Microbe Profile : Akkermansia muciniphila : a conserved intestinal symbiont that acts as the gatekeeper of our mucosa

Akkermansia muciniphila is an abundant inhabitant of the intestinal tract of humans and many other animals. It is the sole intestinal representative of the verrucomicrobia in human stools and depleted in adults suffering from obesity, diabetes and several other diseases. A. muciniphila degrades intestinal mucin into mainly propionic and acetic acid, and lives in symbiosis with its host, marked by signalling to immune and metabolic pathways, priming trophic chains and likely providing competitive exclusion at the host–microbe interface. Since its recent discovery, A. muciniphila has increasingly been studied and recognized as a true intestinal symbiont promoting beneficial interactions in the intestinal tract. Received 7 June 2016; Accepted 27 January 2017 Author affiliations: Laboratory of Microbiology, Wageningen University, The Netherlands; Immunobiology Research Program, University of Helsinki, Finland. *Correspondence: Willem M. de Vos, willem.devos@wur.nl Keyword: microbe profile. MICROBE PROFILE de Vos, Microbiology 2017;163:646–648 DOI 10.1099/mic.0.000444 000444 ã 2017 The Authors

TAXONOMY Domain Bacteria, phylum Verrucomicrobia, class Verrucomicrobiae, order Verrucomicrobiales, family Verrucomicrobiacaea, genus Akkermansia, species A. muciniphila, strain Muc T .Presently, A. muciniphila strain Muc T is the only cultured and deposited human representative of the genus Akkermansia.

PROPERTIES
The type strain of A. muciniphila, strain Muc T , has been isolated under strict anaerobic conditions from a faecal sample of a healthy adult by using purified mucin as the sole carbon, nitrogen and energy source.It is an obligate chemoorganotroph optimally growing at 37 C in anaerobic conditions with a preference for mucus as substrate, yielding doubling times of approximately 1 h.Mucus is degraded by a large set of secreted mucolytic enzymes and its major sugar components, including N-acetyl galactosamine and N-acetyl glucosamine, are converted into the major end products propionate and acetate [1].

GENOME
The complete 2 664 102 bp genome of A. muciniphila Muc T has been determined and found to encode a large secretome that included over 25 % of all predicted proteins, 61 of which were predicted to be involved in mucin [2].The availability of the genome of strain Muc T has sparked various studies into its evolution, distribution and function.Metaproteome analysis revealed A. muciniphila to be highly active in a subject carrying a high level (12 %) of Akkermansia, revealing a set of hundreds of proteins, some of which are present in the outer membrane, including a 33 kD protein that partly recapitulates the beneficial effects of A. muciniphila in a preclinical model (see below; [3][4][5]).

PHYLOGENY
Comparison with genomes of other Verrucomicrobia (sizes from 2.2 to 8.2 Mb) revealed A. muciniphila Muc T to share only very little similarity, indicating a deep rooting.Detailed analysis of human metagenomic datasets suggested the presence of other Akkermansia genomes that have less than 88 % average nucleotide identity with the A. muciniphila genome, suggesting the existence of other human species [2].However, misassembly of short reads, sequence errors and co-occurrence of multiple strains in a single subject cannot be ruled out.The ubiquitous presence of a single species with limited genomic variation in a range of mammals testifies a high level of specialized adaptation to the mucosal environment and is indicative of a conserved symbiosis between A. muciniphila and its hosts [4].

KEY FEATURES AND DISCOVERIES
While mucus degradation has been associated with a potential pathogenic lifestyle, it should be considered that this glycoprotein is highly abundant in the colon and may represent approximately half of the carbon that is found in the human colon.Hence, specialized microbes have been selected that can degrade this complex glycoprotein and live in symbiosis with the host, notably in the mucosal layer that protects the intestinal cells.A. muciniphila is a prime example of the symbiosis that is conserved in many mammalian species and is capable of priming trophic chains (graphical abstract figure).
In a healthy human, A. muciniphila is present in high levels (approximately 3 %) in the adult colon, rendering it one of the most abundant intestinal species and testifying its apparent safety.Moreover, A. muciniphila can be found in all age groups and its capacity to grow on human milk supports its close association with the intestinal tract.Remarkably, A. muciniphila is depleted in faecal samples from adults suffering from a variety of diseases, including obesity, metabolic syndrome and diabetes.Evidence for its impact on the host originated from analysing the transcriptional response of germ-free mice mono-associated with A. muciniphila that showed increased immune and metabolic signalling, indicating specific host-microbe cross-talk [4,5].
A landmark discovery has been the finding that A. muciniphila or a specific 33 kDa outer membrane protein protected mice from diet-induced obesity, increased the mucosal barrier function and reduced insulin resistance as well as intestinal and systemic inflammation [5].Moreover, recent studies revealed that A. muciniphila binds human intestinal cells and increases barrier function, while human dietary intervention studies indicated A. muciniphila to be an indicator of a healthy metabolic status [5].
Since the isolation of A. muciniphila a dozen years ago, the research on this intestinal symbiont has come of age and attracted considerable interest for its physiology, genomics and ecology.Its impact in model animals and intestinal model systems has to be further confirmed and extended.Presently, a human safety and dose-finding trial is ongoing to provide causal relations and may result in the development of A. muciniphila as a next-generation therapeutic microbe with a wide spectrum of applications ( [5]; see www.clinicaltrials.gov).

KEY QUESTIONS
. How widely spread is the conserved symbiosis between A. muciniphila and the mammalian host? .What other Akkermansia species exist and how do they differ at the genomic, physiological and symbiotic level from A. muciniphila? .What are the signalling mechanisms by which A. muciniphila interacts with human and other hosts? .What trophic chains are induced by A. muciniphila and its degradation of mucus? .Can delivery of A. muciniphila alone or in combination with other microbes be used in therapies to increase barrier function, reduce inflammation and cure diseases?