The biofunction of Akkermansia muciniphila in intestinal-related diseases
0 Abstract
Intestinal homeostasis is essential for maintaining human health, and its dysfunction is related to the onset and progression of various diseases, including immune and metabolic disorders, and even tumorigenesis. Intestinal microbiota plays a critical role in intestinal homeostasis, with Akkermansia muciniphila (A. muciniphila) emerging as a key commensal bacterium utilizing mucin as its sole carbon and nitrogen source. A. muciniphila has been recognized in both experimental and clinical studies for its beneficial role in managing intestinal inflammation, tumors, functional gastrointestinal disorders, and secondary conditions such as liver and metabolic diseases. This review provides a comprehensive overview of the research history and current understanding of A. muciniphila, its association with various intestinal-related diseases, and the potential mechanisms behind its effects. This paper also explores the possibilities of leveraging the probiotic enzyme such as the active ingredients of A. muciniphila for the innovative clinical treatment of intestinal-related diseases.
Keywords
INTRODUCTION
The intestinal microbiota is important in maintaining many significant physiological functions of the body, e.g., assisting the host in digesting food and providing nutrients. The occurrence of a variety of diseases is accompanied by the destruction of intestinal microbiota. In recent years, many intestinal diseases have been found to be inextricably linked to intestinal microbiota disorders such as intestinal inflammation, functional gastrointestinal diseases, and intestinal tumors. The development of liver diseases and metabolic syndromes such as diabetes is also accompanied by ecological dysbiosis of the intestinal microbiota associated with the development of intestinal diseases. In light of these factors, probiotics and their derivatives show promise in addressing gut microbiota imbalances and potentially treating a wide array of diseases. Among the identified next-generation beneficial bacteria[1], Akkermansia muciniphila (A. muciniphila, Akk) has been recognized as a particularly promising candidate[2]. Akk is an anaerobic intestinal bacterium belonging to the Verrucomicrobiota, one of the commensal bacteria in the normal intestine. Akk was abundant in the mucosal layer of the host intestine, especially in the cecum. It is prevalent in the gut of healthy adults and infants, accounting for 1%-4% of the total intestinal microbiota colonized from early life[3]. Akk is closely related to the immune response, energy metabolism, microbial composition and intestinal mucin secretion. It may also play an important role in most intestinal diseases such as intestinal inflammation, intestinal tumors, functional gastrointestinal disorders, and other intestinal-related diseases such as diabetes, obesity and liver disease[4-6]. This article reviews the research history of Akk, its relationship with intestinal-related diseases, and the possible mechanisms, with the aim to help lay the theoretical foundation for further research on its specific treatment mechanisms and provide inspiration for the treatment and prevention of related diseases.
THE RESEARCH HISTORY OF A. MUCINIPHILA
Akk is an anaerobic Gram-negative bacterium that is oval in shape, immobile and does not form endospores. Akk belongs to the Verrucomicrobiota, Akkermansiaceae, and Akkermansia[7], and is the first member and the only representative of Verrucomicrobiota in the human gut[8]. The history of research on Akk is not long [Figure 1], with its first isolation and identification in 2004 from human feces via anaerobic culture by researchers from the Microbiology Laboratory of Wageningen University in the Netherlands[7]. In the first 5 years after its identification, there was only 1 report on Akk each year. Since 2010, Akk has been gaining attention with significantly increasing studies on its genomic data and relationship with human health and diseases. In 2007, a study using fluorescence in situ hybridization and real-time PCR analysis for the 16S rRNA gene of Akk showed that it can be colonized in the intestine of infants, reach a level close to the abundance in the intestine as healthy adults within 1 year, and gradually decrease in the elderly[9]. In 2010, Png et al. found that Akk abundance was substantially reduced in the intestinal epithelium of Crohn’s disease (CD) and ulcerative colitis (UC) patients[10]. Furthermore, researchers sequenced the genome of Akk ATCC BAA-835 in 2011 and found that its complete genome was composed of a 2,664,102 bp circular chromosome with an average GC content of 55.8%[11]. In the same year, studies found that Akk colonization altered mucosal gene expression in germ-free mice, increased the expression of genes involved in immune responses[12], and that the relative abundance of Akk was lower in children with autism[13]. In 2012, Hansen et al. found for the first time that the mucolytic bacterium Akk plays a protective role in the development of autoimmune diabetes, especially in the infancy of mice[5]. In 2013, Akk-derived extracellular vesicles were found to be protective in the development of dextran sulfate sodium salt (DSS)-induced colitis[14]. In 2014, studies observed that Akk affects the expression of genes involved in host lipid metabolism and epigenetic activation, reduces the risk of gastrointestinal diseases[15], and that the application of Akk alters the metabolic characteristics of nonalcoholic fatty liver disease (NAFLD) and obesity, thereby alleviating the disease. In 2015, a study using a colorectal cancer (CRC) mouse model revealed that Akk colonization significantly reduced the number of intestinal tumors, goblet cell density, and mucus layer thickness compared to the control group, suggesting that Akk treatment plays a beneficial role in suppressing intestinal tumors[16]. A 2016 study[17] first identified the outer membrane proteins of Akk, and another study found that Akk is involved in the anti-inflammatory effects of the intestinal microbiota in constipated irritable bowel syndrome (IBS)[18]. In 2017, Guo et al. used whole-genome shotgun sequencing to isolate 39 new Akk strains from human and mouse fecal samples, followed by sequencing of the total DNA of all microbes, assembly and annotation to identify 5,644 unique proteins[19]. Another study found that purified membrane protein Amuc_1100 isolated from Akk improved metabolism in diabetic and obese mice[20]. In the following five years, an increasing number of studies began to focus on the mechanisms by which Akk interacted with the host to ameliorate disease, with particular attention to intestinal-related diseases, as well as proteins and extracellular vesicles of Akk. In 2020, Wang et al. demonstrated that Akk or its purified membrane protein Amuc_1100 could inhibit the occurrence of CRC associated with colitis by regulating CD8+ T cells[21]. Furthermore, the researchers recently found a new protein of Akk named Amuc_2172, which was derived from extracellular vesicles of Akk, can serve as acetyltransferase to inhibit the development of CRC by reprogramming the tumor microenvironment, and was also effective in other tumor models, such as melanoma[4]. As Amuc_2172 is an enzyme secreted by bacteria that can improve the function of host cells and alleviate the disease process of the host, we name it a probiotic enzyme.
Figure 1. Timeline of significant research milestones in Akk. Akk was first isolated, identified, and named in 2004. In the first five years, there were few reports on it. After 2010, it gradually received more attention, and research on the relationship between Akk and human health and diseases increased significantly. Since 2017, more and more research has focused on the mechanism of interaction between Akk and the host to enhance disease management, with particular attention to the proteins and extracellular vesicles of Akk. Created with BioRender.com. Akk: Akkermansia muciniphila.
THE THERAPEUTIC POTENTIAL OF AKK IN INTESTINAL-RELATED DISEASES
Akk and intestinal inflammation
Inflammatory bowel disease (IBD) is influenced by a complex interaction between immune, genetic, environmental factors, and the intestinal microbiota. Multiple studies have shown that intestinal inflammation is associated with changes in the abundance of Akk, most of which reveal that Akk may play a beneficial role in controlling intestinal inflammation [Figure 2], as the occurrence of intestinal inflammation is often accompanied by the reduction of Akk, but some findings are not completely consistent with this. Studies on IBD patients showed that compared with healthy people, the relative abundance of Akk in the colon was significantly reduced in UC patients, as well as in CD patients[10,22-24]. Several experiments on mouse models of colitis also support a beneficial role for Akk in controlling intestinal inflammation. For example, a study in 2020 showed that the abundance of Akk was significantly reduced in DSS-induced colitis mice[21]. After treatment of DSS-induced colitis mice with secondary bile acid, the abundance of Akk in the feces was significantly increased[25]. Similar results were obtained with hyaluronic acid-bilirubin nanomedicine (HABN) treatment[26]. It was also found in an Escherichia coli infectious ileitis model that mice overexpressing tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) showed remission of inflammation, thickened intestinal mucus layer, and increased proportion of Akk compared to control mice[27]. Furthermore, in an intestinal epithelium-specific autophagy-related protein 5 (ATG5) knockout mouse model, ATG5 deficiency was found to result in a significant reduction in Akk[28]. Furthermore, extracellular vesicles of Akk (AmEV) were significantly reduced in the intestine of mice with DSS-induced colitis[14].
Figure 2. The effect of Akk on intestinal-related diseases. Administration of Akk or its components to humans or mice can alleviate intestinal inflammation, tumors, and functional gastrointestinal diseases, as well as metabolic regulation such as alleviation of obesity, insulin resistance, and liver disease. Administering Akk or its components to humans or mice has been shown to reduce intestinal inflammation, inhibit tumor growth, and alleviate functional gastrointestinal disorders. Additionally, it contributes to metabolic regulation, including the reduction of obesity, improvement of insulin sensitivity, and mitigation of liver disease. Created with BioRender.com. Akk: Akkermansia muciniphila.
In addition to these correlative studies, researchers have also attempted interventional studies with Akk or its components. The application of Akk reduced the histopathological score of colitis mice by increasing the thickness of the colonic mucus layer, which proved that Akk played a positive role in improving intestinal barrier function and reducing intestinal inflammation[29]. Furthermore, a study in 2020 showed that Amuc_1100, the purified membrane proteins of Akk, attenuated DSS-induced colitis by reducing colon-infiltrating macrophages and cytotoxic T lymphocytes (CTLs)[21]. In addition, Bian et al. in 2019 demonstrated that the application of Akk improved intestinal inflammation in DSS-induced mice. It reduced the levels of inflammatory cytokines such as TNF-α, IL-6, IL-1α, MIP-1A, IL-12A, and G-CSF, while altering the intestinal microbiota of mice[30]. In addition, in vitro treatment of colonic epithelial cells with AmEVs reduced the production of IL-6, and oral administration of AmEV to mice alleviated DSS-induced colitis phenotypes such as inflammatory cell infiltration, weight loss, and shortened colonic length[14]. Studies exploring the anti-inflammatory properties of two Akk strains against DSS-induced chronic colitis in mice also obtained similar results[29].
Akk and intestinal tumors
Many studies have shown that the risk of developing CRC is two to four times higher in patients with IBD than in normal subjects[31]. The IBD-CRC model can destabilize the diversity of the intestinal microbiota[32]. According to a recent study, intestinal microbiota may be a driver of CRC development. The study proposes a “driver-passenger” model in which the original gut bacteria act as drivers to attack the gut, causing DNA damage and thus inducing CRC. Tumorigenesis causes changes in intestinal microbiota, which creates favorable conditions for the propagation of “passenger” bacteria[29]. In this context, the application of probiotics may be a potential strategy to combat intestinal tumors [Figure 2]. In 2013, Grivennikov et al. suggested that supplementation with Akk could prevent intestinal cancer by attenuating DNA damage and inhibiting abnormal proliferation of tumor cells[33]. Another study found that vitamin D supplementation inhibited the development and progression of CRC and increased the integrity of the colonic barrier and the abundance of Akk[34], which suggested that Akk may be a potential probiotic for the treatment of CRC.
Further studies revealed that Akk abundance was significantly reduced in the feces of patients and mice with CRC[35]. In addition, Akk was found to actively promote the response to chemotherapeutic agents and immune checkpoint inhibitors in tumors[36]. In 2017, researchers conducted a trial of 249 patients treated with immune checkpoint inhibitor programmed cell death protein 1 (PD-1) antibodies[37], 69 of whom were also treated with broad-spectrum antibiotics. It was observed that in the group of patients treated with antibiotics, there was a higher probability of tumor recurrence and a shorter survival time. It was found that the presence of Akk was associated with more effective immunotherapy in patients not treated with antibiotics. To verify this correlation, the researchers transplanted feces from patients with good immunotherapeutic effects into germ-free mice and found that the immune effects were higher than those of non-transplanted mice. In mice given Akk by gavage, IL-12 levels increased and promoted the recruitment of T lymphocytes to mouse tumors, which in turn restored the efficacy of the anti-PD-1 antibody, and the tumors almost completely disappeared[37]. This study demonstrates for the first time the role of Akk in the tumor immune response. In addition, Akk was significantly increased in individuals treated with FOLFOX (oxaliplatin + fluorouracil + calcium folinate), the first-line chemotherapy regimen for colon cancer treatment in clinical practice, and Akk was positively correlated with treatment efficacy[38]. In addition, it was found that Akk can inhibit tryptophan metabolism by inhibiting the AhR/β-catenin signaling pathway, so as to inhibit the progress of CRC[39].
In recent years, the role of the components of Akk in intestinal tumors has attracted considerable attention. In an in vitro cellular assay in 2020, the Akk aspartate protease Amuc_1434 was demonstrated to inhibit the viability of human CRC LS174T cells[40]. Furthermore, oral administration of pasteurized Akk or its purified membrane protein Amuc_1100 increased the number of CTL in the colon and mesenteric lymph nodes (MLN) and inhibited azoxymethane (AOM)/DSS-induced colitis and CRC in mice[21]. Recently, extracellular vesicles from Akk were shown to inhibit the development of CRC associated with colitis. The researchers identified a new protein from AmEV, named Amuc_2172, that promotes the activity of CTL to inhibit CRC[4].
In recent years, a cancer vaccine preparation with extracellular vesicles mixed with lipid nanovesicles (Lipo@HEV) was constructed by using exosomes derived from tumor cells as antigen sources, and outer membrane vesicles from Akk (Akk-OMV) as natural adjuvants. It can enhance preventive and therapeutic vaccination by promoting the maturation of dendritic cells (DC) in lymph nodes and activating CTL reaction, and enhance the therapeutic effect of PD-1 blocking by loading PD-L1 trap plasmids[41] [Figure 3].
Figure 3. Diverse active components of Akk exert regulatory effects on intestinal-related diseases through distinct mechanisms. These findings offer insights into the potential use of these components as therapeutic agents in the clinical treatment of gastrointestinal disorders. Created with BioRender.com. Akk: Akkermansia muciniphila.
Akk and functional gastrointestinal disorders
Akk has also been reported to be associated with functional gastrointestinal disorders such as IBS. In 2012, a study discovered that the relative abundance of Akk in the feces of children with diarrhea-predominant irritable bowel syndrome was significantly reduced[42].
Another study in 2017 found that the traditional Chinese medicine Wujiwan can effectively reduce abdominal pain and diarrhea in rats with post-inflammatory irritable bowel syndrome (PI-IBS), and its effect may be related to significantly improving the abundance of Akk[43]. Furthermore, fecal microbiota transplantation (FMT) was shown to effectively relieve gastrointestinal symptoms and relieve depression and anxiety in 30 patients with refractory IBS. The analysis of the fecal microbiota showed that the abundance of Akk was significantly increased one month after FMT[44]. Another study in 2018 also obtained similar results[45] and found that the abundance of Akk is related to the extent of symptom relief of patients, and we speculate that the mechanism may lie in the decreased sensitivity of visceral pain caused by short chain fatty acid (SCFA), one of the metabolites of Akk and other probiotics[46]. Furthermore, in a clinical study, the researchers stimulated biopsied intestinal mucosa of PI-IBS and healthy people with Akk and found that the release of anti-inflammatory cytokine IL-13 in PI-IBS patients increased significantly after Akk stimulation, which was higher than that in the healthy control group, further explaining the anti-inflammatory effect of Akk in IBS[47]. In addition, a study assessing the changes of intestinal mucosa and microbiota associated with air pollution of UC and IBS patients in Ukraine found that the intestinal mucosa of patients in areas with low air pollutants particulate matter 2.5 (PM2.5) was less damaged than that in high PM2.5, and the level of Akk in feces of patients in low PM2.5 was even significantly higher than that in the healthy control group, further suggesting the protective effect of Akk in IBS[48]. In addition, several studies found that the relative abundance of Akk in the intestines of patients with constipation-predominant irritable bowel syndrome(C-IBS) increased[49], which is different from previous studies finding that the abundance of Akk decreased in patients compared with the healthy population. However, Gobert et al., using the model of human microbiota-related rats (HMAR) and experimental colitis induced by DSS, found that animals carrying C-IBS-related microbiota had milder colitis after DSS treatment[18]. Compared with the control group, in mice pretreated with Akk or HMAR, the expression of IL-17, IFN-γ, and TNF-α genes was inhibited, revealing that although the abundance of Akk in the intestines of C-IBS patients increased, its effect was still beneficial, that is, the anti-inflammatory effect of intestinal microbiota in C-IBS patients could have been mediated by Akk to some extent. In addition, another study on intestinal microbial changes in patients with enteritis and IBS shows that there is no significant difference in Akk abundance between IBS patients and the healthy population, which may be due to the limitation of sample size, because it only includes 3 IBS patients[50]. The above studies suggest the potential beneficial effects of Akk in IBS, but they are mostly association studies. There are limited studies using Akk to directly interfere with human or animal models to explore its role in IBS. Furthermore, whether Akk plays a harmful role in IBS in different models and the effects of Akk components in IBS are not fully understood, which warrants further exploration in the future.
Akk and other intestinal-related diseases
Akk and metabolic diseases
Akk has a role in the prevention and treatment of diabetes, obesity, and other metabolic dysfunctions. In diabetes, the decreased expression of intestinal tight junction proteins leads to increased intestinal permeability, resulting in excessive absorption of lipopolysaccharides (LPS) and leading to chronic inflammation[51]. A clinical trial in 2016 showed that obese subjects with a higher abundance of intestinal Akk had healthier metabolic markers such as plasma triglycerides, fasting glucose, and body fat distribution[52]. In 2018, Hänninen et al. found the mice lacking Akk presented a high prevalence of autoimmune diabetes, also known as type I diabetes (T1D). Then, they transferred Akk experimentally to the mice with T1D and found that Akk transfer promoted mucus production and increased expression of antimicrobial peptide, as well as lowering serum endotoxin levels and islet Toll-like receptor (TLR) expression, which suggested that Akk plays a protective role in T1D[53]. The underlying mechanism may be that Akk will increase the production of anti-inflammatory cytokines in pancreatic lymph nodes and enhance the recruitment of Tregs in the pancreas, which will eventually delay the development of T1D[54,55]. Akk can also promote mucus production and increase the expression of antimicrobial peptides, reduce the level of serum endotoxin and the expression of islet TLRs, promote immune regulation, and delay the development of diabetes[53].
The relative abundance of Akk is also significantly reduced during the development of type II[56] diabetes. In addition, a study found that the feces of healthy individuals contained more AmEV compared to those with type II diabetes[57]. The purified membrane protein Amuc_1100 from Akk also improved metabolic disorders in obese and diabetic mice[20]. These studies provide strong evidence that Akk regulates the progress of diabetes. Furthermore, the abundance of Akk was also reduced in high-fat diet (HFD) mice and the metabolic disorders of HFD mice could be reversed through the supplementation of Akk[57,58]. In 2013, a study found that gavage of live Akk to HFD-induced obese mice reduced the level of plasma LPS by increasing intestinal barrier function, lowered the insulin resistance index, and normalized the adipose tissue marker CD11c, whereas heat-inactivated Akk could not exert such effects[58]. Yet another study[20] in 2017 found that pasteurized Akk also significantly improved insulin sensitivity indices and that mice treated with pasteurized strains showed more significant reductions in body weight, plasma lipids, markers of insulin resistance, and blood inflammatory markers, compared with live bacteria[20]. There are many reasons that may lead to the opposite results; for example, the amounts of Akk used in the two experiments are different, and the medium used for bacterial culture is different. In addition, autoclaving Akk eliminated its beneficial effects. However, recent research[59,60] showed that pasteurizing probiotics at 70 °C for 30 min, which is a less extreme treatment method to limit the degeneration of their cell components, can partially or completely retain its beneficial effects[20]. We speculate that the less intense heat inactivation, such as pasteurization, allows Akk to become more stable while retaining some of their beneficial properties, but the dead bacteria after complete thermal inactivation do not have this function.
Furthermore, Akk significantly reduced adipose inflammation by inducing more Foxp3+ regulatory T cells in obese mice[61], Akk was significantly increased after treatment with metformin in obesity mouse model[62], and higher levels of Akk in patients contributed to the efficacy of metformin[63]. It has been demonstrated that intestinal microbes such as Akk may modulate the efficacy of metformin through the production of SCFAs[64]. In 2019, Depommier et al. conducted a pilot study on the administration of Akk in overweight and obese human volunteers and found that oral administration of Akk for 3 months was completely safe and well tolerated by all volunteers. Akk significantly enhanced insulin sensitivity in obese volunteer patients, downregulated total cholesterol levels, and even improved liver tissue lesions, and the volunteers experienced substantial weight loss[65]. Furthermore, Akk has been shown to reduce gene expression involved in adipocyte differentiation and lipid oxidation in mouse mesenteric adipose tissue, suggesting its role in the regulation of lipid metabolism[58] [Figure 2].
Akk and the “intestine-hepatic axis”
The liver is the detoxification organ of the body and is closely related to the intestine through the hepatic portal system. Thus, the occurrence of liver diseases such as hepatitis and hepatic steatosis is also associated with the intestine. The intestinal microbiota plays an important role in the interaction between the intestine and the liver. When the intestinal barrier is damaged, intestinal pathogenic bacteria and LPS translocate and enter the liver via the hepatic portal vein. Liver Kupffer cells phagocytose LPS and release cellular inflammatory factors, which damage liver function[66]. LPS further increases intestinal mucosal permeability, forming a vicious circle that may lead to the development of many liver and intestinal diseases. In this context, the application of probiotics such as Akk to improve the intestinal microenvironment may be effective in treating liver disease. A study using a streptozotocin high-fat diet (STZ-HFD) to induce mice model of liver disease showed that the relative abundance of Akk was reduced in the STZ-HFD group of mice compared to control mice[67]. In 2017, administration of Akk to experimental mice was demonstrated to reduce serum alanine transaminase and aspartate transaminase, attenuate liver damage induced by concanavalin A (Con A), and decrease both pro-inflammatory cytokines such as IL-2 and IFNγ in the serum of mice[68]. Consistent with the serological results, IFNγ expression was significantly reduced in the liver of Akk-treated mice[68]. In the same year, another study showed that rhubarb extract could prevent hepatitis caused by acute alcohol intake and increase the abundance of Akk in the intestine. Subsequent analysis revealed that the abundance of Akk was positively correlated with the expression of the antimicrobial peptide, regenerating islet-derived protein IIIγ (RegIIIγ), which restores the intestinal barrier function and prevents alcohol-induced liver injury. It is speculated that rhubarb extract may promote the expression of RegIIIγ by increasing the number of Akk[69]. In addition, it has been reported that berberine reduced acute-chronic alcoholic liver injury by altering the overall gut microbial community and promoting the abundance of Akk[70]. A study in 2018 found that Akk abundance in the feces of alcoholic hepatitis patients was lower than that of healthy individuals, and the abundance of Akk was significantly reduced by alcohol gavage in wild-type (WT) mice, while oral administration of Akk prophylactically reduced liver injury, fatty liver, and neutrophil infiltration[71]. Consistently, a clinical study showed that patients with either hepatocellular carcinoma or cirrhosis showed a decrease in Akk abundance, along with an increase in intestinal permeability and plasma LPS levels, suggesting that the hepatoprotective function of Akk may be achieved by reducing intestinal-derived inflammation[72]. Recently, it has been found that Akk can alleviate the hepatotoxicity induced by sodium valproate[73], and oral application of Akk can alleviate the liver injury induced by alcohol, increase the serum ornithine level, and reduce the oxalic acid level increased by alcohol intake[74]. In addition, the imbalance of intestinal microbiota and the decrease of SCFA production in nonalcoholic steatohepatitis (NASH) animals may further act through the hepato-intestinal brain axis. It may lead to the exhaustion of dopamine in the frontal cortex, increasing protein oxidation and lipid peroxidation in the frontal cortex, which may eventually lead to mental illness. Akk has also been reported to reduce microglia proliferation and inflammation and improve cognitive impairment induced by NASH, including spatial working memory and new object recognition[75]. The deletion of NOD-like receptor family pyrin domain containing 6 (NLRP6) can enhance the progress of hepatitis, which may be related to the increase of Muribaculum and the decrease of Akk abundance, while Akk supplementation can improve intestinal barrier function, reduce the infiltration of myeloid-derived suppressor cells (MDSC), and inhibit steatohepatitis activity[76]. In addition, some studies have reported the correlation between Amuc_1100 and liver disease in mouse model. Amuc_1100 significantly reduces serum ALT and AST levels and the body weight of NAFLD mice, and ameliorates the blood lipid level. In the liver, Akk and Amuc_1100 significantly reduced the mRNA expression levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and TLR4/nuclear factor κB (NF-κB), as well as the protein and mRNA expression levels of inflammatory cytokines[77]. The above evidence suggests that supplementation with Akk may be a new effective approach for the prevention and treatment of liver injury [Figure 2].
THE POTENTIAL MECHANISM OF AKK AND ITS EFFECTIVE COMPONENTS IN REGULATING INTESTINAL-RELATED DISEASES
In recent years, an increasing number of studies have focused on the potential mechanisms of the regulatory role of Akk and the postbiotics from Akk, such as pasteurized cells and the effective components or metabolites, aiming to provide probiotics in a more appropriate manner to promote the host health. The main potential mechanisms and their effective components are discussed herein [Table 1 and Figure 3].
The mechanism of Akk and its effective components in intestinal-related diseases
| Bacterial components | Experimental model | Strain of A. muciniphila | Target | Mechanism | Ref. |
| Living A. muciniphila | DSS (mice) | 139 | Gut microbiota | Facilitate the normalization of the gut microbiota | [29] |
| DSS (mice) | ATCC BAA835 | Immunity | Promote the differentiation of Tregs and increase production of SCFAs | [29] | |
| DSS (mice) | ATTC BAA835 | Gut barrier function and microbiota | Protect the gut barrier function, reduce the levels of inflammatory cytokines, and improve the microbial community | [30] | |
| Salmonella pullorum (chicken) | ATTC BAA835 | Gut barrier function and microbiota | Downregulate the abundance of S. pullorum and accelerate the proliferation of intestinal epithelium through the Wnt/β-catenin signaling pathway | [78] | |
| DSS (mice) treated with L. pentosus | Unclear | Gut microbiota | Collaborate to produce metabolites beneficial to regulating intestinal immunity | [79] | |
| NOD (mice) | CIP 107961T | Gut microbiota and immunity | Induce gut microbiota remodeling, promote mucus and RegIIIγ production, and decrease the levels of serum endotoxin and islet TLR expression | [53] | |
| HFD (mice) treated with quercetin | CIP-107961T | Gut microbiota and bile acid | Enhance the abundance of Cyanobacterium and Oscillospira and BA synthesis | [80] | |
| APAP-mediated hepatotoxicity (mice) | ATTC BAA835 | Gut microbiota and immunity | Attenuate APAP-induced oxidative stress and the inflammatory response and remodel the gut microbiota | [81] | |
| Chronic intestinal inflammation induced by CMC and P80 (mice) | ATTC BAA835 | Gut microbiota | Prevent the destruction of CMC and P80 on intestinal microbiota and change of the colon gene expression | [82] | |
| HFD (mice) treated with metformin | CIP 107961T | Immunity | Enhance glucose tolerance and reduce inflammation of adipose tissue by inducing Tregs in visceral adipose tissue | [61] | |
| HFD (mice) treated with D3 | ATCC BAA-835 | Gut microbiota | Inhibit lipid absorption by downregulating the expression of CD36 and modulating the gut microbiota | [83] | |
| Pasteurized A. muciniphila | HFD (mice) | ATTC BAA-835 | Gut barrier function | Increase lysozyme Lyz1 expression to enhance intestinal barrier function | [20] |
| DSS (mice) | ATCC BAA-835 | Immunity | Reduce the infiltration of pro-inflammatory macrophages and CTL in the spleen and intestinal lymph nodes of mice with colitis | [21] | |
| AOM/DSS (mice) | ATCC BAA-835 | Immunity | Increase the number of CTL in MLN and inhibit the expression of PD-1 on pro-inflammatory macrophages of MLN and spleen, and reduce the proportion of PD-1+CTL | [21] | |
| HFD/CCl4 (mice) | ATCC BAA-835 | Gut barrier function and immunity | Decrease the expression of TLR-2, TLR-4 and TNF-α genes, and enhance the expression of tight junction protein | [6] | |
| AmEVs | DSS (mice) | ATCC BAA-835 | Immunity | Reduce the production of pro-inflammatory cytokine IL-6 in colon epithelial cells induced by Escherichia coli EV | [14] |
| HFD (mice) | ATCC BAA-835 | Immunity | Reduce the expression of TLR-4 and TLR-2 in colon | [84] | |
| HFD (mice) | ATCC BAA-835 | Gut barrier function | Enhance intercellular tight junctions by upregulating the expression of occludin, ZO, and claudin-5 | [84] | |
| HFD (mice) | ATCC BAA-835 | Gut barrier function | Improve intestinal barrier integrity by inducing AMPK phosphorylation | [57] | |
| Amuc_1434 | Colon cancer cell line LS174T | ATCC BAA-835 | Cell proliferation | Upregulate the expression of p53 and result in the arrest of CRC cells in the G0/G1 phase of the cell cycle | [40] |
| Colon cancer cell line LS174T | ATCC BAA-835 | Cell adhesion | Bind with normal colon cells and degrade Muc2 secreted by colon cancer cells, as well as promoting the mutual adhesion of colon cancer cells with high Muc2 expression | [85] | |
| Amuc_1100 | HFD (mice) | ATCC BAA-835 | Gut barrier function | Interact with TLR2 on the cell surface to improve the intestinal barrier function | [20] |
| PBMC | ATTC BAA-835 | Immunity | Bind TLR2 or TLR4 on PBMCs and activate the NF-κB signaling pathway to produce high levels of IL-10 | [86] | |
| DSS (mice) | ATCC BAA-835 | Immunity | Reduce the infiltration of pro-inflammatory macrophages and CTL in the spleen and intestinal lymph nodes of mice with colitis | [21] | |
| AOM/DSS (mice) | ATCC BAA-835 | Immunity | Increase the number of CTL in MLN and inhibit the expression of PD-1 on pro-inflammatory macrophages of MLN and splenic, and reduce the proportion of PD-1+CTL | [21] | |
| DSS (mice) | Unclear | Trp metabolism | Increase the expression of AhR-targeted genes such as IL-10 and CYP1A1 | [87] | |
| Caco-2 cells | ATCC BAA-835 | 5-HT | Promote the expression of 5-HT synthesis rate-limiting enzyme Tph1 in RIN-14B cells and reduce the expression of SERT in Caco-2 cells through the direct interaction with TLR2 | [88] | |
| Amuc_2172 | AOM/DSS (mice) | ATCC BAA-835 | Immunity | Acetylate the Lys14 site on histone H3 of the HSP70 gene to promote HSP70 secretion and activate CTLs | [4] |
| CT26 bearing (mice) | |||||
| Apcmin/+ (mice) | |||||
| Amuc_2109 | DSS (mice) | Unclear | Gut microbiota and immunity | Reshape the intestinal microbiota and inhibit the expression of the pro-inflammatory factors and NLRP3 | [89] |
| P9 | HFD (mice) | ATCC-BAA-835 | Immunity | Stimulate the expression of IL-6 and promote the secretion of GLP-1 through ICAM2 | [90] |
The effect of living Akk
The development of intestinal diseases is often accompanied by dysbiosis and disturbance of the intestinal microbiota[91]. Studies have shown that intestinal probiotics tend to alleviate intestinal diseases by regulating intestinal homeostasis, inhibiting the growth of harmful bacteria, and promoting the reproduction of beneficial bacteria. Akk gavage has been found to increase the production of the metabolite SCFAs such as acetate and propionate, restore the damaged intestinal microbiota, and alleviate colonic inflammation in mice[29,30]. In addition, Akk inhibits the growth of Salmonella pullorum, thereby reducing colonic mucosal damage[92]. Moreover, Akk was able to interact with other intestinal bacteria to regulate intestinal immune function and alleviate colonic inflammation. In DSS-induced colitis mice, gavage of Lactobacillus pentosus significantly increased the abundance of Akk and made Akk the dominant bacterium in the colon, which reduced colonic inflammation[79]. In another study, the administration of Akk to DSS-induced colitis mice increased the abundance of Clostridia, Firmicutes, Ruminococcaceae, and Akkermansia, and inhibited Bacteroidetes, further demonstrating that Akk reshapes the gut microbial community[30]. Additional studies have observed that Akk induces gut microbiota remodeling and controls islet autoimmunity in non-obese diabetic mice, potentially reducing the incidence of diabetes[53]. Akk promoted mucus production and the expression of the antimicrobial peptide RegIIIγ, decreased the abundance of Ruminococcus and the levels of serum endotoxin, as well as islet TLR expression, thus inhibiting the development of diabetes. It was also found that the combination of Akk and quercetin could drive protective effects against obesity and NAFLD through modulation of the gut microbiota[80]. In addition, recent studies have discovered the potential mechanism of Akk regulating intestinal microbial composition. Firstly, Akk can support the growth of butyrate producers by degrading mucin and producing acetate and propionate[93,94]. Secondly, Akk can use the vitamin B12 produced by other bacteria to produce propionate[95]. Furthermore, another study has shown that Akk can produce sulfatase, thus producing cysteine by hydrogen sulfide, which may alleviate the toxicity caused by sulfate-reducing bacteria in the host[96]. Taken together, the regulation of intestinal microbiota homeostasis is also an important part of the role of Akk per se.
In addition to directly inhibiting or promoting other bacteria, Akk also plays a beneficial role in intestinal-related diseases by inhibiting the toxicity of harmful substances or promoting the effect of beneficial substances[82,83,97]. Increasing evidence showed that some unabsorbed food additives, including the emulsifier carboxymethyl cellulose (CMC) and polysorbate 80 (P80), can cause the destruction of the microbial community, such as the depletion of Akk and the following chronic intestinal inflammation. Supplementing exogenous Akk to mice can prevent the harmful effects of emulsifiers, such as hyper appetite, weight gain, and blood glucose abnormalities. The administration of Akk also alleviated the slight intestinal inflammation induced by CMC and P80[82]. Additionally, Akk supplementation can protect the intestinal microbiota from the damaging effects of CMC and P80[82]. It is noteworthy that the study discovered that CMC and P80 changed inflammation-related gene expression in the colon, which was prevented by Akk. Moreover, it has been reported recently[97] that the colonization of Akk. in the intestine can increase the expression of intestinal cAMP reactive element-binding protein H (CREBH), thus promoting the production of intestinal barrier tight junction protein. In addition, Akk. promotes the binding of CREBH to microRNA-143/145 (miR-143/145), thus promoting intestinal epithelial cell (IEC) regeneration and wound repair through insulin-like growth factor (IGF) and IGF-BP 5 signal transduction[97]. The Amuc_1100 secreted by Akk can also cover this function of Akk cells in IECs[97]. Another study designed a peptide of 9 amino acids named D3, which is a novel drug candidate for inhibiting diet-induced obesity as a non-toxic and bioactive peptide. It was found that after administration of D3, the abundance of intestinal Akk in mice increased by 100 times, which inhibited lipid absorption by downregulating the expression of CD36, thus reducing diet-induced obesity[83].
The effect of AmEVs
The extracellular vesicles derived from probiotics are also beneficial in intestinal-related diseases[84,98], and AmEVs showed a similar effect as Akk in colitis mouse model induced by DSS[57]. AmEVs significantly decreased in the feces of obese patients and DSS-induced colitis mice. The application of AmEVs reduced the weight gain and fat content induced by HFD, and lowered the production of IL-6 in colon epithelial cells. Moreover, oral gavage of AmEVs reduced DSS-induced colitis by alleviating weight loss, colon length reduction, and inflammatory cell infiltration. The underlying mechanism is that the administration of AmEVs significantly reduced the expression of TLR4 and activated TLR2 in the colon of obese mice[84]. On the other hand, AmEVs have been found to enhance intercellular tight junctions by upregulating the expression of occludin, ZO, and claudin-5. In liver diseases, AmEVs prevented chemical-induced liver injury in mice via normalizing fecal bacterial composition, reducing intestinal permeability, and inhibiting inflammatory reactions[6]. Chelakkot et al. found that the administration of AmEVs reduced weight gain and improved glucose tolerance in HFD-induced diabetic mice[57] and illustrated the underscoring mechanism that AmEVs improved intestinal barrier integrity in HFD-induced diabetic mice by inducing adenylate-activated protein kinase (AMPK) phosphorylation, which increased the expression of tight junction proteins in IECs. However, it is noteworthy that the administration of AmEVs reduced the daily food intake of HFD mice, which may be another important factor in improving metabolism besides its own direct effect. In addition, the dose of AmEVs in the experiment is not clear. Despite the aforementioned beneficial effects of AmEVs in intestinal related disease, the components in AmEVs remain unclear and whether these substances mediate the function of AmEVs in intestinal related disease requires further study.
The effect of Amuc_1434
Recent studies have focused on the mechanism of specific components from Akk, such as various proteins, in intestinal-related diseases. It was found that Akk can directly promote apoptosis of tumor cells, and this effect was associated with Amuc_1434, a protein from AmEV. Amuc_1434 binds with normal colon cells and degrades Muc2 secreted by colon cancer cells. Amuc_1434 also promotes the mutual adhesion of colon cancer cells with high Muc2 expression[99]. Subsequently, Amuc_1434 was shown to upregulate the expression of p53, an oncogene that controls cell cycle initiation, which resulted in the arrest of CRC cells in the G0/G1 phase of the cell cycle and inhibited the proliferation of colon cancer cells. Furthermore, Amuc_1434 also induced apoptosis in CRC tumor cells by activating the mitochondrial apoptosis pathway associated with TNF-related apoptosis-inducing ligand[40].
The effect of Amuc_1100
Another protein from Akk is Amuc_1100, which was widely studied and purified from the outer membrane of Akk. Amuc_1100 was isolated and identified for the first time in 2017, and it was demonstrated to improve the metabolism of obese and diabetic mice[20]. The study investigated the potential mechanism of the protective role of Amuc_1100, and confirmed that Amuc_1100[20] was associated with the formation of Akk pili and was capable of interacting directly with TLR2. Activated TLR2 increased the expression of tight junction protein between IECs, and enhanced the anti-apoptosis ability of IECs mediated by phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway through myeloid differentiation factor 88 (MyD88). Furthermore, it was also found that Amuc_1100 and LPS from Akk all bound TLR2 or TLR4 on peripheral blood mononuclear cells (PBMCs) and activated the NF-κB signaling pathway to produce high levels of IL-10, thereby regulating the host immune response[86]. In addition, another study in 2020 further investigated the mechanism of Amuc_1100 in intestinal-related diseases, which found that pasteurized Akk or Amuc_1100 can reduce the infiltration of pro-inflammatory macrophages and CTL in the spleen and MLN of mice with colitis, reduce histological damage in the proximal colon, and alleviate colitis[21]. In addition, it was found that pasteurized Akk or Amuc_1100 attenuated DNA damage, reduced apoptosis, and abnormal proliferation in colonic epithelial cells of colitis-associated CRC mice induced by AOM/DSS. Moreover, Akk or Amuc_1100 significantly increased the number of CTL in MLN and inhibited the expression of PD-1 on pro-inflammatory macrophages and CTL of MLN and spleen[21], which effectively increased the immune effect of the host against CRC. Furthermore, a study in 2021 found that Amuc_1100 can increase the expression of aryl hydrocarbon receptor (AhR)-targeted genes such as IL-10 and CYP1A1 to alleviate colonic inflammation by regulating tryptophan metabolism and activating AhR signaling[100], and this is a novel mechanism by which Amuc_1100 relieved intestinal inflammation. Another study in 2021 found that Amuc_1100 can promote the expression of 5-hydroxytryptamine (5-HT) synthesis rate-limiting enzyme Tph1 and reduce the expression of 5-HT reuptake transporter (SERT) in Caco-2 cells through the direct interaction with TLR2, thus improving the biosynthesis and level of 5-HT. As 5-HT is a neurotransmitter and an important signal molecule for regulating gastrointestinal function, Amuc_1100 can improve the gastrointestinal peristalsis function of mice by regulating the biosynthesis of 5-HT[101]. Although there is no research about the role of Amuc_1100 in IBS, we still infer from this research that Amuc_1100 may have the potential to improve IBS, and this effect may be related to 5-HT.
The effect of Amuc_2172
Amuc_2172 is a newly discovered protein derived from Akk, which is a probiotic enzyme secreted by bacteria that can improve the function of host cells and has been shown to modulate the tumor immune microenvironment and thus inhibit a variety of CRC models and other tumor models such as melanoma. The researchers used proteases to identify Amuc_2172 as a protein from AmEVs. The mechanism of its tumorigenesis inhibition is that Amuc_2172, as a prokaryotic-derived acetyltransferase, can enter colorectal cells via macropinocytosis and acetylate the Lys14 site on histone H3 of the HSP70 gene, thus promoting HSP70 secretion, activating CTLs, and promoting IFN-γ expression to play a role of tumor-killing[4]. The application of macrophage membrane-coated Amuc_2172 nanoparticles can promote the targeted delivery of Amuc_2172 to tumor cells, thus enhancing its antitumor effect. Importantly, it was found that Amuc_1100 protein was not detected in AmEVs and that Amuc_2172 had more potential to activate CTL compared to Amuc_1100. In addition, the results show that the mechanism of activating CTL by Amuc_1100 and Amuc_2172 may be different, because CTL can be activated by Amuc_1100 directly, while the activation of CTL by Amuc_2172 requires the involvement of cancer cells. Specifically, Amuc_2172 promotes the secretion of HSP70 from cancer cells, which in turn indirectly promotes the activation of CTL. However, whether Amuc_2172 can inhibit the development of intestinal-associated metabolic diseases as Amuc_1100 has not been reported and the mechanism of Amuc_2172 in intestinal-related diseases still needs further exploration. Altogether, as a probiotic enzyme, Amuc_2172 could regulate the function of eukaryotic cells and serve as a potential drug by catalyzing eukaryotic protein targets.
The effect of other components
In addition to the above components, other active ingredients of Akk are also important in intestinal-related diseases. Pasteurized Akk can alleviate the progress of intestinal-related diseases by enhancing intestinal barrier function and regulating intestinal immunity, as mentioned above[21]. The metabolite of Akk, SCFA, can act on G-protein-coupled receptor 43 (GPR43). Compared with WT enteritis mice, Gpr43-/- enteritis mice showed higher expression of IL-6 and IL-22 and more tissue damage. After SCFA supplementation, it binds to GPR43 on neutrophils and subsequently induces their apoptosis, which alleviates the progression of enteritis in WT mice[102], whereas no remission was seen in Gpr43-/- mice. SCFA can also affect glucose metabolism to improve type II diabetes, and it regulates intestinal microbial composition and metabolism to inhibit liver injury[81,103]. Moreover, a recent study found that another probiotic enzyme Amuc_2109, a metabolic enzyme (β- N-acetyl hexosaminidase) secreted by Akk, had a significant protective effect against DSS-induced colitis mainly by improvement of the intestinal epithelial barrier function and regulation of intestinal microbiota homeostasis[89], as Amuc_2109 reshaped intestinal microbiota and inhibited the overexpression of TNF-α, IL-6, and NLRP3 in DSS-induced colitis, as well promoting the expression of tight junction protein. However, Amuc_2109 was not detected in Akk grown on mucin[104]; its role in intestinal-related diseases needs to be further explored. Furthermore, a recent study identified a new protein secreted by Akk, named protein 9 (P9), which stimulates human intestinal endocrine L cells to secrete glucagon-like peptide-1 (GLP-1) in vitro and causes a modest increase in circulating GLP1 levels of obese mice, thereby reducing insulin resistance and improving glucose metabolism. The process may be associated with the activation of intercellular adhesion molecule 2 (ICAM2), as the ICAM2 antibody partially abrogated the effect of P9 on GLP1 in vitro[90]. Moreover, the expression of ICAM2 may require the involvement of IL-6. The study illustrates the new mechanism by which Akk-derived proteins act on intestinal endocrine cells to affect the occurrence and development of metabolic diseases. However, the signal pathways through which P9 protein interacts with ICAM-2, and the downstream signal transduction through which ICAM-2 induces GLP-1 secretion are unclear, and the specific molecular mechanism still needs to be explored by more experiments. In addition, ornithine lipid, a lipid component produced by Akk in the intestines of mice and humans, was also reported to have anti-inflammatory effect, which can prevent LPS-induced inflammatory reaction, inhibit the production of pro-inflammatory cytokines, and increase the level of anti-inflammatory cytokine IL-10[105].
PATHOGENESIS OF AKK IN INTESTINAL-RELATED DISEASES
The above research shows the beneficial effect of Akk in intestinal-related diseases. On the other hand, some studies have also found that the application of Akk aggravated intestinal inflammation in mice. A study in mice with secondary metastatic colitis (AdTr-colitis) also found that the abundance of Akk was positively correlated with the degree of colonic inflammation and histopathological score[106]. In 2013, the results of a study showed that commensal Akk exacerbated intestinal inflammation in Salmonella typhimurium-infected germ-free mice[107], and then in 2017, Seregin et al. reported that repeated gavage of Akk could induce increased severity of colitis in IL10-/- mice[108]. There are many possible reasons for the controversial role of Akk in intestinal inflammation. These include the use of various mouse models in different experiments - some are DSS-induced mouse models and some are knockout mouse models - and the different amounts of Akk administrated. In addition, there are differences in the specificity of the strains used: different strains of the same species may have opposite effects in the same disease. Most current studies on Akk are limited to the model strain isolated in 2004, ATCC BAA-835T. However, another newly isolated strain of Akk in 2017 has been shown to exacerbate colitis in IL-10-/- mice. In addition, a study in 2019 reported differences in anti-inflammatory function between Akk BAA-835T and mouse-derived Akk strain 139. Therefore, the strain specificity of Akk may also be the main reason for the different results of different experiments. The pro-inflammatory effect of lipid components of Akk has recently been discovered. As membrane phospholipids from Akk can induce BMDCs to produce pro-inflammatory cytokines such as TNF-α in a TLR2-dependent manner[109]. Furthermore, similar to intestinal inflammation, the role of Akk in CRC is controversial. A recent study in 2022 found that receiving Akk administration exacerbated the development of colitis-associated CRC in AOM/DSS-induced model mice, as evidenced by shorter colon length, more severe weight loss, and more intestinal tumors[110]. There are multiple possible reasons to explain the differences in the results of different experiments. First, the viability of Akk, the frequency of administration, and the number of bacteria, all affect Akk colonization and CRC development. Furthermore, the role of Akk may be different in different CRC models. The classical AOM/DSS-induced CRC model was chosen in this study in 2022, which may be different from the spontaneous CRC models such as APCmin/+ mice in other studies. More studies are required in the future to explore and confirm the role of Akk in intestinal tumors and intestinal inflammation. In addition, future studies on Akk should pay detailed attention to the strains and evaluation of the probiotic effect of each type of Akk strain. So far, there is still a lack of relevant research on whether Akk has adverse effects on intestinal functional diseases and metabolic diseases. In this context, the probiotic role of Akk in intestinal-related diseases and its specific mechanisms need to be explored further in the future.
CONCLUSION AND PERSPECTIVE
In summary, as a paradigm in the new generation of probiotics, the colonization of Akk in the intestine is closely related to maintaining intestinal homeostasis. It plays a critical role in the progression and treatment design of intestinal inflammation, cancer, and other diseases caused by intestinal disorders, such as liver diseases and diabetes. While the majority of research indicates the beneficial effects of Akk treatment, some studies suggest it may exacerbate disease progression. This discrepancy could be attributed to variations across studies, such as differing disease models, the distinct intestinal environments in which Akk operates, the activity levels of various Akk strains, or the specific components of Akk used. It is worth mentioning that the extracellular vesicles and proteins of Akk are increasingly well studied, and studies have shown that these components may be more protective when used alone than active organisms, which is more suitable for clinical applications. In addition, pasteurized intact Akk cells are considered safe for human consumption and thus are suitable for clinical application. They have been shown to be as effective or even more effective than living cells in the treatment of metabolic disorders. Therefore, it is of interest to continue exploring the pasteurized cells, extracellular vesicles, and bacterial outer membrane fractions of Akk to extract and utilize the fractions that play an important role. Furthermore, studies on the brain-gut axis and lung-gut axis have been emerging in recent years, and in addition to metabolic and liver diseases, the association between intestinal homeostasis and other systemic diseases is gaining more attention, and future studies may explore the role of Akk in other diseases in the future. In conclusion, as a potential probiotic, Akk is stably colonized in the intestine, and there is substantial evidence of its positive effects on intestinal-related diseases. Further evaluation of Akk’s safety, or the development of its active ingredient for targeted drug delivery, could pave the way for its clinical application as a therapeutic agent. Additionally, probiotic enzymes could be defined as prokaryotic isoenzymes from intestinal bacteria, which catalyze eukaryotic targets from host cells and function as potential drugs. As probiotic enzymes from Akk, both Amuc_2172 and Amuc_2109 could be potential drugs for colitis and inspire novel strategies in the treatment of intestinal-related diseases.
DECLARATIONS
Authors’ contributions
Performed the literature search and drafted the manuscript: Jiang P, Ji S
Contributed intellectually and provided critical comments on the manuscript: Zhang M, Su D, Jiang P, Goncalves VBE, Ji S
Supervised the drafting and revised the manuscript: Zhang M, Zhao Y, Xu G
All authors read and approved the final version of the manuscript for publication.
Availability of data and materials
All data relevant to the review are included in the article.
Financial support and sponsorship
This work was supported by grants from the Natural Science Foundation of China (No. 82322010, 82273272, 81970487) and the Shanghai Pujiang Program (No. 21PJ1409500).
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. Cani PD, Depommier C, Derrien M, Everard A, de Vos WM. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol 2022;19:625-37.
2. Cani PD, de Vos WM. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front Microbiol 2017;8:1765.
3. Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM. The mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol 2008;74:1646-8.
4. Jiang Y, Xu Y, Zheng C, et al. Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment. Gut 2023;72:1308-18.
5. Hansen CHF, Krych L, Nielsen DS, et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 2012;55:2285-94.
6. Keshavarz Azizi Raftar S, Ashrafian F, Yadegar A, et al. The protective effects of live and pasteurized Akkermansia muciniphila and its extracellular vesicles against HFD/CCl4-induced liver injury. Microbiol Spectr 2021;9:e0048421.
7. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 2004;54:1469-76.
8. Dubourg G, Cornu F, Edouard S, Battaini A, Tsimaratos M, Raoult D. First isolation of Akkermansia muciniphila in a blood-culture sample. Clin Microbiol Infect 2017;23:682-3.
9. Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol 2007;73:7767-70.
10. Png CW, Lindén SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420-8.
11. van Passel MW, Kant R, Zoetendal EG, et al. The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes. PLoS One 2011;6:e16876.
12. Derrien M, Van Baarlen P, Hooiveld G, Norin E, Müller M, de Vos WM. Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader Akkermansia muciniphila. Front Microbiol 2011;2:166.
13. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol 2011;77:6718-21.
14. Kang CS, Ban M, Choi EJ, et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One 2013;8:e76520.
15. Lukovac S, Belzer C, Pellis L, et al. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. mBio 2014;5:e01438-14.
16. Dingemanse C, Belzer C, van Hijum SAFT, et al. Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice. Carcinogenesis 2015;36:1388-96.
17. Ottman N, Huuskonen L, Reunanen J, et al. Characterization of outer membrane proteome of Akkermansia muciniphila reveals sets of novel proteins exposed to the human intestine. Front Microbiol 2016;7:1157.
18. Gobert AP, Sagrestani G, Delmas E, et al. The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties. Sci Rep 2016;6:39399.
19. Guo X, Li S, Zhang J, et al. Genome sequencing of 39 Akkermansia muciniphila isolates reveals its population structure, genomic and functional diverisity, and global distribution in mammalian gut microbiotas. BMC Genomics 2017;18:800.
20. Plovier H, Everard A, Druart C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 2017;23:107-13.
21. Wang L, Tang L, Feng Y, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice. Gut 2020;69:1988-97.
22. Bajer L, Kverka M, Kostovcik M, et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroenterol 2017;23:4548-58.
23. Kump P, Wurm P, Gröchenig HP, et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Aliment Pharmacol Ther 2018;47:67-77.
24. Earley H, Lennon G, Balfe Á, Coffey JC, Winter DC, O’Connell PR. The abundance of Akkermansia muciniphila and its relationship with sulphated colonic mucins in health and ulcerative colitis. Sci Rep 2019;9:15683.
25. Van den Bossche L, Hindryckx P, Devisscher L, et al. Ursodeoxycholic acid and its taurine- or glycine-conjugated species reduce colitogenic dysbiosis and equally suppress experimental colitis in mice. Appl Environ Microbiol 2017;83:e02766-16.
26. Lee Y, Sugihara K, Gillilland MG 3rd, Jon S, Kamada N, Moon JJ. Hyaluronic acid-bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis. Nat Mater 2020;19:118-26.
27. Alvarado DM, Chen B, Iticovici M, et al. Epithelial indoleamine 2,3-dioxygenase 1 modulates aryl hydrocarbon receptor and notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota. Gastroenterology 2019;157:1093-108.e11.
28. Yang L, Liu C, Zhao W, et al. Impaired autophagy in intestinal epithelial cells alters gut microbiota and host immune responses. Appl Environ Microbiol 2018;84:e00880-18.
29. Zhai R, Xue X, Zhang L, Yang X, Zhao L, Zhang C. Strain-specific anti-inflammatory properties of two Akkermansia muciniphila strains on chronic colitis in mice. Front Cell Infect Microbiol 2019;9:239.
30. Bian X, Wu W, Yang L, et al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol 2019;10:2259.
31. Johnson CM, Wei C, Ensor JE, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control 2013;24:1207-22.
32. Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut 2016;65:330-9.
33. Grivennikov SI. Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol 2013;35:229-44.
34. Zhou X, Chen C, Zhong YN, et al. Effect and mechanism of vitamin D on the development of colorectal cancer based on intestinal flora disorder. J Gastroenterol Hepatol 2020;35:1023-31.
35. Fan L, Xu C, Ge Q, et al. A. Muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-mediated M1-like TAMs. Cancer Immunol Res 2021;9:1111-24.
36. Niederreiter L, Adolph TE, Tilg H. Food, microbiome and colorectal cancer. Dig Liver Dis 2018;50:647-52.
37. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-7.
38. Hou X, Zhang P, Du H, et al. Akkermansia Muciniphila potentiates the antitumor efficacy of FOLFOX in colon cancer. Front Pharmacol 2021;12:725583.
39. Zhang L, Ji Q, Chen Q, et al. Akkermansia muciniphila inhibits tryptophan metabolism via the AhR/β-catenin signaling pathway to counter the progression of colorectal cancer. Int J Biol Sci 2023;19:4393-410.
40. Meng X, Zhang J, Wu H, Yu D, Fang X. Akkermansia muciniphila aspartic protease Amuc_1434* inhibits human colorectal cancer LS174T cell viability via TRAIL-mediated apoptosis pathway. Int J Mol Sci 2020;21:3385.
41. Tong Q, Li K, Huang F, et al. Extracellular vesicles hybrid plasmid-loaded lipid nanovesicles for synergistic cancer immunotherapy. Mater Today Bio 2023;23:100845.
42. Rigsbee L, Agans R, Shankar V, et al. Quantitative profiling of gut microbiota of children with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2012;107:1740-51.
43. Chen Y, Xiao S, Gong Z, et al. Wuji Wan Formula ameliorates diarrhea and disordered colonic motility in post-inflammation irritable bowel syndrome rats by modulating the gut microbiota. Front Microbiol 2017;8:2307.
44. Huang HL, Chen HT, Luo QL, et al. Relief of irritable bowel syndrome by fecal microbiota transplantation is associated with changes in diversity and composition of the gut microbiota. J Dig Dis 2019;20:401-8.
45. Cruz-Aguliar RM, Wantia N, Clavel T, et al. An open-labeled study on fecal microbiota transfer in irritable bowel syndrome patients reveals improvement in abdominal pain associated with the relative abundance of Akkermansia Muciniphila. Digestion 2019;100:127-38.
46. Liu MJ, Yang JY, Yan ZH, et al. Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases. Clin Nutr 2022;41:2333-44.
47. Sundin J, Rangel I, Repsilber D, Brummer RJ. Cytokine response after stimulation with key commensal bacteria differ in post-infectious irritable bowel syndrome (PI-IBS) patients compared to healthy controls. PLoS One 2015;10:e0134836.
48. Dorofeyev A, Dorofeyeva A, Borysov A, Tolstanova G, Borisova T. Gastrointestinal health: changes of intestinal mucosa and microbiota in patients with ulcerative colitis and irritable bowel syndrome from PM2.5-polluted regions of Ukraine. Environ Sci Pollut Res Int 2023;30:7312-24.
49. Lo Presti A, Del Chierico F, Altomare A, et al. Exploring the genetic diversity of the 16S rRNA gene of Akkermansia muciniphila in IBD and IBS. Future Microbiol 2019;14:1497-509.
50. Lopez-Siles M, Enrich-Capó N, Aldeguer X, et al. Alterations in the abundance and co-occurrence of Akkermansia muciniphila and Faecalibacterium prausnitzii in the colonic mucosa of inflammatory bowel disease subjects. Front Cell Infect Microbiol 2018;8:281.
51. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091-103.
52. Dao MC, Everard A, Aron-Wisnewsky J, et al; MICRO-Obes Consortium. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 2016;65:426-36.
53. Hänninen A, Toivonen R, Pöysti S, et al. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut 2018;67:1445-53.
54. Kihl P, Krych L, Deng L, et al. Oral LPS dosing induces local immunological changes in the pancreatic lymph nodes in mice. J Diabetes Res 2019;2019:1649279.
55. Guimarães JB, Rodrigues VF, Pereira ÍS, et al. Inulin prebiotic ameliorates type 1 diabetes dictating regulatory T cell homing via CCR4 to pancreatic islets and butyrogenic gut microbiota in murine model. J Leukoc Biol 2024;115:483-96.
56. Zhang J, Ni Y, Qian L, et al. Decreased abundance of Akkermansia muciniphila leads to the impairment of insulin secretion and glucose homeostasis in lean type 2 diabetes. Adv Sci 2021;8:e2100536.
57. Chelakkot C, Choi Y, Kim DK, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med 2018;50:e450.
58. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066-71.
59. Peng GC, Hsu CH. The efficacy and safety of heat-killed Lactobacillus paracasei for treatment of perennial allergic rhinitis induced by house-dust mite. Pediatr Allergy Immunol 2005;16:433-8.
60. Sakai T, Taki T, Nakamoto A, et al. Lactobacillus plantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fat diet. J Nutr Sci Vitaminol 2013;59:144-7.
61. Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727-35.
62. Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol 2014;80:5935-43.
63. Santacruz A, Collado MC, García-Valdés L, et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr 2010;104:83-92.
64. Forslund K, Hildebrand F, Nielsen T, et al; MetaHIT consortium. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262-6.
65. Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019;25:1096-103.
66. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol 2013;59:583-94.
67. Xie G, Wang X, Liu P, et al. Distinctly altered gut microbiota in the progression of liver disease. Oncotarget 2016;7:19355-66.
68. Wu W, Lv L, Shi D, et al. Protective effect of Akkermansia muciniphila against immune-mediated liver injury in a mouse model. Front Microbiol 2017;8:1804.
69. Neyrinck AM, Etxeberria U, Taminiau B, et al. Rhubarb extract prevents hepatic inflammation induced by acute alcohol intake, an effect related to the modulation of the gut microbiota. Mol Nutr Food Res 2017;61:1500899.
70. Li S, Wang N, Tan HY, et al. Modulation of gut microbiota mediates berberine-induced expansion of immuno-suppressive cells to against alcoholic liver disease. Clin Transl Med 2020;10:e112.
71. Grander C, Adolph TE, Wieser V, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 2018;67:891-901.
72. Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology 2019;69:107-20.
73. Cui Z, Xu L, Zhao M, Zhou L. Akkermansia muciniphila MucT attenuates sodium valproate-induced hepatotoxicity and upregulation of Akkermansia muciniphila in rats. J Cell Mol Med 2024;28:e18026.
74. Fang C, Cheng J, Jia W, Xu Y. Akkermansia muciniphila ameliorates alcoholic liver disease in experimental mice by regulating serum metabolism and improving gut dysbiosis. Metabolites 2023;13:1057.
75. Higarza SG, Arboleya S, Arias JL, Gueimonde M, Arias N. Akkermansia muciniphila and environmental enrichment reverse cognitive impairment associated with high-fat high-cholesterol consumption in rats. Gut Microbes 2021;13:1-20.
76. Schneider KM, Mohs A, Gui W, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun 2022;13:3964.
77. Qu D, Chen M, Zhu H, et al. Akkermansia muciniphila and its outer membrane protein Amuc_1100 prevent high-fat diet-induced nonalcoholic fatty liver disease in mice. Biochem Biophys Res Commun 2023;684:149131.
78. Zhu L, Lu X, Liu L, Voglmeir J, Zhong X, Yu Q. Akkermansia muciniphila protects intestinal mucosa from damage caused by S. pullorum by initiating proliferation of intestinal epithelium. Vet Res 2020;51:34.
79. Ma Y, Hu C, Yan W, Jiang H, Liu G. Lactobacillus pentosus increases the abundance of Akkermansia and affects the serum metabolome to alleviate dss-induced colitis in a murine model. Front Cell Dev Biol 2020;8:591408.
80. Juárez-Fernández M, Porras D, Petrov P, et al. The synbiotic combination of Akkermansia muciniphila and quercetin ameliorates early obesity and NAFLD through gut microbiota reshaping and bile acid metabolism modulation. Antioxidants 2021;10:2001.
81. Xia J, Lv L, Liu B, et al. Akkermansia muciniphila ameliorates acetaminophen-induced liver injury by regulating gut microbial composition and metabolism. Microbiol Spectr 2022;10:e0159621.
82. Daniel N, Gewirtz AT, Chassaing B. Akkermansia muciniphila counteracts the deleterious effects of dietary emulsifiers on microbiota and host metabolism. Gut 2023;72:906-17.
83. Li Z, Zhang B, Wang N, Zuo Z, Wei H, Zhao F. A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota. Gut 2023;72:686-98.
84. Ashrafian F, Shahriary A, Behrouzi A, et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front Microbiol 2019;10:2155.
85. Meng X, Wang W, Lan T, et al. Correction: Wu, H.; et al. A purified aspartic protease from Akkermansia Muciniphila plays an important role in degrading Muc2. Int. J. Mol. Sci. 2020, 21, 72. Int J Mol Sci 2021;22:3122.
86. Ottman N, Reunanen J, Meijerink M, et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One 2017;12:e0173004.
87. Liu X, Wang Z, Xu C, Guan J, Wei B, Liu Y. [Study on the gelatin methacryloyl composite scaffold with exogenous transforming growth factor β1 to promote the repair of skull defects]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2021;35:904-12.
88. Wang J, Xu W, Wang R, Cheng R, Tang Z, Zhang M. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct 2021;12:3597-610.
89. Qian K, Chen S, Wang J, Sheng K, Wang Y, Zhang M. A β-N-acetylhexosaminidase Amuc_2109 from Akkermansia muciniphila protects against dextran sulfate sodium-induced colitis in mice by enhancing intestinal barrier and modulating gut microbiota. Food Funct 2022;13:2216-27.
90. Yoon HS, Cho CH, Yun MS, et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol 2021;6:563-73.
91. Axelrad JE, Shah SC. Diagnosis and management of inflammatory bowel disease-associated neoplasia: considerations in the modern era. Therap Adv Gastroenterol 2020;13:1756284820920779.
92. Kuczma MP, Szurek EA, Cebula A, et al. Commensal epitopes drive differentiation of colonic Tregs. Sci Adv 2020;6:eaaz3186.
93. Elzinga J, Narimatsu Y, de Haan N, Clausen H, de Vos WM, Tytgat HLP. Binding of Akkermansia muciniphila to mucin is O-glycan specific. Nat Commun 2024;15:4582.
94. Soto-Martin EC, Warnke I, Farquharson FM, et al. Vitamin biosynthesis by human gut butyrate-producing bacteria and cross-feeding in synthetic microbial communities. mBio 2020;11:e00886-20.
95. Belzer C, Chia LW, Aalvink S, et al. Microbial metabolic networks at the mucus layer lead to diet-independent butyrate and vitamin B12 production by intestinal symbionts. mBio 2017;8:e00770-17.
96. Hiippala K, Jouhten H, Ronkainen A, et al. The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation. Nutrients 2018;10:988.
97. Wade H, Pan K, Duan Q, et al. Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145. J Biomed Sci 2023;30:38.
98. Luo ZW, Xia K, Liu YW, et al. Extracellular Vesicles from Akkermansia muciniphila elicit antitumor immunity against prostate cancer via modulation of CD8+ T cells and macrophages. Int J Nanomedicine 2021;16:2949-63.
99. Meng X, Wang W, Lan T, et al. A purified aspartic protease from Akkermansia Muciniphila plays an important role in degrading Muc2. Int J Mol Sci 2019;21:72.
100. Gu Z, Pei W, Shen Y, et al. Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis. Food Funct 2021;12:10184-95.
101. Ma J, Tan Q, Nie X, et al. Longitudinal relationships between polycyclic aromatic hydrocarbons exposure and heart rate variability: exploring the role of transforming growth factor-β in a general Chinese population. J Hazard Mater 2022;425:127770.
102. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282-6.
103. Palmnäs-Bédard MSA, Costabile G, Vetrani C, et al. The human gut microbiota and glucose metabolism: a scoping review of key bacteria and the potential role of SCFAs. Am J Clin Nutr 2022;116:862-74.
104. Segers A, de Vos WM. Mode of action of Akkermansia muciniphila in the intestinal dialogue: role of extracellular proteins, metabolites and cell envelope components. Microbiome Res Rep 2023;2:6.
105. Zhang Q, Linke V, Overmyer KA, et al. Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut. Nat Microbiol 2023;8:424-40.
106. Castro-Mejía J, Jakesevic M, Krych Ł, et al. Treatment with a monoclonal anti-IL-12p40 antibody induces substantial gut microbiota changes in an experimental colitis model. Gastroenterol Res Pract 2016;2016:4953120.
107. Ganesh BP, Klopfleisch R, Loh G, Blaut M. Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella typhimurium-infected gnotobiotic mice. PLoS One 2013;8:e74963.
108. Seregin SS, Golovchenko N, Schaf B, et al. NLRP6 protects Il10-/- mice from colitis by limiting colonization of Akkermansia muciniphila. Cell Rep 2017;19:733-45.
109. Bae M, Cassilly CD, Liu X, et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature 2022;608:168-73.
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Jiang, P.; Ji S.; Su D.; Zhao Y.; Goncalves V. B. E.; Xu G.; Zhang M. The biofunction of Akkermansia muciniphila in intestinal-related diseases. Microbiome. Res. Rep. 2024, 3, 47. http://dx.doi.org/10.20517/mrr.2024.12
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