{"paper_id":"ab8487bc-c258-49b7-b269-97f82955bb1f","body_text":"Akkermansia muciniphila  is a commensal bacterium of the intestinal niche first isolated in 2004 by Derrien and colleagues [ 1 ]. Since then, researchers and physicians have increased their interest on such microbe, especially in recent years, as it has been emerging as “a promising next-generation beneficial microbe” due to its role in maintaining host wellbeing with a particular regard for the management of metabolic diseases [ 2 ].\nIn detail,  Akkermansia  is an oval-shaped, anaerobic Gram-negative bacterium, representing about 3% of the gut microbial community. It is the only representative member of the  Verrucomicrobia  phylum found in mammal gastrointestinal samples, and its abundance gradually increases throughout the life course [ 3 , 4 ]. It starts colonizing the intestinal tract early, and from the first year of life, its levels become equal to those observed in healthy adults, and then decrease in the elderly.\nThe core of its life cycle and metabolism relies on the process of degrading mucin as a source of carbon, nitrogen and energy, thanks to several mucolytic enzymes encoded by its genome (glycosyl hydrolases, proteases, sulfatases, and sialidases). Mucin is secreted by the glandular epithelium of the gastro-intestinal tract and represents the main glycoprotein of the mucus. It plays a crucial role in physical protection as well as in regulating the passage of water within the gut, along with ions and immune mediators such as antimicrobial peptides and immunoglobulin-A [ 5 , 6 ]. In addition, mucin also acts as the first line of defense against mechanical damage, pathogen invasion and toxins, providing a surface layer to bacteria for their growth, adhesion and protection [ 7 , 8 ]. Therefore, the process of mucin degradation by  Akkermansia  needs to be highly regulated. Indeed, the activity of degrading mucin stimulates mucosa to produce new mucus, thus strengthening the epithelial barrier, but the excessive degradation may induce a severe susceptibility to pathogens, inflammatory intestinal diseases and colorectal cancer. Moreover, at the same time, an excessive presence of mucus may be symptomatic of mucosal inflammatory processes.\nThe scientific interest on  Akkermansia muciniphila  arises from evidence highlighting that its abundance in the gut correlates with host health, while its alterations with several dysfunctions [ 9 , 10 , 11 ]. This is the case of metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD) and non-alcoholic fatty liver disease (NAFLD), in which the levels of  Akkermansia muciniphila  decrease. However, at the same time, an excessive enrichment in  Akkermansia muciniphila , in specific intestinal microenvironments, may exacerbate local inflammation caused by damages on the epithelial barrier [ 12 , 13 , 14 ]. For instance, increasing  Akkermansia  in a condition of  Salmonella typhimurium  infection or in a condition of intestinal bowel diseases could have no expected beneficial effects [ 14 , 15 ].\nIn addition, a cautionary note on its wide use has come from the neurologic field since in some pathological contexts, including Parkinson’s disease (PD) and multiple sclerosis (MS), the intestinal microbiota exhibits a characteristic signature of  Akkermansia municiphila  abundance [ 16 ].\nTherefore, in light of these controversial points, evaluating the use of  Akkermansia  on an individual basis should be critically considered.\n\nSeveral pieces of evidence refer to  Akkermansia muciniphila  as a promising therapeutic agent with a probiotic role and several metabolic applications [ 17 ]. Indeed, both pre-clinical and clinical studies demonstrated its efficacy in improving the clinical picture of metabolic syndrome and obesity with beneficial effects on insulin sensitivity, lipoprotein metabolism and hepatic metabolic inflammation [ 18 , 19 , 20 ]. A recent review focused on the correlation between gut microbiota and intestinal homeostasis by exploring the involvement of  Akkermansia  in the development of metabolic disorders and its role in the maintenance of intestinal health and host metabolic modulation [ 21 ].  Akkermansia muciniphila  is highly present in the intestinal microbiota of healthy individuals: its levels correlate with body weight and its supplementation may induce preventive and therapeutic effects against metabolic dysfunctions [ 2 , 22 , 23 ].\nThe best-described effects of  Akkermansia  regard its ability to strengthen the integrity of the intestinal barrier, modulate insulin resistance and protect from metabolic inflammation. A study by Reunanen et al. found that  Akkermansia  could adhere to the intestinal epithelium and enhance the enterocyte monolayer integrity in vitro, suggesting its ability to enhance the thickness of the mucus layer and repair the damaged gut barrier [ 24 ].\nPreclinical studies on murine models of obesity revealed that such beneficial effects rely on its ability to increase (i) the expression of tight junction proteins; (ii) the number of goblet cells, which are specialized epithelial cells secreting mucin and creating a protective mucus layer; (iii) the thickness of the mucus layer.\nAkkermansia  also helps to preserve the epithelial barrier’s integrity by stimulating anti-inflammatory pathways [ 9 , 25 , 26 ]. In fact, from the fermentation of mucin,  Akkermansia muciniphila  produces short chain fatty acids (SCFAs) such as acetate and propionate [ 1 ], thus improving intestinal integrity and reducing endotoxemia [ 25 ] arising, for instance, from a condition of obesity [ 27 ].  Akkermansia  also participates in the host immune regulation: a preclinical study on obese mice demonstrated that  Akkermansia  may improve glucose tolerance and attenuate adipose inflammation by inducing Foxp3, which is the lineage specification factor of regulatory T cells [ 28 ] that are involved in regulating the immune response to self-antigens, allergens, commensal microbiota as well as infectious agents and tumors [ 29 ].\nNoteworthy such beneficial effects are not related only to live  Akkermansia muciniphila , but also to pasteurized  Akkermansia . The latter may enhance the gut barrier’s function and lead to the attenuation of metabolic endotoxemia. A clinical trial by Depommier and colleagues demonstrated that the oral assumption of pasteurized  Akkermansia muciniphila  in overweight or obese individuals significantly ameliorated insulin sensitivity, decreased insulinemia and plasma total cholesterol, and slightly reduced body weight compared to the placebo group. In addition, pasteurized  Akkermansia  also slightly decreased fat mass and hip circumference compared to the baseline [ 30 ].\nConsidering all the evidence, the European Food Safety Authority (EFSA) recently approved the use of pasteurized  Akkermansia muciniphila  as a safe novel food, opening to the possibility of its commercialization as a food supplement.\nOverall, the reported studies suggest that  Akkermansia muciniphila  is a promising probiotic strategy for the treatment of metabolic conditions such as obesity and diabetes. However, extending its wide use in clinical practice needs deeper critical considerations and more clinical trials to test and verify its safety and efficacy.\n\nDespite the beneficial effects on the metabolic profile, it is worth noting that in some cases the abundance of  Akkermansia  may be not effective to induce a clinical metabolic improvement, as recently reported in a study on bariatric patients [ 31 ]. In such patients with severe obesity, the increased relative abundance of  Akkermansia  observed after bariatric surgery, failed to correlate with improvements in glucose homeostasis compared to the baseline. The authors explained such discrepancy in respect to previous findings in less obese individuals, linking this result to the severity of both obesity and gut microbiota dysbiosis.\nFurthermore, in some other conditions, orally supplementing  Akkermansia  may not have the expected effects on intestinal health and clinical conditions, and therefore, considering the safety and efficacy of its widespread application is quite crucial. Indeed, a study by Dingemanse and colleagues demonstrated that in the case of  Salmonella typhimurium  infection, the procolonization of  Akkermansia  makes  Salmonella  a dominant bacterium of microbiota [ 13 , 15 ]. In addition, in a mouse model of intestinal neoplasia, a gavage with  Akkermansia  may influence the development of colorectal cancer by increasing the number and the size of tumors [ 32 ].\nInflammatory bowel disease (IBD) is another condition in which the use of  Akkermansia  should be carefully evaluated. In this condition, the gut barrier function is already compromised, and a mucin-degrader probiotic may not be the appropriate choice. This was evidenced in a preclinical study on a mouse model of IBD (IL-10 −/− ), in which the supplementation of  Akkermansia  may be not indicated due to the development of colitis [ 14 ]. A condition of prolonged intestinal inflammation, as occurs in the IBD, may be of risk for colonic tumorigenesis, and it is referred to as colitis-associated colorectal cancer (CAC) [ 33 ]. Therefore, the risk of exacerbating pathogenic infections and intestinal inflammation in conditions of compromised gut barrier functionality, is a common problem to consider before using mucin-degrading bacteria such as  Akkermansia  [ 34 ].\nNoteworthy IBD may also often occur in women suffering from endocrine and gynecological disorders such as polycystic ovary syndrome (PCOS) or endometriosis [ 35 ]. Although patients with PCOS may exhibit glucose and lipid metabolic alterations, the use of  Akkermansia  needs proper attention in this context. Indeed, these patients may also suffer from dysbiosis of the gut microbiota with chronic intestinal inflammation, which can expose them to a higher risk of developing IBD [ 36 , 37 ]. A longitudinal study found that women with endometriosis may be 80% more likely to develop IBD compared with women without endometriosis [ 38 ]. Therefore, considering that patients suffering from PCOS or endometriosis have a higher risk of developing IBD compared to healthy controls, extending the use of  Akkermansia  in the management of such diseases should be carefully evaluated on an individual basis.\nThe excessive enrichment of  Akkermansia  may alter the process of mucin degradation, thus impairing the intestinal barrier and inducing the secretion of inflammatory cytokines (IL-1β, IL-6, and TNF-α) [ 12 , 14 , 39 ]. Of course, the mucosal barrier damage and the pro-inflammatory effects of  Akkermansia  are certainly context-dependent [ 14 , 40 ], and studies on the immune-compromised model cannot be directly translated into a human context.\nHowever, considering that other studies also report controversial results in these contexts [ 41 , 42 ], further studies are needed to determine the exact role of  Akkermansia , live or pasteurized, or its metabolites, in developing colitis and CAC.\nThe extensive use of  Akkermansia  in the post-antibiotic reconstitution of the microbial community may further make the intestinal barrier’s functionality even worse. A recent study by Wang and colleagues [ 43 ] demonstrated that in the particular context of CAC, post-antibiotic  Akkermansia  replenishment exacerbates the intestinal barrier damage and increases colonic and systemic inflammation, thus interfering with the reconstitution of the intestinal microbiota and its metabolic function [ 44 ]. Once antibiotic treatments are stopped, the microbiota undergoes a dynamic rebuilding process, which is often slow and incomplete [ 45 , 46 , 47 ]. Therefore, stimulating such changing microbiota by using probiotics may be not beneficial in this phase. In this scenario, we take the opportunity to remark that probiotics should be used with caution, particularly after antibiotic treatment.\nAlong with the attention of using  Akkermansia muciniphila  in compromised intestinal conditions, recent findings from the neurologic field indicated a cautionary use of such probiotic. Different studies revealed an increase in  Akkermansia  abundance in patients suffering from Parkinson’s disease (PD) [ 16 , 48 , 49 ]. The elevated abundance of  Akkermansia  seems to be one of the features of the intestinal microbiota in such patients. In line with this, in 2017, a study found that individuals with rapid eye movement sleep behavior disorder, which is considered a pre-motor symptom of PD, exhibited elevated intestinal  Akkermansia  levels [ 50 ]. In addition, other studies revealed an increased intestinal abundance of  Akkermansia  also in subjects with multiple sclerosis (MS) [ 51 , 52 , 53 , 54 ]. Different studies demonstrated that transplanting into a mouse model of MS fecal microbiota samples from MS-affected mice, exposed to a worse disease progression compared to transplanting fecal microbiota samples from healthy controls. Although speculative, some authors hypothesized that the activation of the Toll-like Receptor 2 (TLR2) or the modulation of glucose and cholesterol homeostasis [ 9 , 25 ], induced by  Akkermansia , may determine unexpected deleterious consequences for neurological health in certain individuals. Even though PD and MS all involve the immune system as well as metabolic alterations, to date, no mechanistic studies have deeply explored this association, and evidence underpinning these observations is still lacking.\nAnother crucial aspect to bear in mind, especially when evaluating the safety of  Akkermansia , is its evolutionary potential to acquire antimicrobial resistance genes (ARGs) under antibiotic selective pressure [ 55 , 56 , 57 ].  Akkermansia  is gaining significant attention for its potential application in food supplements and pharmaceutical formulations as well as other anaerobic gut commensals associated with human health ( Bacteroides  spp.,  Clostridium butyricum ,  Faecalibacterium prausnitzii ), however, all these genera and microbial species do not have a history of safe use yet [ 58 , 59 ]. With the introduction of  Akkermansia muciniphila  in the food chain, the evaluation of the antimicrobial susceptibility of this bacterium becomes fundamental to meet the safety recommendations of EFSA. Phenotypic tests have confirmed the antibiotic resistance profile of some strains of  Akkermansia ; however, further studies involving a larger number of  Akkermansia  strains are necessary to demonstrate the safety of this microbial species, considering that the coexistence of several microbial populations in the gut provides ideal conditions for gene exchange [ 56 ].\n\nConsidering all the benefits and harms, the supplementation of  Akkermansia muciniphila  should be critically evaluated. Although it has extensive and well-proven positive effects on metabolic profiles, some different behaviors have questioned its beneficial clinical effects, as in the case of bariatric patients. In addition, some critical questions arise from (i) the use in the context of chronic intestinal inflammation, (ii) the neurologic field and (iii) the evaluation of its safety regarding the potential of carrying antimicrobial resistance. Further studies are necessary to clearly elucidate the fields of application and to delineate the safety of  Akkermansia , avoiding its use when it is unhelpful or not strictly recommended, as in the case of IBD and related endocrine and gynecological disorders such as PCOS or endometriosis, and in the case of PD and MS. It is worth bearing in mind that the administration of  Akkermansia  should be carefully evaluated on an individual basis, thus tailoring therapies on patients’ clinical conditions. Maintaining the homeostasis of gut microbiota by just providing substrates useful for bacterial proliferation, could be a safe approach without the unexpected effects.","source_license":"CC-BY-4.0","license_restricted":false}