A study analyzed 23 whole genome sequences of the Akkermansia genus and revealed that these strains formed four clades, divided into four species based on dDDH values (28), while a more recent study has divided Akkermansia strains into five distinct group (29). Moreover, it has been shown that single nucleotide polymorphisms (SNPs) were not evenly distributed throughout the A. muciniphila genomes, while genes in regions with high SNPs are found to be related to metabolism and cell wall/membrane envelope biogenesis (28).

When it comes to A. muciniphila, many genomic studies have been conducted in order to study its genomic diversity. A. muciniphila can be subdivided into three phylogroups, with high nucleotide diversity and distinct metabolic and functional profiles (30). However, a recent study has reported the presence of four different Akkermansia phylogroups, based on pangenome analysis (31). Another study analyzed different A. muciniphila strains from different phylogroups and revealed that each phylogroup has some specific phenotypes such as oxygen tolerance or sulfur assimilation. These phenotypes can influence the colonization of the gastrointestinal tract (32).

This genus uses mucin as its only carbon and nitrogen source, but it has been proven that it can grow in a medium containing glucose, N-acetylglucosamine and N-acetylgalactosamine, when provided with other protein sources (7, 25). The uptake of these sugars can also be enhanced by adding mucin, revealing the role of other mucin-derived components in its growth (33).

A. muciniphila has numerous candidate mucinase-encoding genes but surprisingly lacks genes coding for canonical mucus-binding domains (27). This capacity to degrade mucin might be essential to the survival of other bacteria in the human gut, as mucin degradation by A muciniphila provides metabolites that supports the growth of other bacteria such as Anaerostipes caccae by changing the transcriptional profile to induce an increase in the expression of mucin degradation genes and a reduction in the expression of ribosomal genes (34). Among the various studies aiming to identify the enzymes involved in mucin degradation, one has succeeded in identifying a novel phospholipid‐regulated β‐galactosidase involved in mucin degradation (35). Further work revealed other beta galactosidases involved in the complex mucin degradation machinery (36). A. muciniphila can survive without the addition of vitamins to the medium. It was even proven in a recent study that some A. muciniphila strains were able to synthesize vitamin B12 (31).

A. muciniphila and A.glycaniphila strains have been shown to be resistant to ampicillin and vancomycin (7, 25, 37, 38). Specifically, A. muciniphila Muc^T was also found to be resistant to other antibiotics, including metronidazole and penicillin G, but susceptible to doxycycline, imipenem, and piperacillin/tazobactam (38). This antibiotic profile can change from one strain to another. For example, another A. muciniphila strain isolated in 2017 was sensitive to penicillin, imipenem, ceftriaxone and amoxicillin but resistant to ofloxacin (37). In 2015, a study aimed at assembling the genome of a strain sequenced directly from a human stool sample detected its presence, by performing an in-silico prediction of eight beta lactamase genes. Moreover, three macrolide resistance genes were detected with only one sharing 65% similarity with a known macrolide gene. Finally, resistance to vancomycin, chloramphenicol, sulfonamide, tetracycline and trimethoprim was associated with only one gene (39).

A. muciniphila is a common bacterial component of the human intestinal tract (9). A study by Collado et al. found that the presence of A. muciniphila presence increases from 16% of the samples of one-month-old infants to 90% at 12 months, while it is present in all the adult samples. Similarly, levels also increase in early life to reach levels similar to that observed in adults within a year. On the other hand, this level decreases significantly in the elderly (8).

Aiming to characterize the whole gut microbiota, Mailhe et al. collected samples from various parts of the digestive tract: the stomach, duodenum, ileum, and the left and right colon and analyzed those samples using culturomics and metagenomics. They succeeded in cultivating Akkermansia muciniphila in the left colon. In terms of metagenomic analysis, the Verrucomicrobia phylum, represented by the Akkermansia genus, was detected in the duodenum, ileum, and the right and left colon (40). Moreover, Ye et al., detected Akkermansia-like sequences in three out of six duodenal fluid samples (41). Another study exploring the duodenal and rectal microbiota in luminal contents and biopsy tissues in healthy volunteers found Verrucomicrobia sequences in duodenal biopsies, mucus and rectal biopsies (42). The presence of Akkermansia sequences was reported in the jejunal fluid, the pancreas and the bile with mean relative abundance of 0.01%, 0.05% and 0.01%, respectively, in a study exploring disturbances in the microbiome in patients undergoing pancreaticoduodenectomy (43). Analysis based on 16S rRNA genes uncovered the presence of Akkermansia sequences in ileocecal biopsies of patients with primary sclerosing cholangitis (PSC), ulcerative colitis and in non-inflammatory controls, with no significant differences between the different groups (44). The presence of Verrucomicrobia or Akkermansia-like sequences were detected much more frequently in the large intestine (45, 46) (Figure 1).

There is no significant evidence of the presence of A. muciniphila in the oral cavity. Le et al. highlighted an absence of A. muciniphila in the oral cavities of 47 pediatric patients after PCR screening (47). A study performed in 2017 by Coretti et al. assessed the subgingival microbiota of smokers and non-smokers with chronic periodontitis compared to a control group. They found that the Verrucomicrobia phylum was significantly lower in people with chronic periodontitis (48). A. muciniphila was also detected in the saliva sample of a choledocholithiasis patient. He was the only positive patient out of six and the relative abundance was very low (41) (Figure 1). While its presence is not abundant in the oral cavity, A. muciniphila can be a potential therapeutic agent for periodontitis. In an experimental periodontitis mouse model, A. muciniphila showed protective effects by decreasing inflammatory cell infiltration and reducing alveolar bone loss (49).

Although urine was long considered sterile, some studies have proved the presence of resident microorganisms by using culture and molecular based techniques (50). Few studies have detected the presence of A. muciniphila in the urine. Mansour et al. analyzed tissue and urine samples from patients with bladder carcinoma in order to compare the microbiota in both type of samples. Sequencing results showed that the Akkermansia genus was present in both type of samples but was over-represented in the tissue samples compared to the urine samples (51). Another sequencing-based study reported a decrease in the levels of the phylum Verrucomicrobia in urine samples from an elderly Type 2-diabetes mellitus group compared with a control group (52).

Human milk contains nutrients providing immunological and other health benefits to new-born babies. Studies on human milk show that it provides a source of commensal microorganisms for the new-born gut (53). As for A. muciniphila, its presence in human breast milk was reported for the first time in a study conducted by Collado et al. (54) The study showed that A. muciniphila was found in milk samples taken from women shortly after giving birth (colostrum), as well as at one and six months, with mean concentrations of 1.25, 1.09, and 1.20 log number of gene copies/mL, respectively. Moreover, they demonstrated that A. muciniphila was more abundant in overweight mothers than in normal weight mothers. Another study in 2014 discovered the presence of Akkermansia-like species using 16S rRNA sequencing in human breast tissue samples of 43 women (aged 18 to 90 years) (55). In addition, A. muciniphila was also found by qPCR analysis in milk colostrum samples collected from 11 women after an elective caesarean section, with a median count of 0.9 (56). Furthermore, metagenomic analysis of breast milk samples from healthy Korean mothers detected the presence of the Akkermansia genus (57). Finally, in a study aiming to evaluate the impact of maternal breast milk composition on children who develop coeliac disease (CD), milk samples were collected from mothers with a genetic predisposition to CD and a control group. The genus Akkermansia was found in milk from mothers in the CD group and the control group but was more abundant in the CD group (58). The presence of A. muciniphila in the human breast milk might be due to its ability to use human milk oligosaccharides (59). Although it is important to note that this ability is strain dependent (60).

The association between cancer and changes in the gut microbiota in humans has been widely investigated. More specifically, the role of A. muciniphila in different types of cancer has been assessed (75). One study highlighted the decrease in the abundance of faecal A. muciniphila among non-small-cell lung cancer patients compared to controls (15), through metagenomic and metabolomic profiling, while an increase was detected using real time PCR on gut mucosal tissues samples of colorectal cancer patients compared to controls (16), Similarly, an abundance of A. muciniphila along with other bacteria was significantly increased in patients with different gastrointestinal cancer such as esophageal, gastric and colorectal cancer, compared to the control group (17) (Table 2).

A study performed on pancreatic cancer xenograft mice model showed an increase in A. muciniphila in the guts of mice receiving Gemcitabine treatment, as well as a decrease in tumour volume (92). In a prostate cancer mice model, the relative abundance of A. muciniphila in the gut was decreased. However, this decrease was reversed after receiving androgen deprivation therapy (93).

In other studies concentrating on the role of gut microbiota in the response to anti-PD1 (Programmed cell Death protein 1) immunotherapy, the presence of species such as Bifidobacterium breve, Bifidobacterium longum, Faecalibacterium prausnitzii and, most importantly, A. muciniphila in the gastro-intestinal tract of cancer patients was associated with a stronger immune response to the therapy and subsequently an extended survival of these patients (94). In another study based on anti-PD1 therapy for non-small cell lung cancer (NSCLC), two genera, Akkermansia and Olsenella, were significantly higher in the stable disease group than in the progressive disease group (95). Similarly, gastric cancer patients showed an enrichment for the genus Akkermansia before and after radical distal gastrectomy (96).

In epithelial tumours, metagenomic analysis of stool samples from patients receiving immune checkpoint inhibitors showed correlations between clinical responses to the treatment and the relative abundance of A. muciniphila (97). The same team also found an increase in A. muciniphila levels in patients responding favourably to immune checkpoint blockade treatment in a cohort of renal cell carcinoma patients (98).

In a study of anti-colon cancer therapy based on treatment with FOLFOX, it was demonstrated that the abundance of A. muciniphila significantly increased in patients receiving the treatment, which was positively correlated with the therapeutic effect (99).

In terms of colorectal cancer (CRC), it has been demonstrated that CRC tissues increase the expression of mucin2 compared to normal mucosa (100).

Finally, in a randomized trial evaluating the impact of probiotic supplementation on the outcome of gut microbiome and metastatic renal cell carcinoma (mRCC), patients who had received a treatment and had been supplemented with probiotics present a higher abundance of A. muciniphila in the gut (101). Furthermore, there was a positive and significant association between the presence of A. muciniphila and the clinical benefit of the treatment (101).

The abundance of A. muciniphila is decreased in many metabolic disorders, such as inflammatory bowel diseases, appendicitis and obesity (76, 77, 79) suggesting its association with healthy intestine and normal mucosa. Eating disorders, such as binge eating disorder (78) (Table 2) have also been associated with a decrease in the levels of A. muciniphila.

These findings reveal the importance of A. muciniphila as a biomarker of health status (102). Many studies targeted treating metabolic diseases have focused on tracking the levels of A. muciniphila to assess the success of the therapy (103).

The consumption of certain beneficial microbes, known as probiotics, has been known to affect the gut microbiota. This is because the consumption of these organisms can trigger a variety of health benefits for the host (113). It has been noted that most of the probiotics sold on the market are microorganisms from the Bifidobacterium and Lactobacillus genera (114). They are safe to use and approved by the United States Food and Drug Administration (FDA) (115). Recently, however, new microbes identified by next generation sequencing methods are emerging and are also associated with health promotion. The safety of these microbes, called next generation probiotics (NGPs), as well as their formulation and administration are currently being processed (115). A. muciniphila has emerged as a potential NGPs due to its various benefits on health (116). For this purpose, an efficient and scalable workflow has been developed for the cultivation and preservation of A. muciniphila cells. This study resulted in viable Akkermansia colonies with high yields and stability, with a survival up to 97.9 ± 4.5% for one year if stored in glycerol-amended medium at -80°C (117) (Figure 2).

In recent years, there has been a lot of focus on the use of nonviable bacterial supplements (pasteurized forms) known as paraprobiotics (118) (Figure 2) as an alternative to live bacteria to lower the risk of infection. for example Druart et al. demonstrated that pasteurized A. muciniphila is safe to use as a food ingredient based on rat models (119). The safety of A. muciniphila products has also been recently reported in humans (12, 107). The pasteurized form is achieved when the bacteria suspension was heated at 70°C for 30 minutes, as described by Plovier et al. (12) By comparing the effects of live and pasteurized A. muciniphila on normal diet-fed mice, Ashrafian et al. showed that both forms of A. muciniphila could modulate lipid and immune homeostasis and improved health by modulating gut microbiota, while all these effects were dominantly observed in the pasteurized form (120). Another study conducted by Grajeda-Iglesias et al. demonstrated that pasteurized A. muciniphila was more efficient than the live version in elevating the intestinal concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, as well multiple bile acids. All these metabolites have been described to be associated with human health (121). Recent studies also started focusing on postbiotics, which refers to using inactivated cell components to promote health (122). In the case of A.muciniphila, many studies started focusing on the potential use of its extracellular vesicles (EVs) as postbiotics (Figure 2). For example, a study by Ghaderi et al. showed that live and pasteurized forms of A.muciniphila and its EVs can affect the expression of the endocannabinoid system and peroxisome proliferator-activated receptors (PPARs) genes involved in metabolic pathways, suggesting the potential possibility to use them as probiotic, parabiotic and postbiotic respectively in order to prevent metabolic diseases (123). Furthermore, in vitro study showed that treatment with A. muciniphila or its EVs could influence the expression of genes involved in the serotonin system and thus can be used as a serotonin modulation therapy (124).

Many studies have focused on the causal link between A. muciniphila and improvements in metabolism (Figure 2). It has been shown that daily oral supplementation with live A. muciniphila at the onset of obesity, diabetes and gut barrier dysfunction in mice at the dose of 2.10⁸ bacterial cells per day improves glucose tolerance, reduces adiposity and inflammation, therefore partly protecting against diet-induced obesity in mice (108, 125). In addition, animals receiving live A. muciniphila no longer exhibited insulin resistance, nor infiltration of inflammatory cells (CD11c) in the adipose tissue, which is a key characteristic of obesity and associated low-grade inflammation (108). In addition, it was noted that live A. muciniphila prevented the development of metabolic endotoxemia as an effect associated with the restoration of a normal mucus layer thickness (108). It is worth mentioning that all these findings have subsequently been confirmed by different groups and extended to other specific disorders such as atherosclerosis, hepatic inflammation and hypercholesterolemia (20, 126, 127). Furthermore, the administration of pasteurized A. muciniphila was correlated with an increase in energy expenditure in diet-induced obese mice, possibly explaining the mechanism by which administration of A. muciniphila can reduce body weight and fat mass gain (128).

The role and administration of A. muciniphila have been notably investigated in cancer. For instance, a study using prostate cancer mice model showed that the extracellular vesicles of A. muciniphila can be used as an immunotherapeutic agent for prostate cancer treatment, demonstrated by the decrease in tumors and the upregulation of immune cells such as tumor-killing M1 macrophages after injection of these vesicles in cancer bearing mice (129). Furthermore, the effect of the mucin degrading enzyme of A. muciniphila Amuc_1434* (130) was investigated in the inhibition of the proliferation of CRC tissues. The study has showed that the mucin degrading enzyme Amuc_1434* was able to inhibit the proliferation of CRC cells lines by mediating apoptosis via the TRAIL pathway (131). However, Wang et al. suggested that treatment of CRC-mice with A. muciniphila increases the early level of inflammation and proliferation of the intestinal cells and therefore promotes the formation of tumors (132).

In liver diseases, recent studies have investigated the potential anti-fibrotic effects of heat-killed A. muciniphila Muc^T on the activation of hepatic stellate cell (HSC), where they demonstrated that heat-killed A. muciniphila Muc^T was safe and capable of improving LPS-induced HSC activation by modulating fibrosis markers (133). Moreover, oral supplementation in alcoholic steatohepatitis mice model induced a reduction in hepatic injury and steatosis, while enhancing mucus thickness and tight-junction expression (20). In an induced liver fibrosis mice model, it was revealed that treatment with live or pasteurized A. muciniphila or with its extracellular vesicles (EVs) can improve gut permeability, attenuating the expression of inflammatory biomarkers and subsequently preventing liver injury in treated mice (134). Another study showed that oral administration of A. muciniphila or its EVs could improve the anti-inflammatory responses eventually leading to a prevention from liver injury in mice (135). A recent study conducted by Rao et al. in mice explored the therapeutic effect of A. muciniphila in metabolic dysfunction-associated fatty liver disease (MAFLD). The study results indicated that A. muciniphila exhibited anti-MAFLD activity correlated with lipid oxidation and an improvement in gut-liver interactions by regulating the metabolism of L-aspartate (136).

The importance of A. muciniphila in maintaining good health and the negative correlation between its presence and obesity (81, 107) have initiated many studies focusing on using the mucin-degrading bacteria as a treatment. For example, studies performed on high-fat diet-fed mice models treated with A. muciniphila showed that this treatment prevents body weight gain, calorie intake and reduces the weight of adipose tissues, thus improving the induced metabolic disorders. In addition, it had many other beneficial effects such as improving glucose homeostasis and insulin sensitivity, inhibition of intestinal inflammation and restoration of damaged gut integrity (108, 137, 138). Administration of the pasteurized form had similar effects. A study by Ashrafian et al. showed that the pasteurized A. muciniphila and its EVs totally reduced the High-fat diet (HFD) induced intestinal inflammation and preserved intestinal permeability (139). Pasteurized A. muciniphila was shown to attenuate inflammatory response and improve intestinal barrier integrity. This is probably due to stimulating AMP-activated protein kinase (AMPK) and inhibiting Nuclear Factor-Kappa B (NF-κB) activation through the stimulation of TLR2 on intestinal epithelial cells (140). Aiming to understand the mechanisms of A. muciniphila involved in modulating the host metabolism, Yoon et al. identified a protein named P9 which induces glucagon-like peptide-1 (GLP-1) secretion and brown adipose tissue thermogenesis (141). Ashrafian et al. demonstrated that A. muciniphila or its EVs significantly reduced the body and fat weight of HFD mice and improved intestinal barrier integrity and energy balance (142).

Another study has been conducted to prove that deficiency in A. muciniphila is correlated with a high incidence of diabetes in a NOD mouse model. This study showed that the oral transfer of A.muciniphila could delay the onset of diabetes through promoting mucus production, increasing the expression of antimicrobial peptide Reg3y, lowering serum endotoxin levels and the expression of islet toll-like receptor (143). Chellakot et al. found that the administration of A. muciniphila EVs improved intestinal tight junction function, glucose tolerance in high-fat diet-induced diabetic mice and reduced weight gain, indicating a potential role for EVs in diabetes and thus indicating its use as a therapy (144).

The therapeutic role of A. muciniphila has also been studied in inflammatory bowel diseases. It has been found that treatment of ulcerative colitis dextran sulfate sodium (DSS)-induced mice with metformin alleviates the phenotype associated with an increase in the expression of mucin2 and in the abundance of A. muciniphila compared to the control group. Moreover, the administration of A. muciniphila decreases disruption of the mucus barrier and colonic inflammation (145). Similarly, another study conducted on a colitis DSS-induced mice model showed that the oral application of EVS protects against colitis phenotypes, such as body weight loss and inflammatory cell infiltration of the colon wall (146). Similar effects were also observed after treatment of the mice model with Amuc_2109, a β-acetylaminohexosidase secreted by A. muciniphila. Treatment with Amuc-2109 also had anti-inflammatory effects by inhibiting the expression of inflammatory cytokines (147).

It was found that the outer membrane protein Amuc_1100 of A. muciniphila promotes the biosynthesis of 5-HT, which is a neurotransmitter and a key signal molecule regulating the gastrointestinal tract functions and other organs (112). Wang et al. found that A. muciniphila or Amuc_1100 improved gastrointestinal motility function and restored gut microbiota abundance and species diversity in antibiotic-treated mice. This finding represented an important approach through which A. muciniphila interacts with the host and further influences 5-HT-related physiological functions (148).

The anti-inflammatory and immunoregulatory roles of A. muciniphila has been assessed in other diseases in mice models. It was shown that the administration of pasteurized A. muciniphila in a mouse model of H7N9 influenza viral infection reduced mortality, given its anti-inflammatory and immunoregulatory roles (149). Likewise, the administration of A. muciniphila resulted in a decrease in inflammatory cell infiltration and bone destruction in a mouse model of calvarial infection (49). Treatment with A. muciniphila also resulted in decreased alveolar bone and systemic inflammation loss in an experimental Porphyromonas gingivalis induced periodontitis model (49, 150). These findings highlight the protective effects of A. muciniphila and its use as a potential therapeutic agent to various diseases. However, Lawenius et al. showed that treatment with pasteurized A. muciniphila in mice reduces the accumulation of fat mass but does not protect against bone loss in a model of ovariectomized mice (151).

Moreover, another study performed in mice has reported that the presence of A. muciniphila and its EVs in the gut promote serotonin concentration, and also has an impact on serotonin signaling/metabolism through the gut-brain axis. These results suggest that A. muciniphila and its EVs can be considered as a new therapy for serotonin-related disorders (152). Ding et al. demonstrated that treatment of mice with depression induced by chronic restraint stress with A. muciniphila can reduce the depressive-like behavior of the mice, which was correlated with the increase in β-alanyl-3-methyl-l-histidine and edaravone (153).

Few studies on the use of A. muciniphila as a probiotic in humans have been conducted. The study by Plovier et al. was the first to demonstrate that the administration of live or pasteurized A. muciniphila is safe in humans in a cohort of 20 subjects with excess body weight. An exploratory study conducted by Depommier et al. on 32 overweight and obese insulin-resistant human volunteers also demonstrated that daily oral supplementation with either live or pasteurized A. muciniphila bacteria was safe and well-tolerated up for three months. Furthermore, they showed that pasteurized A. muciniphila improves insulin sensitivity and reduces insulinemia and plasma total cholesterol, while slightly decreasing body weight and fat mass compared to a placebo group (23). Moreover, the same team suggested that peroxisome proliferator-activated receptor alpha activation by mono-palmitoyl-glycerol might underlie some of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome (24). Metabolome analysis illustrates that administration of A. muciniphila in prediabetic individuals leads to a decrease in some amino acids (tyrosine and phenylalanine), potentially explaining its hepato-protective role (154). Two clinical studies are ongoing to prove the efficacy of pasteurized A. muciniphila in improving insulin sensitivity, and to assess the weight-loss and glucose-lowering effects of A. muciniphila WST01 strain in overweight or obese patients with type 2 diabetes (Table 3).

One method of favorably modulating the gut microbiota is to administer growth-promoting substrates that can be used preferentially by health-promoting bacteria to promote their growth and the production of associated desirable metabolites. The rationale of selectively enhancing beneficial microbes in the gut led to the concept of prebiotics, initially described in 1995 by Roberfroid and Gibson (158).

While some technological and regulatory hurdles may limit the use of certain strains of probiotics, it should be possible to use prebiotics and other dietary components to selectively enhance their growth in situ. The prebiotic paradigm has shifted in recent years, following the discovery of newly identified putatively beneficial gut microbiota members to target for enrichment. Through the development of new cultivation techniques and high-throughput sequencing, these studies have been able to explore the various impacts of specific fibers and products which represent untapped source of food bioactive on gut microbiota (159). For example, Anhe et al. showed that cranberry extract, rich in polyphenols, has been shown to improve diet-induced obesity and several features of metabolic syndrome (MetS) in mice, while increasing the abundance of A. muciniphila (160). Moreover, studies demonstrated that supplementation with grape polyphenols can promote increased intestinal abundance of A. muciniphila in mice fed either high-fat or low-fat diet, thus resulting in lower intestinal and systemic inflammation (161, 162). The administration of polymeric procyanidins in mice fed a high-fat/high-sucrose diet increases the proportion of A. muciniphila by eight times, producing beneficial effects on metabolic homeostasis (163). Another interesting fruit extract rich in polyphenols is camu-camu extract. This prebiotic can also improve the homeostasis of glucose and lipids while also increasing the abundance of A. muciniphila after five weeks of supplementation in HFD fed mice (164). Dietary supplementation with polysaccharides such as fucoidan decreased body weight in HFD-fed mice and also improved glucose intolerance and insulin resistance. Both fucoidans separately improved intestinal dysbiosis caused by a HFD and significantly increased the abundance of A. muciniphila (165). Inulin-type fructan prebiotics were found to significantly enhance the presence of A. muciniphila, linked to a decrease in obesity and fat mass and an improvement in insulin resistance in genetic obese and diet-induced leptin-resistant mice (166). An increase in the cecal content of A. muciniphila was detected by targeted qPCR following four weeks’ supplementation with berberine in genetically obese mice, associated with an improvement in gut barrier function and hepatic inflammatory and oxidative stress (167). (167) Jiang et al. showed that total flavone (TFA) extracted from the flowers Abelmoschus manihot (TFA) can also enhance A. muciniphila in DSS-induced experimental colitis (168). Finally, dry extract of rhubarb root has also been shown to cause an increase in levels of A. muciniphila associated with the increased expression of Reg3γ in the colon, an anti-microbial peptide with an important role in the host defense system, thus protecting against metabolic disorders (169).

Clinical trials and human studies are essential when assessing the benefits of newly identified prebiotics. Of the many potential prebiotics which have been studied, only a few substrates, including Xylo-oligosaccharides (XOS) and resistant starch (RS) have been validated through human studies. Finegold et al. demonstrated that xylo-oligosaccharides promoted intestinal health by modulating the microbial community: an increase in the levels of Faecalibacterium sp. and Akkermansia sp. as well as Bifidobacteria was detected (155). Moreover, a randomized dietary study by Maier et al. proved that resistant starch increased the levels of A. muciniphila in participants who followed a high resistant starch diet (156). Other ongoing clinical studies involve the use of various prebiotics in different diseases such as T2D, cancer and other diseases in order to uncover their potential in enriching the abundance of A. muciniphila.

Other probiotic treatments may also increase the levels of A. muciniphila. For example, a fasting programme combined with laxative treatment for one week followed by a six-week probiotic intervention with a probiotic containing several different bacterial strains showed an increase in the abundance of Akkermansia (157). Four other clinical studies are in progress about the use of different bacteria as probiotics and their effect on modulation of the intestinal flora in cancer or IBS and, most importantly, on increasing the abundance of A. muciniphila (Table 3).

Other than natural components, A. muciniphila has been used by Payahoo et al. as a marker to assess the efficiency of a pharmaceutical agent, Oleoylethanolamide, for treatment of obese people. This study showed that abundance of A. muciniphila bacterium increases significantly in oleoylethanolamide group compared to the placebo group and modifies the energy balance (170).