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Kumar et al. Microbiome Res Rep 2024;3:37 https://dx.doi.org/10.20517/mrr.2024.28 Page 5 of 8

beneficial effects on health, including positive impacts on cardiometabolic health, inflammation, gut barrier
integrity, outcomes to checkpoint blockade response in cancer immunotherapy, homeostatic immunity, and
maintenance of microbial balance in the gut [16,17] . Research on Akkermansia is moving beyond association
studies, with research increasingly focusing on the elucidation of the mechanisms underlying efficacy.
Several possible mechanisms have been published to demonstrate the dynamics of this commensal in the
gut. Plovier et al. have shown very elegantly the role of an outer membrane protein Amuc_1100 in
metabolic and gut health . Yoon et al. have identified another factor, P9 protein encoded by Amuc_1631,
[18]
[19]
which interacts with ICAM2 and stimulates GLP1 secretion . Recently, it has been shown that mediated
production of a tripeptide [Arg-Lys-His (RKH)] can negate inflammation via TLR4 in a sepsis model . Bae
[20]
et al. have identified an active lipid molecule from the A. muciniphila membrane and the immunogenic
activity of diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE) has been shown to
be via an unexpected toll-like receptor TLR2-TLR1 heterodimer . Interestingly, Kumar et al. have shown
[21]
variation in a15:0-i15:0 PE between A. muciniphila and A. massiliensis sp. nov., where A. massiliensis sp.
nov. shows a higher abundance of a15:0-i15:0 PE as compared to A. muciniphila . It will be worth
[13]
investigating the impact of differential abundance of a15:0-i15:0 PE on the immunogenic properties of
different Akkermansia strains.

Bacterial-derived extracellular vesicles have been investigated for their impact on physiological functions.
Chelakkot et al. investigated the role of A. muciniphila-derived extracellular vesicles (AmEV) and showed
that AmEV administration enhanced tight junction function, reduced body weight gain, and improved
glucose tolerance in high-fat diet-induced diabetic mice . What is unknown at present is whether AmEV
[22]
serve as carriers for any of the possible effector molecules such as a15:0-i15:0 PE, Amuc_1100, and P9 or
they act via another mechanism to provide the described benefits.

Advances in sequencing and bioinformatic tools have resulted in the identification of new Akkermansia
phylotypes or species and highlighted the genomic and phenotypic diversity in the genus Akkermansia. The
actual isolation of such novel Akkermansia strains enables further exploration in the field with the objective
to understand if this variation is associated with unique properties and health benefits of the different
Akkermansia species and phylotypes. This diversity also provides the opportunity to identify new
mechanisms of action to understand differences in interaction between Akkermansia species and the host,
raising interesting questions about the relative expression of effector molecules between different species
and how this may impact efficacy. Recently, Kumar et al. have shown the health benefits of A. massiliensis
[13]
sp. nov. in a DIO mouse model and have highlighted several new possible mechanisms of action . They
have shown that A. massiliensis sp. nov. can degrade extracellular adenosine triphosphate (eATP). It has
been shown that eATP is a key inducer of inflammation in the gastrointestinal tract and is strongly
associated with inflammatory bowel disease . Extracellular ATP limits T follicular helper cells in the
[23]
Peyer’s patches and thereby limits SIgA generation; thus, the degradation of eATP mediated by
Akkermansia sp. in the lumen may play a vital role in modulating the immune structure in the gut .
[24]
Kumar et al. also described microbial agmatine production by the A. massiliensis sp. nov. strain, and
agmatine has been shown to have metabolic and neuroprotective effects [13,25] . The in vitro production of
agmatine was higher with A. massiliensis sp. nov. compared to A. muciniphila based on relative area
concentrations. Pryor et al. have demonstrated that microbial agmatine is a major contributor to the
agmatine pool in the gastrointestinal tract . If it can be shown that Akkermansia contributes to this pool,
[25]
then exploring the role of Akkermansia in relation to the gut-brain axis presents an interesting avenue to
explore. Further in vivo studies are needed to validate the physiological significance of eATP degradation
and agmatine production by Akkermansia sp.