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Page 2 of 19 Misera et al. Microbiome Res Rep 2024;3:48 https://dx.doi.org/10.20517/mrr.2023.81

INTRODUCTION
Akkermansia muciniphila mucin degradation and psychobiotic mechanisms of action
Generally, mucin degradation in the digestive tract has been considered harmful to host health. However,
Akkermansia muciniphila (A. muciniphila), a mucus-degrading bacterium of human gut microbiota,
[1]
benefits one’s physiology . An increasing amount of evidence indicates that this bacterium has beneficial
systemic effects on host health, primarily by enhancing immunological and metabolic functions, making it a
[2]
promising potential probiotic . Recent clinical and preclinical research has demonstrated that
A. muciniphila also plays a crucial role in various neuropsychiatric disorders by affecting the host brain
[3]
through the microbiota-gut-brain axis (MGBA) . Recently published reviews have described that
A. muciniphila and its metabolic products can effectively alleviate symptoms of neuropsychiatric disorders
like depression, anxiety, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, strokes, and autism
spectrum disorders by restoring gut microbiota, repairing the gut mucosal barrier, regulating host
immunity, and modulating gut and neuroinflammation . The supplementation of A. muciniphila boosts
[3,4]
host metabolism, and the outer membrane protein Amuc_1100 plays a pivotal role . Importantly,
[5]
Amuc_1100 binds with Toll-like receptor 2 (TLR2) to further lower the expression of serotonin reuptake
transporter (SERT) and increase 5-hydroxytryptamine (5-HT) as evidenced in Caco-2 cells and mice .
[6]
These metabolites, in turn, affect emotional states and have been linked to depression, anxiety, and
[7,8]
potentially other psychiatric illnesses . It is noteworthy that A. muciniphila contains not only Amuc_1100,
but also so-called A. muciniphila-derived extracellular vesicles (EVs), which can possibly enhance its
biological effects . Additionally, EVs could play some role in mediating the psychobiotic effects of the
[9]
bacterium . EVs synthesized in psychobiotic bacteria cells were found to induce many central nervous
[10]
system (CNS)-linked effects. For instance, in a study by Yaghoubfar et al., a 4-week administration of EVs
resulted in an increase in the serotonin pool in the colon and hippocampus in mice and in a Caco-2 cell line
while decreasing it in serum . Moreover, EVs affected the mRNA expression of genes involved in
[11]
serotonin signaling and its metabolism in the colon and hippocampus and the mRNA expression of IL-10
and TNF-α in the colon of the mice. The 4-week treatment is comparable to the time necessary to achieve
therapeutic benefits with other antidepressants . Notably, the metabolic benefits observed with EVs were
[12]
more pronounced than those achieved with live or pasteurized A. muciniphila cells . This might occur due
[9]
to the increased bioavailability of active substances (and their higher concentrations), which more readily
interact with host cells due to their small size and ability to cross biological barriers. This allows the
bioactive components within EVs to reach target sites more efficiently than whole bacterial cells.
Additionally, EVs provide a stable and protected environment for their cargo, ensuring that the bioactive
molecules are delivered intact to the target cells. This stability can improve the efficacy of the therapeutic
components compared to those released from whole cells, which might degrade in the gut environment [13,14] .

Overall, the benefits of harboring A. muciniphila might not only be due to mucus degradation promoting
the renewal of the mucus layer and maintaining gut barrier function, but also because of the production of
EVs that can interact with the host’s gut epithelium, improving gut barrier function, reducing body weight
gain, and enhancing glucose tolerance. Other mechanisms that have been proposed include :
[9]

1. Pilus-associated signaling (PAS) protein (Amuc_1100), which can interact with host immune receptors
like TLR2-, enhancing gut barrier function and having immunomodulatory effects, including reducing
inflammation and promoting the production of beneficial cytokines.
2. Short-chain fatty acids (SCFAs) affecting gut health by interacting with host receptors (e.g., FFAR2,
FFAR3) to regulate inflammation and gut hormone release.
3. Metabolite Harmaline modulating host immune responses, enhancing bile acid signaling and reducing
inflammation.
4. Glucagon-like peptide-1 (GLP-1)-inducing protein (P9) involved in regulating glucose homeostasis and