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Page 8 of 19 Misera et al. Microbiome Res Rep 2024;3:48 https://dx.doi.org/10.20517/mrr.2023.81

A. MUCINIPHILA AND STRESS MANAGEMENT
Psychobiotic potential and challenges
Live psychobiotics have certain limitations concerning their standardization and shelf-life stability [73,74] . The
alternative is using postbiotics, which contain inactivated microorganisms and/or their components . One
[75]
[76]
novel postbiotic that interests scientists and clinicians is pasteurized A. muciniphila . These bacteria are
produced by anaerobic growth followed by pasteurization and freeze-drying. A. muciniphila is an anaerobe
and Gram-negative bacterium, with an approximate gut relative abundance of 1% to 3%; however, the
abundance of this bacterium is variable and can be much lower in many individuals and some may not
harbor it. A. muciniphila subsists in the intestinal mucus layer and contacts epithelial cells at the top of villi.
Intestinal mucins are a significant carbon and nitrogen source for producing SCFAs like acetate and
propionate .
[77]
Since its discovery, A. muciniphila has been used successfully in multiple clinical phenotypes,
predominantly of metabolic origin . Discovering the mechanism through which pasteurized
[78]
A. muciniphila works has been the subject of several experimental studies. When pasteurized A. muciniphila
was administered to mice, colitis-associated colorectal cancer progression was delayed via modulating
[79]
CD8+ T cells . Experiments suggest that a major mechanism is exerted through interacting with the host
intestinal epithelial cell via the TLR2 directly with the protein Amuc_1100 [80-82] . Pasteurized A. muciniphila
attenuated inflammatory response in Caco-2 cell monolayers: it enhanced AMP-activated protein kinase
(AMPK) activation and inhibited nuclear factor-kappa B (NF-κB) . A. muciniphila and Amuc_1100 were
[83]
reported to regulate the kynurenine pathway involved in several mental processes . Ottman et al. found
[84]
[85]
[86]
that Amuc_1100 significantly increased trans-epithelial electrical resistance (TEER) in vitro . It has also
been found that Amuc_1100 treatment in mice lowered the expression of CNR1, encoding the cannabinoid
receptor 1 (CB1) in the jejunum , thus increasing gut barrier integrity . Through these studies,
[80]
[87]
pasteurized A. muciniphila is emerging as a novel postbiotic with potential psychobiotic activity and
particularly stress-management benefits.
Review of experimental evidence
Pasteurized A. muciniphila was experimentally demonstrated to restore gut barrier integrity, a key element
[88]
of the proper flow of signals within the MGBA . Additionally, a body of evidence exists to link TLR
signaling with stress response and psychiatric phenotypes [89-93] . Thus, a postulation on the potential use of
A. muciniphila was made to reduce the negative effects of stress in animals and humans. However, a limited
number of studies have aimed to assess such potential and exclusively in animal models.

One of the very first analyses was conducted by Chen et al. in male C57BL/6N mice, which were subjected
to chronic restraint stress (CRS), an established protocol to achieve a mouse model of depression, and
[94]
further given dextran sodium sulfate (DSS) to induce colitis . In the second stage of the experiment, mice,
after microbiota depletion with the ABX cocktail, received fecal microbiota transplantation (FMT) with
A. muciniphila (1 × 10 CFU/mL). The experiments showed that overall CRS induced behavioral deficits, as
9
evaluated by open field test (OFT), tail suspension test (TST), and forced swim test (FST). It was found that
DSS, but not CRS, diminished gut microbiota diversity. Nevertheless, at the phylum and genus levels, major
alterations for the CRS group and in the DSS + CRS group compared to controls were found. FMT from
CRS mice induced depression in recipient mice, but A. muciniphila implementation improved the scores in
behavioral tests. In the DSS + CRS group, A. muciniphila supplementation elongated the colon and reduced
the histopathological scores. A. muciniphila also improved mucosal barrier defects induced by FMT from
CRS mice and rescued MUC2 gene expression and elevated the number of goblet and MUC2-positive cells
in each villus. A higher alpha diversity on the Shannon Index metric was demonstrated in mice receiving
DSS and A. muciniphila. Notably, A. muciniphila increased the relative abundance of Verrucomicrobia and