European Review for Medical and Pharmacological Sciences 2019; 23: 8075-8083 Akkermansia muciniphila: key player in metabolic and gastrointestinal disorders I.G. MACCHIONE1,2, L.R. LOPETUSO1,2, G. IANIRO1,2, M. NAPOLI1,2, G. GIBIINO1,2, G. RIZZATTI1,2, V. PETITO1, A. GASBARRINI1,2, F. SCALDAFERRI1,2 1Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Rome, Italy 2UOC Medicina Interna e Gastroenterologia, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Abstract. – OBJECTIVE: Gut microbiota has as the “gut microbiota”, has been estimated to a key role in host metabolic regulation and im- exceed 1014 microorganisms, which encompasses mune response, and its dysbiosis represents ~10 times more bacterial cells than the number one of the main causes of gastrointestinal dis- of human cells and over 100 times the amount eases. In this scenario, Akkermansia muciniph- of genomic content (microbiome) as the human ila is a crucial player in keeping the integrity of 1,2 the gastrointestinal tract. genome . MATERIALS AND METHODS: This review fo- Latest evidence supports the role of gut micro- cuses on the correlation between gut microbio- biota in several host functions, and this dysbiotic ta and intestinal homeostasis, primarily explor- condition has been linked to cardiovascular dis- ing A. muciniphila and its involvement in the de- ease, neurodegenerative conditions, psychiatric velopment of metabolic disorders and gastroin- disorders, and autoimmune conditions3-6. testinal diseases. 7,8 RESULTS: Akkermansia muciniphila belongs to Early studies sought to identify the normal the Verrucomicrobia phylum, and it colonizes the set of microbes that colonizes healthy people, mucus layer in the gastrointestinal tract, repre- by culture and characterization of physiological senting 1 to 4% of the fecal microbiota. It stimu- properties. The introduction of strictly anaerobic lates mucosal microbial networks, and it improves techniques in the 1970s allowed the recovery of intestinal barrier function, providing crucial host immunological responses. Several studies have more than 300 bacterial species. demonstrated the possible involvement of A. mu- Then, above all, the introduction of 16SrRNA ciniphila in the development of intestinal and met- profiling studies provided invaluable insights into abolic disorders. Indeed, adipose and glucose the taxonomic composition of the gut microbio- metabolisms are influenced by A. muciniphila, ta, which in turn has facilitated the inference of and its levels inversely correlate to inflammatory conditions, such as inflammatory bowel disease, broad evolutionary patterns. However, species obesity, and diabetes. Conversely, its therapeutic diversity may only present the top of the iceberg administration decreases their development. of microbial complexity in the gut9-12. Recent CONCLUSIONS: A. muciniphila exerts a key studies applying methods that go beyond the typ- role in the maintenance of intestinal health and ical 16SrRNA profiling approach have provided in host metabolic modulation. Future studies compelling evidence that the bacterial species of could open new horizons towards its potential therapeutic applications in gastrointestinal and the gut microbiota are composed of a multitude of extra-intestinal diseases. strains, which are likely to influence gut microbi- Key Words: ota functions. Akkermansia muciniphila, Gut microbiota, Gastro- Despite variability in species composition, the intestinal diseases, Metabolic diseases, Obesity, IBD, mammalian gut microbiota is dominated by rela- Colitis. tively few bacterial phyla, including Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Introduction and Verrucomicrobia. Each phylum is generally classified in a hierarchical manner into sub-phy- The collection of bacteria, Archaea and Eu- la, classes, orders, families, genera, and finally karya colonising the GI tract, usually known species and strains. Some of the earliest efforts to Corresponding Author: Franco Scaldaferri, MD; e-mail: [email protected] 8075 I.G. Macchione, L.R. Lopetuso, G. Ianiro, M. Napoli, G. Gibiino, et al. sequence 16SrRNA genes directly from samples survival when exposed to atmospheric oxygen, so showed that 85-95% of bacterial abundance cor- that it can be defined as an aerotolerant anaerobic responding to known species could be attributed bacterium. to three bacterial groups related to Bacteroides, A. muciniphila encodes for 567 secreted pro- Clostridium cluster XIVa, and Clostridium clus- teins, such as sugar hydrolase, sialidase, and ter IV13,14. sulfatase, which are involved in mucin utilization. Among these, Verrucomicrobia belongs to the It is thus considered a mucin-degrading bacteri- Planctomycetes-Verrucomicrobia-Chlamydiae um31. In fact, intestinal mucins, the highly gly- bacterial superphylum15. The first microbe of this cosylated proteins of the epithelial mucus layer, phylum, Akkermansia muciniphila, was original- represent the main source of carbon and nitrogen ly isolated from a fecal sample from a healthy for this species16 that can be found in high num- female in a specific medium that contained pu- bers in mucosal biopsy specimens of the human rified mucins, sole carbon source, suggesting colon32. Moreover, A. muciniphila has been found specific metabolic properties located in the inter- to have a role not only in mucins biodegradation, face between the luminal bacteria and the host16. but also in stimulating mucin production33,34. Be- Since then, many functions were hypothesized to cause of its influence on mucin metabolism and support the role of Verrucomicrobia in the mod- consequently on the thickness of the mucus layer, ulation of metabolism in the human host. In this a crucial role of A. muciniphila in gut barrier review, we will summarize the current evidence function is easy to be hypothesized. Indeed, it has on Verrucomicrobia, gut pathophysiology, and been demonstrated that A. muciniphila is depleted metabolic disorders. in patients affected by inflammatory bowel dis- ease (IBD), in which a reduction in barrier func- The Verrucomicrobia Phylum tions has been largely proved35,36. A. muciniphila Verrucomicrobia are Gram-negative bacteria reduction has been shown in ulcerative colitis belonging to the Planctomycetes, Verrucomi- (UC) and Crohn’s disease (CD), both in clinically crobia, Chlamydiae (PVC) superphylum, that is active disease and during remission35,36. A study a group of six bacterial phyla: Planctomycetes, of 2011 also demonstrated an inverse correlation Verrucomicrobia, Chlamydiae, Lentisphaerae, between A. muciniphila levels and the severity of Poribacteria, and OP317,18. The bacteria from acute appendicitis37. this superphylum were previously suggested Moreover, Reunanen et al30 examined the ef- to have a compartmentalized cell plan with a fects of A. muciniphila on in vitro colonic cells cytoplasmic membrane as the outermost mem- lines Caco2 and HT-29, highlighting the capacity brane, and an intracytoplasmic membrane con- of this bacteria to adhere to the epithelium and taining a condensed nucleoid and ribosomes19. to strengthen the intestinal barrier. The same However, more recently it has been suggested study showed that A. muciniphila can induce that these bacteria have an outer and an inner a weak pro-inflammatory activity stimulating membrane (IM) with possible invaginations enterocytes production of interleukin 8 (IL-8) at of the IM inside the cytoplasm, representing a cell concentrations 100-fold higher than those of variation and not an exception of the Gram-neg- E. coli. Thus, this bacterium does not activate a ative cell plan20. strong inflammatory cascade in the epithelium Verrucomicrobia phylum is involved in but seems to be able to keep the mucosa-asso- soil-based environments21, in aquatic environ- ciated immune system alerted at an appropriate ments22,23 and, not secondarily, is associated with level. These results are in line with other in vivo eukaryotic species24-27. studies that link A. muciniphila to a non-inflamed Akkermansia muciniphila belongs to this phy- mucosa35,36 and suggest important host-bacteria lum, a bacterium that shares only very little simi- interactions involved in the maintenance of host larity with Verrucomicrobia genomes, indicating immune response. how this phylum includes a vast bio-diversity of Moreover, A. muciniphila has a crucial role in species28. metabolic homeostasis. Studies on animals38-40 A. muciniphila colonizes the mucus layer of the showed a lower abundance of A. muciniphila human gastrointestinal (GI) tract (12) and consti- in mice fed with high-fat diet (HFD), obese tutes 1 to 4% of the fecal microbiota29. It is con- mice, and with type 2 diabetes-like symptoms. sidered to be an anaerobic bacterium, although These results were confirmed by clinical trials a more recent study30 showed that it has a good that reported a negative correlation between A. 8076 Akkermansia muciniphila: key player in metabolic and gastrointestinal disorders muciniphila and dietary fat intake, serum total diet for one year, when compared to lean, nor- cholesterol, and LDL41. A possible role of A. mal-weight individuals at baseline. However, the muciniphila in preventing metabolic disorders ratio returned to normal in those individuals who was supposed by a study42 on HFD fed mice, had successful