patients who received autologous FMT failed to reduce the liver fat fraction after six months [62]. Furthermore, the procedure was unable to improve insulin resistance [62]. The study showed that allogeneic FMT reduced small intestine permeability in patients with high permeability at baseline and increased fecal microbial diversity in allogeneic receivers; however, no significant differences were observed for any particular taxa [62]. Overall, questions remain regarding whether FMT—possibly in combination with lifestyle changes—will eventually be proven effective as a clinical therapy for MASLD. If so, investigation will also be needed to determine whether the effects of such treatment will be long-lasting [68]. Moreover, more research is needed to better define donor and recipient specifics that predict the engraftment of the transplanted community [69]. Despite these challenges, FMT is still considered to have great potential, warranting further clinical research for MASLD treatment. However, substantial data is needed, and advanced stratification may facilitate the understanding of the multisystemic implication this therapy has on fatty liver diseases [70].

2.2. Different biotics as future treatments of liver disease

Now that dysbiosis of the intestine has been established as a driving cause for the development of MASLD, the oral administration of probiotics, prebiotics, or synbiotics has been investigated and proposed as a treatment of MASLD due to their modulating effect on the gut microbiome. Such treatment has been shown to reconstitute the physiological state of the gut microbiome in diverse randomized clinical trials, as well as basic research. Probiotics have been defined as “live organisms that when administered in adequate doses confer a health benefit to the host;” they can be administrated in various ways, such as via liquid drops, powders, fermentable foods, and pills [70]. Prebiotics have been characterized as “metabolic substrates that encourage the growth and activity of microorganisms” that are beneficial to health, generally in the gastrointestinal tract [71]. Synbiotics, a synergistic combination of probiotics and prebiotics, are considered to combine the stimulation of growth and metabolism, thereby benefitting the host [72].

Several studies have aimed to elucidate the effects of these three biotics on chronic liver disease. In a recent double-blind, placebo-controlled trial, Chong et al. [73] evaluated prebiotic inulin in combination with metronidazole in 62 MASLD patients. After a four-week, very-low-calorie diet (600 kcal∙d−1), patients who were on metronidazole for one week followed by the consumption of inulin for 11 weeks exhibited significantly reduced alanine aminotransferase (ALT) levels compared with the placebo arm. However, body mass index (BMI) did not significantly change between treatments. Aller et al. [74] reported the same findings from their pilot trial: The researchers administered to 30 MASLD patients a mixture containing 500 million Lactobacillus bulgaricus and Streptococcus thermophilus (S. thermophilus) per day and found a reduction in aspartate aminotransferase (AST) and ALT after three months in the treatment group, with no change in BMI. This treatment was also correlated with a high representation of Firmicutes/Bacteroidetes phyla, such as Roseburia and Streptococcus in MASLD patients compared with healthy controls in other studies [75], [76], [77].

A second double-blind randomized placebo-controlled study on 48 patients evaluated the efficacy of the coadministration of a live multi-strain probiotic mixture of 14 alive probiotic strains with omega-3 fatty acids in type 2 diabetes (T2D) patients with MASLD [78]. In summary, this combination has demonstrated the potential to improve liver fat, serum lipids, and metabolic profiles. It also improved systemic inflammation [78]. Overall, favorable effects of probiotics and prebiotics in MASLD have been shown in a few clinical trials, but the results need to be replicated in larger studies. The underlying mechanisms leading to those beneficial effects on MASLD also require further elucidation.

Even though most of the probiotics available on the market are from bacteria, many studies support the yeast-based probiotic S. boulardii as an effective probiotic in regulating gut dysbiosis, avoiding pathogen colonization, regulating the immune system, lowering inflammation, and stabilizing the gut barrier, resulting in the improved absorption of nutrients [79]. In a murine study by Martins et al. [79], mice were infected with Salmonella typhimurium and then challenged with the administration of S. boulardii as probiotic treatment. It was found that the probiotic fungus decreased the inflammatory responses by shutting down inflammation pathways that could result in the production of pro-inflammatory cytokines such as TNF-α and chemokine C-X-C motif ligand 1 (CXCL1).

As a combination of probiotics and prebiotics, synbiotics have repeatedly been demonstrated to provide potential therapeutic effects for the treatments of liver diseases. In their randomized controlled clinical trial, Bakhshimoghaddam et al. [78] investigated whether the combination of yogurt containing inulin, Bifidobacterium animalis (B. animalis), and a healthy lifestyle (i.e., diet and exercise) would influence the pathogenesis of MASLD. The study, which was carried out in 102 Iranian MASLD patients, demonstrated that 85.29% of the patients who received treatment were able to reduce their grade of fatty liver compared with the control group. Moreover, the patients receiving treatment demonstrated a reduction in their ALT, AST, alkaline phosphatase (ALP), and γ-glutamyl transpeptidase (γ-GT) levels [78].

Likewise, Malaguarnera et al. [80] investigated Bifidobacterium in combination with fructo-oligosaccharides for their effects on MASH disease and its potential resolution. After six months, patients exhibited significantly decreasing transaminase levels [80]. Similarly, Eslamparast et al. [81] investigated the supplementation of 52 MASLD patients with several Lactobacillus, Streptococcus, and Bifidobacterium strains in addition to prebiotic fructo-oligosaccharides. The patients also had to follow a balanced diet with physical activity. After 28 weeks, the symbiotic treatment was shown to significantly reduce hepatic enzymes and inflammatory markers in MASLD patients. Thus, the future potential of the synergistic therapeutic effects of those two components looks promising. However, just as for probiotics and prebiotics, larger (and more ethnically diverse) studies are necessary to identify potential routine applications of these substances in MASLD and/or MASH treatment. Lastly, in high-fat-diet-induced obese mice, the chitin-glucan prebiotic, derived from a fungus, demonstrated the potential to reduce stomach fat, hepatic triglycerides, and body weight gain through modulation of the gut microbiota [82].

However, some studies have challenged the concept of altering gut dysbiosis with these substances. Recently, a randomized trial by Scorletti et al. [83] that treated 104 MASLD patients with fructo-oligosaccharides in combination with B. animalis did not show a significant benefit regarding liver fat accumulation or fibrosis after one year.

Overall, prebiotics, probiotics, and synbiotics strategies have been shown to be a supportive supplement to reduce inflammation, hepatic steatosis, and liver stiffness measurements. Various meta-analyses have reported positive effects on hepatic enzymes such as ALT and AST resulting from treatment with prebiotics, probiotics, and symbiotics [84], [85], [86], [87], [88], [89], [90]. In a meta-analysis by Sharpton et al. [91] examining the effects of nine probiotics and 12 synbiotics on the gut microbiome in MASLD patients across 21 randomized controlled trials, the use of probiotics/synbiotics was linked to improvement in markers of inflammation, hepatic stiffness, and steatosis. Also, Khan et al. [84] performed a meta-analysis including 12 randomized controlled trials of probiotic/synbiotic therapies, which evidenced a reduction in AST and ALT, significant improvement in liver fibrosis score, and lowered pro-inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and TNF-α. Another example is a meta-analysis by Liu et al. [85] that looked at 15 randomized controlled trials on supplementation with probiotics and synbiotics and investigated the improvement in liver enzymes and liver stiffness, finding an improvement in the lipid profiles of patients.

Despite the promising potential of probiotics in manipulating the gut microbiome and treating MASLD, this field suffers from a significant degree of heterogeneity among studies and a lack of large-scale, well-controlled clinical trials. Further research is necessary to gain increasingly comprehensive knowledge on the use of probiotics in treating MASLD.

2.3. BA pathway-based therapeutics

MASLD patients suffer from an excessive hepatic accumulation of triglycerides and cholesterol. Cholesterol is metabolized to BAs via two central biosynthetic pathways that are closely regulated by feedback mechanisms [92] whose pathophysiological changes have recently gained significant interest, as they may greatly contribute to the development of the disease [93]. BAs are synthesized in the liver via a multistep enzymatic process, conjugated to glycine or taurine, and released as primary conjugated BAs into the duodenum [94]. There, they modulate the intestinal microbiota composition and are subject to microbial BA metabolism, including deconjugation and enzymatic conversions, which shapes their signaling properties on specific BA receptors. Importantly, BA synthesis in the liver is regulated via a negative feedback mechanism mediated by ileal FXR [94]. FXR and other specific BA receptors, such as the Takeda G-protein coupled receptor 5 (TGR5), are involved in diverse molecular mechanisms, including alteration of lipid [95], glucose homeostasis [96], and energy and immunity [97].

Puri et al. [98] investigated the plasma BA profile in biopsy-proven fatty liver disease and were able to demonstrate that the total conjugated primary BAs were significantly elevated in MASH compared with MASLD and/or controls. Furthermore, BA composition differed significantly, and increased key BAs were correlated with higher grades of steatosis (taurocholate), lobular (glycocholate), and portal inflammation (taurolithocholate), as well as hepatocyte ballooning (taurocholate). These alterations may in turn be involved in diverse molecular and (patho-)physiological mechanisms such as the reduction of intestinal FXR signaling, mucous and antimicrobial peptide synthesis, and the integrity of the gut-vascular barrier [99].

Targeting bile-acid-centered mechanisms currently seems to be one of the most promising approaches to treating patients with MASLD [100]. Obeticholic acid (OCA) is an effective and selective agonist for FXR; therefore, it has a significant impact on BA regulation, consequently reducing lipid absorption and liver fibrosis [100]. Triggering this nuclear receptor reduces intracellular hepatocyte concentrations for BAs by increasing BA transport out of hepatocytes and suppressing cholesterol synthesis [100], [101]. In this regard, clinical OCA treatment was shown to ameliorate hepatic steatosis in two randomized controlled trials, as demonstrated by an improvement in liver histology compared with the placebo in MASLD/MASH patients [99], [100].

OCA has also been demonstrated to impact intestinal permeability, microbiome abundance, and bacterial translocation [102]. In turn, various reports investigating murine models have described the relevance of the gut microbiome in the regulation of OCA and FXR [103]. In a study conducted by Liu et al. [85], metagenomic and metabolomic analyses of mice with MASLD and antibiotic-induced dysbiosis were used to evaluate the abundance and role of the microbiota in treatment with OCA. The researchers found that OCA treatment increased the microbiota responsible for BA homeostasis (A. muciniphila, Bacteroides massiliensis, S. thermophilus, and Bifidobacterium spp.). The increase in these species was associated with a reduction in the levels of primary BAs (cholic and deoxycholic) and increased levels of conjugated BAs (taurodeoxycholic and tauroursodeoxycholic) [85]. Hence, the promising effects of OCA could be mediated, to some extent, by regulating the intestinal microbiome.

For example, this BA regulation by the gut microbiome even impacts HCC development, which has been demonstrated to be increased in patients with MASLD and particularly MASH [104]. The gut microbiome is known to be involved in secondary BA metabolism and the inhibition of primary BAs synthesis by decreasing the inhibition of FXR in enterocytes, leading to a decreasing production of secondary BA, which is modulated by the microbiome. This process induces the synthesis of chemokine CXCL16 in liver sinusoidal endothelial cells, which increases the presence of hepatic C-X-C chemokine receptor 6+ (CXCR6+) and finally advances the activation of natural killer T cells. As a result, antitumor immunity in the liver is promoted [105].

Targeting the FXR with a potent agonist, OCA, resulted in significant improvement in liver fibrosis and activity of MASH in a recent multicenter phase-III trial. A dose-dependent decrease in ATL and AST and improvement in the key histological features of MASH were observed. However, approval was not granted by the US Food and Drug Administration (FDA) due to limited non-alcoholic steatohepatitis (NASH) resolution, as just 11%-12% of treated patients experienced improvement, compared with 8% of placebo recipients [106]. Finally, the ALPINE 4 trial recently demonstrated favorable outcomes in assessing the efficacy, safety, and tolerability of aldafermin, a fibroblast growth factor 19 (FGF19) analogue, in MASH. The effects of aldafermin were attributed to reduced BAs production, the promotion of insulin sensitization, and decelerated de novo lipogenesis [107].

2.4. Short-chain fatty acids

Gut microbes convert food fibers into SCFAs such as acetate, propionate, and butyrate, among other compounds [108], [109], [110]. After being released into the gut, 60%-70% of the SCFAs are used to satisfy the energy requirements of colonic cells and enterocytes. A small proportion of 5%-15% of the SCFAs enters the systemic blood supply, subsequently having beneficial effects on host immunity and insulin sensitivity [85]. By triggering the G-protein-coupled receptor 41 (GPR41) and GPR43, SCFAs have a significant impact on hepatic steatosis, appetite, insulin resistance, and inflammatory response, all of which may contribute to a constant aggravation of MASLD and MASH [111].

The exact mechanisms by which SCFAs impact fatty liver disease are not well understood. However, a general therapeutic potential must be assumed from various clinical observations, such as the finding that some probiotics were able to inhibit inflammation and stimulate changes in lipid metabolism. It is believed that these effects are at least partly due to increased SCFA production in the gut [112].

SCFAs promote the reduction of fat accumulation in the adipose tissue and are important for the protection of the intestinal barrier in the colon mucosa [113]. Among the three major SCFAs, butyrate has shown the most promising results; it has been reported to improve the gut barrier through induction of tight junction proteins, especially mucins [114], [115], [116], [117], and to reduce inulin permeability in physiological concentrations [118]. By regulating inflammatory cytokines and facilitating tight junction assembly through adenosine monophosphate-activated protein kinase (AMPK) activation, butyrate also improves insulin sensitivity and MASLD progression by reducing liver injury and fibrosis [3], [119].

Furthermore, butyrate may enhance peroxisome proliferator-activated receptor (PPAR)-dependent signaling, which is known to regulate metabolism and inflammation [120], [121]. Interestingly SFCAs were unable to reduce the fat fraction in the liver of PPARγ-deficient mice. Thus, PPARγ must be assumed to be critical for beneficial SCFA-mediated effects on metabolic syndrome [122]. Butyrate has been found to induce the inhibition of histone deacetylase proteins (HDACPs), and subsequent epigenetic modifications may also enhance glucagon-like peptide-1 receptor (GLP-1R) expression [123], downregulate nuclear factor-κB (NF-κB) transcription, and ultimately attenuate inflammation and fibrosis [124], [125].

Overall, the evaluation of SCFAs for their therapeutic potential in MASLD has just begun. Their impact on well-established molecular mechanisms involving fatty acid metabolism and inflammation raises hope for the development of these substances into potent and cheap modulators of MASLD.

2.5. Antibiotics as modulators of inflammation and fibrosis through the microbiome

Antibiotics modulate the abundance of the commensal microbiota and may cause dysbiosis and bacterial resistance. Furthermore, antibiotic treatment may reduce inflammation and leakiness of the gut [126]. However, antibiotics can also promote beneficial bacterial growth. It was recently reported that rifaximin, a non-absorbable antibacterial agent, modulated intestinal permeability, thus preventing bacterial translocation and conferring anti-inflammatory properties, and played an immunomodulatory role in patients with MASH or liver cirrhosis [127]. These observations were the basis for several murine studies and small human trials to characterize the potential efficacy of rifaximin in the treatment of MASLD. Jian et al. [128] investigated rifaximin treatment in mice with methionine- and choline-deficient (MCD) diet-induced MASH and demonstrated a substantial amelioration of liver steatosis, lobular inflammation, and fibrogenesis. Finally, Enomoto et al. [129] investigated the effects of a combination of rifaximin and lubiprostone in a choline-deficient l-amino acid-defined (CDAA) rat model. Overall, they demonstrated that this combination significantly reduced macrophage expansion, pro-inflammatory responses, and liver fibrosis.

Few clinical observations or small trials translating these findings into humans are available. The notion that rifaximin may be an effective treatment for liver fibrosis is supported by a recent double-blind, placebo-controlled, phase-II trial in patients with alcohol-related liver disease (GALA-RIF) [130]. These data suggest that rifaximin might reduce the progression of liver fibrosis in alcohol-related liver disease (ALD). Abdel-Razik et al. [131] also conducted a double-blind randomized controlled study in 50 patients. In general, the researchers reported improvement in liver enzymes, reduction of pro-inflammatory cytokines, and an improved MASLD-liver fat score compared with the placebo group. However, some researchers working with smaller cohorts found no benefit in rifaximin for patients with MASH [132]. Furthermore, it is necessary to investigate whether rifaximin can not only improve steatosis but also protect from fibrosis in MASLD.

There is little research on the use of other antibiotics against MASLD. Using metronidazole and inulin supplementation, Chong et al. [73] reported that the abundance of bacteria from the genera Streptococcus, Dialister, and Roseburia were significantly reduced. In addition, metronidazole-inulin treatment with a very-low-calorie diet significantly decreased hepatic enzyme levels for ALT and AST.

To summarize, murine and some human pilot trials suggest that antibiotics—particularly rifaximin—may hold potential for the treatment of MASLD. Possible mechanisms include cytoprotective effects, the prevention of bacterial translocation, and anti-inflammatory properties, resulting in an improvement in laboratory and fibrosis biomarkers in MASH patients. However, some studies showed no significant therapeutic efficacy of rifaximin or other antibiotics, and the reported trials were small; therefore, further research and, in particular, larger study populations are needed to further define the potential of rifaximin or other antibiotics for the treatment of MASLD and/or MASH.

3. Personalized treatment: A microbiome perspective

3.1. The gut microbiome as a noninvasive tool for liver diseases profiling

Clinical and preclinical studies have demonstrated the relevance of the gut-liver axis for the maintenance of homeostasis at a multisystemic level in the human body. Dysbiosis has been demonstrated to trigger a variety of pathophysiologically relevant mechanisms, from endotoxin accumulation [120] to chronic inflammation [133] or even liver carcinogenesis [134]. However, depending on the predominant changes in microbiome composition, these changes may be very diverse, opening up subgroups of patients with differing prognoses and/or response to treatment. Currently, it is uncertain which patients may benefit from microbiome modulation, and treatment approaches are not tailored to the individual. Thus, unraveling specific subgroups and specifically targeting these mechanisms, as well as the microbiome changes behind them, are of high interest for the personalized treatment of chronic liver disease.

Concerning prognostic subgroups, Loomba et al. [135] showed that age and BMI, combined with gut microbial markers as obtained from metagenomic sequencing, can identify patients with MASLD who suffer from advanced fibrosis with high precision. In their study [135], the fecal microbiomes in MASLD were dominated by Firmicutes and Bacteroidetes, followed by Proteobacteria and Actinobacteria. Nevertheless, with an increasing grade of fibrosis in MASLD, Proteobacteria significantly increased in quantity, whereas Firmicutes declined.

On the other hand, an international multicenter cohort of 88 patients with alcoholic hepatitis revealed cytolysin, a two-subunit toxin expressed and secreted by Enterococcus faecalis, to be a cause of hepatocyte death and liver injury [136] and demonstrated that its existence is correlated with the severity of the disease. The bacteriophage-mediated targeting in this study showed the feasibility of therapeutic editing of the intestinal microbiome using bacteriophages [136]. Although larger clinical trials may be necessary to explore the causal relationship between these results and evaluate the treatment in a real-world setting, the study demonstrated the potential effects and safety of bacteriophages as a possible therapeutic strategy [136].

3.2. Pharmacomicrobiomics and its role in drug efficacy

Pharmacomicrobiomics is an emerging field that explores the interactions of microbiome variation and drug response and disposition (i.e., absorption, distribution, metabolism, and excretion) [137], [138], [139]. The microbiome is an interesting target for improving drug safety and efficacy due to its plasticity and the capacity to alter and manipulate its composition. Focusing on disease and gut microbiome drug signatures in humans with T2D, a recent study using shotgun sequencing-based metagenomic analyses described a rise in Escherichia spp. and a decrease in Intestinibacter spp. with metformin-treated T2D [140]. These findings were similar to those by Bryrup et al. [141], who reported a decreased population of Intestinibacter spp. and Clostridium spp. and an increased population of Escherichia/Shigella and Bilophila wadsworthia directly related to treatment with metformin. All these findings showed a substantial impact from metformin treatment on the gut microbiome. It is important to note that, in a study from Seoul National University, metformin treatment significantly increased the abundance of A. muciniphila and Clostridium cocleatum compared with the control group, which correlated with an increase in intestinal mucosa thickness and mucins abundance in the intestine, as well as overall improvement in biomarkers of metabolic disease such as total cholesterol and body weight [142].

Another key example of the interaction of the gut microbiome with xenobiotics is the response to immunotherapy. The gut microbiome can modulate the host immune system both locally and systemically. Numerous physiological functions are influenced by the microbiome, especially immunity, metabolism, and inflammation. There is a wide range of evidence endorsing the fact that the gut microbiome affects the therapeutic efficacy of cancer immunotherapy, especially regarding immune checkpoint inhibitors [143], [144], [145], [146].

For example, a large amount of evidence from past decades endorses the idea that the microbiome is a key factor in different aspects of liver disease progression, as well as in establishing a hepatic environment that enhances the progression of HCC [34], [111], [134], [147] via the mechanism of dysbiosis. This in turn leads to altered bacterial metabolites, such as cancer-promoting secondary BA or DCA [17], causing leaky gut and increasing the chances of developing inflammation via TLR4 signals [148], [149].

Furthermore, immune checkpoint inhibitors (ICIs) such as those targeting anti-programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) have been demonstrated to be highly effective in patients with HCC and against many other tumor entities [150]. However, almost 30% of eligible patients for breakthrough treatments do not respond to therapy [151]. A recent study demonstrated that FMT from healthy donors plus anti-PD-1 immunotherapy was safe in a first-line setting against advanced melanoma, and similar studies in HCC are expected [152]. Pharmacomicrobiomics constitutes a promising field for the treatment of fatty liver diseases and systemic pathologies due to the intrinsic role of the gut-liver axis in human biology. Currently, efforts are being made to develop accurate integrated microbiome prediction indexes to facilitate the translation of this modifiable biomarker (i.e., the gut microbiome) for tumor response rate into the clinic [153]. Predictive models have shown promising results for the identification of non-responders to ICI therapies in HCC [154]. However, due to limited evidence and low sample sizes in studies characterizing ICI efficacy with respect to the gut microbiome, many more studies are needed in order to increase the accuracy of these models and thus fulfill their potential to provide personalized treatment. It is imperative to translate this approach to the treatment of chronic liver diseases, as both patient outcomes and the entire health system could benefit from more efficient therapies. Further research and larger sample sizes may allow for the use of microbiome biomarkers in clinical settings to aid in diagnosis and potentially predict the prognosis of patients with fatty liver diseases and gut-liver-related pathologies (Fig. 2).

4. Summary

The progression of MASLD to MASH, cirrhosis, or HCC is increasingly being linked to gut microbes and their products. Key mechanisms include interference with intestinal permeability, inflammatory signaling, and SCFA production. Given its central role in MASLD pathophysiology, the microbiome has emerged as a promising therapeutic target, particularly since alternative drug options are still lacking. Several approaches including probiotics, prebiotics, synbiotics, antibiotics, and FMT have been investigated and have shown partially promising results in smaller studies. However, further research and, in particular, larger clinical trials are needed to understand the potential of such approaches as low-risk, safe, and inexpensive (adjuncts to) treatment for MASLD and MASH.

Acknowledgments

Andreas Teufel received grants from the Federal Ministry of Education and Research (Q-HCC, 01KD2214), the Sino-German Center for Research Promotion (GZ-1546 and C-0012), the State Ministry of Baden-Wuerttemberg for Sciences, Research and Arts supporting the Clinical Cooperation Unit Healthy Metabolism at the Center for Preventive Medicine and Digital Health (CCU Healthy Metabolism), the Baden-Wuerttemberg Center for Digital Early Disease Detection and Prevention (BW-ZDFP), and the Foundation for Biomedical Alcohol Research, Schriesheim, Germany. Kai Markus Schneider is funded by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine-Westphalia (MKW) (NRW Rueckkehrprogramm) under the Excellence Strategy of the Federal Government and the Länder, and the German Research Foundation (DFG, 403224013-SFB1382, gut–liver axis).

Compliance with ethics guidelines

Ernesto Saenz, Nathally Espinosa Montagut, Baohong Wang, Christoph Stein-Thöringer, Kaicen Wang, Honglei Weng, Matthias Ebert, Kai Markus Schneider, Lanjuan Li, and Andreas Teufel declare that they have no conflict of interest or financial conflicts to declare.

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