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Page 2 of 18 Mueller et al. Microbiome Res Rep 2024;3:33 https://dx.doi.org/10.20517/mrr.2024.09

the genus Akkermansia into several species. In addition, A. muciniphila sensu stricto, the most prevalent Akkermansia
species in humans, should be subdivided into two subspecies. For a pediatric cohort, we observed species-specific
correlations between Akkermansia abundance with baseline obesity or after various interventions. For inflammatory
bowel disease cohorts, we identified a decreased abundance of Akkermansia in patients with ulcerative colitis or
Crohn’s disease, which was species and subspecies-dependent. In patients undergoing immune checkpoint
inhibitor therapies for non-small cell lung carcinoma, we observed a significant association between one A.
muciniphila subspecies and survival outcomes.

Conclusion: Our findings suggest that the prevalence of specific Akkermansia species and/or subspecies can be
crucial in evaluating their association with human health, particularly in different disease contexts, and is an
important consideration for their use as probiotics.

Keywords: Akkermansia, phylogeny, microbiome, IBD, obesity, immunotherapy

INTRODUCTION
Akkermansia muciniphila (A. muciniphila) is a Gram-negative, mucin-degrading bacterium that is prevalent
[1,2]
in the mammalian gastrointestinal tract . The relative abundance of A. muciniphila is associated with
improved human health in a variety of contexts, such as obesity, metabolic disorders, responsiveness to
cancer therapy, seizures, neuroinflammation, inflammatory bowel disease, and healthy aging [3-12] . Indeed,
these associations with positive health outcomes have generated interest in developing A. muciniphila into a
new class of probiotic for the treatment and prevention of multiple metabolic and immunological
disorders [13-16] .

T
Most studies on the biology of A. muciniphila have focused on the original Muc (BAA-835) strain, which
was isolated from human stool in the Netherlands [1,2,17,18] . When additional A. muciniphila isolates became
available, Guo et al. first proposed three genetically distinct sub-species-level phylogroups, AmI, AmII, and
AmIII . As more isolates and genome sequences became available, additional phylogroups were proposed,
[19]
including AmIV and AmV [20,21] . In addition, the A. muciniphila AmI phylogroup could be further
[20]
subdivided into two sub-phylogroups, AmIa and AmIb . Whole-genome analyses revealed potential
phylogroup-specific metabolic differences. These were confirmed through the characterization of
representative isolates demonstrating variations in growth rates in mucin medium, aerotolerance, ability to
metabolize human milk oligosaccharides, vitamin B production, and activation of toll-like receptors
12
(TLR) [20-23] . Based on the comparison of additional genomes from newly isolated human strains and near
complete metagenome-assembled genomes (MAGs), there is an emerging consensus that genomes that
were originally referred to as A. muciniphila should be sub-divided into several distinct species based on
whole-genome nucleotide identity or conserved gene alignment [24-28] . Not all sub-species terminology used
has been consistent with the original description of Akkermansia phylogroups , and the overlap in
[19]
genomes used between studies has been limited. Recently, it was proposed that the AmIV phylogroup met
the criteria of a new species of Akkermansia and was renamed Akkermansia biwaensis (A. biwaensis) . A
[29]
similar proposal was made for the AmII phylogroup to be renamed Akkermansia massiliensis
[30]
(A. massiliensis) . For consistency, we will refer to the AmII phylogroup as A. massiliensis and the AmIV
phylogroup as A. biwaensis. Whether this assignment of new Akkermansia species or A. muciniphila
phylogroups leads to different health outcomes remains an open question, especially since only one
Akkermansia species at a time predominates within a single human host . Of note, most reports exploring
[20]
the role of A. muciniphila in human trials or preclinical murine models have focused on the AmIa strain
Muc T[15,31] .