Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer. Akkermansia muciniphila (A. muciniphila) is a next-generation probiotic that has been reported to improve metabolic disorders. Emerging evidence indicates the therapeutic potential of A. muciniphila for NAFLD, especially in the inflammatory stage, nonalcoholic steatohepatitis. Here, the current knowledge on the role of A. muciniphila in the progression of NAFLD was summarized. A. muciniphila abundancy is decreased in animals and humans with NAFLD. The recovery of A. muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD. The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed. The modulation mechanisms by which A. muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells (such as macrophages). This review provides insights into the roles of A. muciniphila in NAFLD, thereby providing a blueprint to facilitate clinical therapeutic applications.

Keywords

Akkermansia muciniphila / NAFLD / NASH / steatosis / inflammation

1 Introduction

Liver disease is a major worldwide health problem and heavy economic burden; liver cirrhosis and cancer account for 3.5% of global mortality [1]. Nonalcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately 25% of the global population [2]. It is one of the major risk factors for cirrhosis, hepatocellular carcinoma, and liver-related mortality [3]. NAFLD comprises a continuum of liver conditions varying from steatosis alone (NAFL) to nonalcoholic steatohepatitis (NASH). Currently, the “two-hit” theory, which consists of a first “hit” from steatosis (NAFL) and a second “hit” from other factors (e.g., oxidant stress), is not sufficient to explain NASH pathogenesis [4]. Multiple factors contribute to the development of NAFLD. In recent years, increasing evidence has indicated that the gut microbiota and its derived molecules act as vital players in the pathogenesis of NAFLD, especially the pathogenesis of NASH [5–8]. Hence, several approaches targeting the crosstalk between the gut microbiota and liver (gut–liver axis) have attempted to improve liver diseases [9].

In recent decades, Akkermansia muciniphila (A. muciniphila) has been regarded as a promising beneficial probiotic [10–13]. It is a strictly anaerobic, Gram-negative, mucin-degrading bacterium [14] that accounts for approximately 1%–3% of total bacteria in the intestinal tract of healthy adults [15]. A. muciniphila exhibited beneficial effects on host health and disease [16]. Several studies highlighted the therapeutic efficacy of A. muciniphila on metabolic disorders [17–19] and immune diseases [20]. In addition, A. muciniphila presented potential for the prevention of liver diseases [21–23], especially NAFLD [21]. However, key questions regarding its contribution to NAFLD need to be elaborated. Are there cause-and-effect evidence? What are the key components of A. muciniphila? How does the interaction occur between hepatic immune cells/signals and A. muciniphila? What are the roles of the intestinal barrier-protecting effect of A. muciniphila in NAFLD? In the present study, the current knowledge highlighting the role of A. muciniphila in NAFLD was systemically summarized, and the details of how the microbiota interferes with immunity and metabolic processes of the liver were discussed. An enhanced understanding of the A. muciniphilag–NAFLD interactions could facilitate the development of novel preventative or therapeutic strategies.

2 A. muciniphila and gut–liver axis

A. muciniphila attracted much attention for its ability to protect intestinal barrier function. Despite the mechanisms of this process are not completely understood, several theories support the role of A. muciniphila in maintaining such function.

First, A. muciniphila protects the physical and microbial barrier of the intestine. For example, A. muciniphila colonizes the mucus layer of the intestine, and it is involved in the turnover of mucin (degradation and synthesis) [24]. A. muciniphila and its-derived extracellular vesicles (AmEVs) could also promote the expression of tight junction proteins, such as Tjp1 and Occludin [25,26]. In addition, A. muciniphila could stimulate the proliferation and migration of enterocytes adjacent to colonic wounds [27] and accelerate the epithelial development mediated by intestinal stem cells (ISCs) [28]. Furthermore, A. muciniphila could promote the gene expression of antimicrobial peptides (including Lyz1, DefA, and Reg3g) in the gut [25] and further regulate the microbial community [25].

Second, sound evidence supported an important role of A. muciniphila in maintaining the intestinal immune homeostasis, including the regulation of IgA, IL-17 signals, and macrophages. For example, A. muciniphila was reported to promote the expression of immunoglobulin A (IgA) levels [19]. Interestingly, HFD-fed IL-17RA^−/− mice displayed reduced abundance of A. muciniphila [29]. IL-17 could induce secretion of antimicrobial peptides and regulate intestinal IgA production, and it exhibited protective and pathogenic roles in the gut homeostasis [30]. Importantly, IL-17 plays a key role in the main comorbidity of NAFLD, that is, early atherosclerosis, as evident in a report on obese patients with NAFLD [31]. Thus, the findings implied that IL-17 signals could favor the enrichment of A. muciniphila and provided a clue for the association between A. muciniphila and intestinal innate immunity response. Further, researchers found that A. muciniphila regulated macrophages and the expression of NLRP3 of macrophages to alleviate acute intestinal inflammation [32]. Besides the innate immune cells, A. muciniphila coordinated the intestinal adaptive immune (T cell) responses that prevent colitis [33]. A. muciniphila supplementation also ameliorated TLR4-deficient-induced colitis by upregulating RORγt⁺ Treg cell-mediated immune responses in mice [34].

Lastly, the effects of A. muciniphila-mediated metabolites, such as short-chain fatty acids (SCFAs) and tryptophan derivatives, on the intestinal barrier have raised concern. A study showed that A. muciniphila promoted SCFA secretion (including acetic, propionic, and butyric acids), and antagonists of SCFA receptors could diminish epithelial development [28]. The influence of A. muciniphila on SCFAs was also confirmed in intestinal organoids [35]. One study reported that A. muciniphila regulated tryptophan metabolism [36], which activated the aryl hydrocarbon receptor (AhR) in the gut and further exerted barrier-protective effects [37]. In addition, A. muciniphila promoted bile acid (BA) salt uptake [38], reflected by the upregulation of ASBT, IBABP, and OSTβ expression in the ileum of mice, which may be beneficial to the remodeling of the gut microbiota structure [38]. Therefore, A. muciniphila enhances intestinal barrier function by regulating mucosal, microbial, epithelial, metabolic, and immunological components (Fig.1).

Owing to the unique anatomy of the enterohepatic circulation, the gut–liver axis refers to the bidirectional relationship between the gut (especially the microbiota) and the liver [39]. On the one hand, the portal vein carries gut-derived products (such as lipopolysaccharide, secondary bile acids, and SCFAs) directly into the liver. On the other hand, the liver shapes intestinal homeostasis via the feed-back route. A. muciniphila promoted beneficial effects on hepatic immunity and metabolism on the basis of the gut–liver axis.

Once the balance of the gut–liver axis is disrupted, the gut-derived molecules in the blood induce a sustained immune response that promotes liver disorders [40]. Given its efficacy in the enhancement of the intestinal barrier, A. muciniphila could decrease the microbiota-derived products in circulation and further regulate the immune response in the liver. In mouse models, A. muciniphila markedly reduced the level of lipopolysaccharides in the serum [19,22,25] and portal plasma [41]. Accordingly, A. muciniphila downregulated proinflammatory factors, such as IL-6 [21], IL-1β [22], and TNF-α [23]; immune cell infiltration, such as neutrophils [22]; and fibrosis-related genes, such as TGF-β, α-SMA, TIMP1, Col1a1, and PDGF [23], in the liver. These studies highlighted the role of A. muciniphila in the interaction between microbial lipopolysaccharides and liver immunity. Recent studies found that A. muciniphila could alleviate hepatic macrophage and neutrophil infiltration [22]. Wu et al. showed that A. muciniphila enriched the anti-apoptosis factor Bcl-2 and suppressed the cytotoxic factors Fas and DR5 [25]. In general, existing evidence affirmed the potential effects of A. muciniphila in regulating the hepatic immune response.

Interestingly, A. muciniphila was also found to be involved in liver metabolism pathways, such as glucose, lipid, and BA metabolism. Yoon et al. recently showed that A. muciniphila promoted glucagon-like peptide-1 (GLP-1) secretion in the intestine [42], which was previously reported to reduce hepatic glucose output [43]. A decrease in A. muciniphila abundance was notably accompanied by an increase in hepatic triglyceride levels [44]. By contrast, an increase in A. muciniphila abundance was accompanied by a decrease in total cholesterol and triacylglycerol levels [45]. Kim et al. further reported that A. muciniphila downregulated the expression of the fat synthesis gene SREBP in the liver [21]. Rao et al. revealed that A. muciniphila increased the expression of genes involved in cholesterol transport (NPC1L1) in the ileum and those involved in cholesterol transport (LDLR) in the liver. Thus, it acts to facilitate cholesterol transport [38]. Moreover, Rao et al. found that A. muciniphila promoted the expression of genes related to BA metabolism, including BA synthesis and efflux (CYP7A, CYP8B1, CYP27A1, TGR5, BSEP, MPR2, MPR3, and FXR) and BA salt uptake (NTCP and OATP), in the liver [38]. Plovier et al. suggested that pasteurized A. muciniphila could reduce trimetlylamine oxide production in the liver [41]. Overall, the beneficial effects of A. muciniphila on the liver may depend, in part, on its regulation of metabolism and immunity, both of which affect the gut.

3 Decreased Akkermansia muciniphila abundance in mice and patients with NAFLD

The role of A. muciniphila in metabolic diseases, such as obesity and T2DM, is a hot topic in recent studies [13]. The association between A. muciniphila and NAFLD, the hepatic manifestation of metabolic syndrome, has aroused increasing concern. Differential changes in A. muciniphila in animals with short-term high-fat/sugar diet-induced obesity (that had not yet advanced into NAFLD) remain inconsistent [46,47]. However, previous studies reported that the administration of a high-fat diet (HFD) for 9 [48], 10 [21], 12 [49,50], or 13 [51] weeks induced fatty liver (confirmed by liver histology), and a lower abundance of A. muciniphila was observed in these mice. Another NAFLD mouse model induced by saccharin/sucralose diets for 11 weeks showed a decrease in A. muciniphila abundance [44]. Schneeberger et al. revealed a progressive decrease in A. muciniphila abundance in mice fed with HFD for 16 weeks [52]. In addition, a methionine and choline-deficient (MCD) diet for 4 [53] or 8 (unpublished data) weeks induced NASH, accompanied by a decrease in the abundance of A. muciniphila. Overall, a decrease in A. muciniphila abundance was widely observed in animal models of NAFLD induced by different diets with different intervention times (Tab.1).

Studies have shown decreased A. muciniphila abundance in patients with metabolic syndrome, including those who are overweight and with obesity, untreated type 2 diabetes mellitus (T2DM), and hypertension [54–58]. However, the results of current clinical studies about the alterations in A. muciniphila abundance in patients with NAFLD or NASH are conflicting. A clinical study of obesity in females with liver steatosis found an increasing trend in the abundance of the genus Akkermansia as the steatosis level increased [59]. Conversely, a reduction in Akkermansia was observed in obese patients with NAFLD (diagnosed by ultrasonography without liver pathology), although the difference was not statistically significant [60]. Patients with T2DM with moderate/severe NAFLD also showed a decreasing trend in A. muciniphila abundance compared with patients with T2DM with no or mild NAFLD [61]. Another study revealed a significant decrease in Akkermansia in patients with NAFLD with elevated liver enzymes (diagnosed by abdominal ultrasound or computed tomography) compared with healthy controls [62]. A total of 46 patients with biopsy-proven NASH had significantly decreased A. muciniphila abundance levels compared with 38 healthy controls [63]. In addition, children with NAFLD demonstrated similar changes. For example, a study in pediatric patients with NAFLD showed a decreasing trend in the abundance of A. muciniphila when compared with healthy controls [64]. Pan et al. analyzed the alterations of the gut microbiota in 75 children, including 25 patients with NAFL (diagnosed by ultrasonography), 25 patients with NASH (unknown diagnostic criterion), and 25 patients who are obese without NAFLD. They showed that the abundance of Akkermansia in individuals with NAFL significantly decreased compared with that of control individuals [65]. Children with NASH had a lower abundance of Akkermansia than those with NAFL [66]. Moreover, patients with NAFLD and cirrhosis [67] showed a lower abundance of Akkermansia than healthy control individuals.

In addition, several studies have provided evidence for a negative correlation between A. muciniphila abundance and human NAFLD [58,68]. For example, patients with obesity with a low abundance of A. muciniphila presented with higher levels of liver enzymes (ALT and GGT) [58]. A. muciniphila was positively correlated with the concentration of circulating adiponectin (a potential anti-inflammatory effect [69]) levels in humans [68]. Interestingly, a study of 241 predominantly Latino children (with NASH and NAFL and control individuals) indicated that children with more severe liver pathology had enrichment of bacterial genes related to lipopolysaccharide biosynthesis, which is partly driven by A. muciniphila. However, no specific evidence was found for decreases in A. muciniphila abundance in children with NASH [70]. In general, current studies largely supported the reduction in A. muciniphila abundance in clinical patients with NAFLD (Tab.1). However, direct evidence for the alteration of A. muciniphila in patients with NAFLD with histopathological diagnosis is still being further analyzed.

4 Therapeutic role of A. muciniphila in NAFLD

At present, many agents that aimed to cure NAFLD/NASH have been reported in recent papers, including antidiabetic, anti-obesity, antioxidant, and cytoprotective agents [71]. Interestingly, the abundance of A. muciniphila was increased in the gut after NAFLD therapies, such as probiotics, dietary fiber, prebiotics, and traditional Chinese medicine (Tab.1) [72–88]. Moreira et al. reported that liraglutide could reverse HFD-induced NAFLD by reducing lipid droplets and inflammatory cell infiltration in the liver, and enrich the abundance of A. muciniphila [72]. Du et al. found that dietary betaine prevented hepatic steatosis and increased ALT/AST in mice with HFD treatment for 23 weeks, accompanied by an increase in A. muciniphila [73]. A clinical study of NAFLD-related metabolic syndrome also presented similar findings [58,89,90]. In a clinical study of adults who are overweight and obese, the increased abundance of A. muciniphila was also observed to be involved in the effects of calorie restriction on metabolic disorders [58]. Another study of individuals with morbid obesity, who underwent weight-loss surgery (Roux-en-Y gastric bypass), showed that the abundance of A. muciniphila increased within 3 months after surgery and remained high 1 year later. The abundance increased in parallel with metabolic improvements [90]. In addition, A. muciniphila showed therapeutic potential for ethanol or drug-induced liver injury [22,23,25]. These findings suggested that A. muciniphila could be a potential target for the treatment of NAFLD.

Several studies have provided evidence for the beneficial role of A. muciniphila in the prevention of NAFLD (Tab.2). In animal experiments, several studies have demonstrated the protective role of A. muciniphila in a short-term HFD-induced metabolic disorder mouse model [42,91]. Interestingly, a study reported that the oral administration of A. muciniphila (dose of 10⁸–10⁹ CFU/mL) could prevent HFD-induced NAFLD in mice, as reflected by decreased ALT levels and improvements in hepatic steatosis [21]. Rao et al. recently demonstrated that 6 weeks of A. muciniphila (2 × 10⁷ CFU) treatment showed a therapeutic effect on NAFLD in mice [38]. They found that the withdrawal of A. muciniphila treatment after 4 weeks maintained the efficient persistence of its anti-NAFLD activities due to the reshaping of the gut microbiota [38]. Furthermore, antibiotic treatment decreased A. muciniphila abundance, accompanied by an exacerbation of NAFLD manifestations in HFD-fed mice. Co-treatment with antibiotics and A. muciniphila also demonstrated robust NAFLD-attenuating effects [38]. These findings showed the inhibition and therapeutic effects of A. muciniphila on NAFLD in animal models.

Notably, a clinical study of 32 humans who were overweight and obese addressed the therapeutic efficacy of A. muciniphila [18]. The results showed that pasteurized A. muciniphila treatment for 3 months reduced the levels of blood markers for liver dysfunction, including γ-glutamyltransferase (GGT) and AST [18]. They also confirmed the safety and tolerability of A. muciniphila in individuals with excess body weight at different doses of live (10¹⁰ or 10⁹ CFU per day) or pasteurized A. muciniphila (10¹⁰ CFU per day) [18]. However, the above clinical study was performed in humans with obesity, not those with NAFLD, and enrolled a small number of individuals. Thus, future clinical interventions with more cases of obesity and even NASH in humans are needed to confirm and extend these findings.

Studies also reported the beneficial effects of A. muciniphila on the complications of NAFLD. For example, Higarza et al. reported that A. muciniphila administration reversed NASH-induced cognitive dysfunction, including spatial working memory and novel object recognition, in rats [92]. Another study further explained the potential mechanisms for these effects; that is, A. muciniphila restored microgliosis, neurodevelopment, and neuronal plasticity in the hippocampus of HFD-fed mice by enhancing gut barrier function [93]. In summary, these animal experiments and related human studies provided support for the role of A. muciniphila in the treatment or prevention of NAFLD.

5 Underlying mechanisms of action of A. muciniphila in NAFLD prevention

The importance of A. muciniphila in NAFLD has been investigated in recent decades. Yet, the exact mechanisms of action and the active components of A. muciniphila remain unclear. Hepatic fat accumulation and inflammation are two essential factors of NASH. Existing evidence suggested that A. muciniphila protects against NAFLD by alleviating hepatic steatosis (Fig.2) and inflammation (Fig.3).

5.1 Functional components of Akkermansia muciniphila that play a role in hepatic steatosis

In 2020, experts reached a consensus that metabolic dysfunction-associated fatty liver disease “MAFLD” is a more appropriate overarching term than NAFLD [94]. This term highlights the wide range of metabolic dysfunction phenotypes, including insulin resistance and abnormal lipid profiles, in NAFLD. In general, NAFLD coexists with obesity, diabetes, and dyslipidaemia, all of which interact with one another. A previous study indicated that impaired insulin signaling in adipose tissue contributed to NASH by dysregulating lipolysis, resulting in the excessive delivery of fatty acids to the liver [95]. The progression of hepatic steatosis to the state of inflammation is triggered by adipocytokine imbalances and lipotoxicity [96]. Hence, preventing steatosis and its related metabolic dysfunction is an appropriate therapeutic target for NASH.

Notably, current studies strongly demonstrated the protective potential of A. muciniphila on steatosis-related insulin resistance and lipid accumulation. Several studies have suggested that the beneficial effects of A. muciniphila on insulin resistance are partly due to the remission of metabolic endotoxaemia [19,41] or adipose tissue inflammation [41,97]. In 2013, Cani et al. demonstrated that supplementation with live, not heat-killed (121 °C, 225 kPa, 15 min) A. muciniphila (2 × 10⁸ CFU) for 4 weeks could prevent HFD-induced insulin resistance and metabolic endotoxaemia by enhancing the gut barrier [19]. Later, they found that supplementation with pasteurized A. muciniphila (70 °C, 30 min) for 5 weeks had a better capacity to reduce endotoxaemia (also called LPS) and adipose tissue inflammation in HFD mice than that with live A. muciniphila [41]. They also identified an active ingredient called Amuc_1100 and demonstrated a similar efficacy of 3 μg Amuc_1100 on insulin sensitivity [41]. In 2018, Chelakkot et al. isolated the active ingredient called AmEVs and found that 2 weeks of feeding AmEVs could improve 12-week HFD-induced glucose intolerance in mice [26]. Consistently, AmEVs (10 μg) significantly decreased the expression of inflammatory markers in adipose tissue [97]. According to these studies, the improvement in insulin resistance by A. muciniphila is negatively linked with a reduction in circulating LPS, and the latter could be responsible for the enhancement of intestinal permeability. Live or pasteurized A. muciniphila, Amuc_1100, and AmEVs were reported to strengthen the intestinal barrier function in HFD-induced metabolic dysfunction in mice [19,26,41,97].

In addition to its ability to improve insulin resistance, A. muciniphila could considerably regulate lipid metabolism in animals [98–102] and humans [18]. For instance, in mice with metabolic dysfunction induced by HFD, oral administration of A. muciniphila (2 × 10⁸ CFU) downregulated the expression of genes related to fatty acid synthesis and transport in liver/muscle and further reduced fat deposition in the liver and muscle [99]. A. muciniphila also activated hepatic genes related to lipid oxidation (LPL, PCG-1α, CPT-1β, UCP2, and LXR), lipid transportation (FATP4 and FAT/CD36), and cholesterol transportation (LDLR) and increased the levels of hepatic proteins related to energy expenditure (pLKB1, pAMPK, and mitochondrial complexes I, II, IV, and V) in the liver of NAFLD mice. These alterations contribute to the improvement of fat accumulation [38]. AmEVs were as effective as A. muciniphila in improving lipid profiles [97,103]. In a prospective study of individuals who were overweight/obese, live and pasteurized A. muciniphila showed therapeutic efficacy on dyslipidaemia, but pasteurized A. muciniphila was superior to live A. muciniphila in lowering serum total cholesterol levels [18]. The latest identified P9 protein of A. muciniphila could improve glucose intolerance by promoting GLP-1 secretion by intestinal endocrine cells and reduce hepatic lipid accumulation in mice fed with HFD for 8 weeks [42]. Overall, existing evidence confirmed the protective role of A. muciniphila and its active components in steatosis-related metabolic dysfunction (Fig.2), which may, at least partly, account for the mechanism of action of A. muciniphila in NAFLD improvement.

5.2 Modulation of hepatic innate immune response in NAFLD by A. muciniphila

NASH is the inflammatory form of NAFLD, and it is characterized by hepatic inflammation and fibrosis. It is regarded as a major cause of liver cirrhosis. In addition to steatosis, hepatic inflammation in NAFLD is triggered by multiple mechanisms [96]. In fact, whether NASH is always preceded by NAFL is not certain [4], suggesting the existence of other potential mechanisms of NASH development. The gut microbiota affects immune homeostasis and metabolism in the liver, thereby affecting NAFLD progression [6,7]. Emerging evidence indicated that A. muciniphila regulates hepatic inflammation and the immune response in NAFLD via multiple potential mechanisms.

5.2.1 Signals of A. muciniphila downregulate hepatic inflammation

The signals of proinflammatory cytokines, such as IL-6 and TNF-α, are critically involved in the pathophysiology of human NAFLD. These cytokines trigger the production of other cytokines and recruit inflammatory cells in the liver [104]. Interestingly, the levels of IL-6 and TNF-α, which are negatively correlated with decreased A. muciniphila abundance in the gut, were reduced in the serum and liver of mice with sucralose-induced NAFLD [44]. Notably, some studies reported that A. muciniphila prevented the hepatic expression of the proinflammatory factor IL-6 in HFD-fed [21] or high-fat and high-cholesterol diet-fed [38] NAFLD mice. Similarly, in HFD/CCl₄-induced fibrotic mice, not only live A. muciniphila but also pasteurized A. muciniphila and its AmEVs could reduce the levels of serum IL-6 and TNF-α and downregulate hepatic TNF-α expression [23]. These findings indicated a link between A. muciniphila and hepatic proinflammatory factors (IL-6 and TNF-α, Fig.3). However, further analysis is needed to explore the original cells of the proinflammatory factors and how A. muciniphila communicates with these hepatic proinflammatory factors in the progression of NAFLD.

5.2.2 A. muciniphila and gut-derived LPS signaling in liver

LPS is a typical pathogen-associated molecular pattern (PAMP) that activates the hepatic innate immune response [40]. A high level of serum LPS, hepatocyte LPS localization, and upregulation of downstream TLR4 signaling have been observed in patients with NASH [105,106]. A study showed that A. muciniphila reduced LPS signaling (including JNK and IKBA) in the liver of chow diet-fed mice [99]. A. muciniphila was reported to reduce circulating LPS levels by enhancing gut barrier function in HFD-induced models of metabolic disorders [19]. In other models of liver injury, A. muciniphila was found to downregulate LPS levels and its related signaling pathway. For instance, A. muciniphila could suppress LPS production by regulating the gut microbiota in mice with immune-induced liver injury [25]. The inhibitory effect of live and pasteurized A. muciniphila and AmEVs on liver TLR4 expression was also observed in HFD/CCl₄-induced fibrotic mice [23]. Furthermore, a cell experiment demonstrated that live/pasteurized A. muciniphila and AmEVs could markedly inhibit the gene expression of LPS-targeted receptors (TLR4) and even fibrosis markers (a-SMA, TIMP1, Col1a1, and TGF-β) in hepatic stellate cells [23]. These findings suggested a potential mechanism by which A. muciniphila acts on liver inflammation in NAFLD by regulating the LPS signaling pathway (Fig.3). However, whether A. muciniphila specifically affects the expression of TLR4 in hepatic stellate cells or other immune cells in NAFLD remains unclear.

5.2.3 A. muciniphila and TLR2 signaling in liver

In addition to the PAMPs of the microbiota, microbial metabolites, especially BAs and tryptophan metabolites, are implicated in immune system functions [107]. Gut-derived signals could activate the hepatic innate immune response, contributing to the development of NASH [40,108]. Live and pasteurized A. muciniphila and its AmEVs were also reported to downregulate hepatic TLR2 expression in HFD/CCl₄-induced fibrotic mice [23]. TLR2 knockout suppressed the progression of NASH [109]. A. muciniphila was hypothesized to downregulate TLR2 expression and further prevent HFD-induced liver inflammation (Fig.3). Of course, these findings warrant further investigation in NAFLD models with TLR2 knockout.

5.2.4 A. muciniphila and macrophages in liver

Macrophages are one of the most important types of innate immune cells in the liver, and they have been shown to play an important role in NAFLD in human and animal models [110]. A. muciniphila or Amuc_1100 could reduce the infiltration of macrophages in the colon [33]. However, the specific mechanism by which the microbial signaling of A. muciniphila affects hepatic macrophages in NAFLD remains unclear.

Interestingly, recent studies suggested the importance of A. muciniphila in modulating the network between AhR and macrophages against NASH. The modulation of AhR in macrophage polarization was confirmed in other models of immune disorders [111–113]. Previous studies have discussed the anti-inflammatory actions of AhR in NAFLD [114–116]. For instance, Lin et al. demonstrated that liver-specific AhR knockout aggravated HFD-induced hepatic inflammation in mice [115]. The depletion of A. muciniphila abundance together with a reduction in liver AhR ligands was observed in saccharin/sucralose-induced NAFLD mice [44]. Live and pasteurized A. muciniphila and Amuc_1100 could upregulate AhR targeted genes (including CYP1A1, IL-10, and IL-22) [36], and A. muciniphila was regarded as a key contributor to tryptophan metabolism (which provides AhR ligands) [36,117]. These results indicated that A. muciniphila may protect against NASH, partly by regulating the dialog between AhR and macrophages (Fig.3). Whether and how A. muciniphila affects hepatic macrophage polarization of NAFLD warrant further research.

Notably, in other models of liver injury, the current focus on hepatic immune cells regulated by A. muciniphila is neutrophils and macrophages [22,25]. For instance, in a model of acute and chronic alcoholic hepatitis, A. muciniphila decreased neutrophil infiltration (MPO⁺) in the liver, showing its preventive and therapeutic efficacy [22]. A. muciniphila was also reported to protect against immune-mediated liver injury by reducing the accumulation of hepatic immune cells, including neutrophils (Ly6G⁺) and macrophages (F4/80⁺), in mice [25]. Despite these advanced findings, some limitations exist in current studies targeting the functional mechanism of A. muciniphila in NAFLD. First, A. muciniphila-regulated inflammatory cells were only quantified by immunohistochemical staining methods. Thus, more accurate methods, such as flow cytometry, are needed. Second, how A. muciniphila communicates with hepatic immune cells in NAFLD remains unclear. Taken together, these findings provided additional knowledge on how A. muciniphila functions in the processes of liver immunity of NAFLD, that is, it likely acts by inhibiting the microbiota-related innate immune response in the liver.

In addition, A. muciniphila exhibited protective effects against liver fibrosis, which is the advanced stage of NAFLD. Administration of live and pasteurized A. muciniphila and extracellular vesicles of A. muciniphila for 4 weeks prevented HFD/CCl₄-induced liver fibrosis [23] and hepatic stellate cell (LX-2 cell) activation [118]. These findings indicated the promise of the application of A. muciniphila for treating liver fibrosis. However, further studies are needed to confirm the effects of A. muciniphila or its derivatives on the progression of NAFLD to fibrosis and its exact functional mechanism.

6 Conclusions and perspectives on the role of A. muciniphila in NAFLD

Numerous studies mostly reported the decreased abundance of A. muciniphila in animals with NAFLD induced by HFD, MCD, and saccharin/sucralose diets (summarized in Tab.1). However, the alterations of A. muciniphila in patients with NAFLD (with histopathological diagnosis) rather than those who are overweight/obese still need further investigation. Current studies linked the increased abundance of A. muciniphila with beneficial effects in NAFLD therapy (summarized in Tab.2). Different NAFLD interventions also boost A. muciniphila abundance. Consistently, the administration of A. muciniphila directly benefits the prevention and therapy of NAFLD. Present animal experiments strongly supported the efficacy of A. muciniphila in treating hepatic steatosis and improving glucose and lipid metabolism in NAFLD. However, the efficacy of A. muciniphila in treating patients with NAFLD has not been assessed, although few clinical studies have reported its application in patients with obesity and T2DM [13,18], largely due to less evidence for the underlying mechanism by which A. muciniphila acts on hepatic manifestations (especially inflammation) in NAFLD.

In summary, much of the current knowledge on the mechanisms of A. muciniphila in NAFLD relies on research in vitro and in animal models. This study summarized the potential mechanisms in accordance with the current findings (Fig.2 and Fig.3). First, convincing evidence exists for the ability of A. muciniphila to improve hepatic lipid accumulation in the process of NAFLD. In addition to live and pasteurised A. muciniphila, the active components of A. muciniphila, such as Amuc_1100, AmEVs, and P9 protein, have demonstrated similar actions, and more components have yet to be discovered. Second, A. muciniphila protects against hepatic inflammation in NAFLD by regulating the hepatic immune response, which may be related to the production of inflammatory factors (IL-6 and TNF-α), LPS signals, and macrophages. The current focus on the regulation of A. muciniphila on the hepatic immune response of NAFLD is relatively limited.

Some concerns on the regulation of A. muciniphila on the hepatic immune response of NAFLD need to be resolved (Fig.4). First, a cause-and-effect evidence that A. muciniphila acts on immune cells/signals in NAFLD improvement remains to be gathered. A combination of germ-free mice (or antibiotic clearance) and A. muciniphila supplementation (or symbiotic microbial consortia transplantation) could help clarify the role of A. muciniphila. Second, whether and how these immune cells/signals interact with each other in the process of which A. muciniphila prevents NAFLD remain elusive. The importance or necessity of immune cells/signals needs to be confirmed by gene knockout mice. Third, the specific mechanism involved in the crosstalk between the discovered immune signals/cells and A. muciniphila remains unknown. What are the key components of A. muciniphila? Do the reported active components of A. muciniphila have similar efficacy in preventing NASH? Given the contribution of the intestinal barrier in the development of NAFLD, is the efficacy of A. muciniphila in the hepatic immune response entirely based on its gut barrier protection functions? Finally, does A. muciniphila present the same benefits for fibrosis or cancer that could progress from NAFLD? The understanding of the underlying mechanisms of action could pave the way for the application of A. muciniphila in treating patients with NAFLD and other related liver injuries. A notable detail is that most of the present studies were performed in animal NAFLD models that do not completely reflect human NAFLD. Thus, the results require further validation and investigation. In addition, clinical trials on the safety and effectiveness of A. muciniphila in treating human NAFLD are urgently needed.

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