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Page 10 of 19 Misera et al. Microbiome Res Rep 2024;3:48 https://dx.doi.org/10.20517/mrr.2023.81

behavioral deficits significantly, which was not observed with FLX treatment, but the authors did highlight a
high statistical tendency toward such. 5-HT levels in the serum and colon increased in FLX and Amuc_1100
interventions compared to CUMS-only group. When the dorsal raphe nucleus (DRN) involved in serotonin
synthesis was immunohistochemically analyzed, it was revealed that both interventions elevated the process.
The neurocompetent factors: BDNF, CREB1, and 5-HTR1A expression were restored following CUMS
exposure when A. muciniphila and FLX were administered.

Similarly, the hippocampal expression of pro-inflammatory cytokines (IL-6, IL-1B, TNF-α), initially
elevated by CUMS, lowered significantly in both treatment groups. CUMS diminished the diversity of gut
microbiota to a large, but not significant, extent as compared to control mice. The abundance of
Bacteroidota was lowered, and the Firmicutes increased in the CUMS group, and both FLX and Amuc_1100
interventions ameliorated these changes. The other CUMS-mediated alterations (higher counts of Clostridia
and lower of Bacteroidia) were only partly and non-significantly recapitulated by FLX and Amuc_1100 .
[96]

Similarly, stress induction, in the form of CUMS, and chronic alcohol exposure were utilized in a study by
Guo et al. . C57BL/6J specific pathogen free (SPF) mice were treated with A. muciniphila (2.5 × 10 CFU/
[97]
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200 μL) via oral gavage for five weeks. A. muciniphila improved the loss of weight post alcohol exposure,
immobility time in TST, and sucrose preference in the sucrose preference test (SPT). In addition, such
bacterial supplementation diminished the liver enzyme elevation induced by alcohol. Stress induced via
alcohol and CUMS was alleviated with A. muciniphila, which was confirmed by decreasing immobility time
in FST and TST and an elevated preference toward sucrose in the SPT. However, A. muciniphila did not
alter the mice’s global locomotor abilities, anxiety, or fear memory. The tested intervention increased 5-HT
in the prefrontal cortex and the gut, as the expression of the rate-limiting enzyme of 5-HT was not altered
between A. muciniphila and vehicle-treated mice exposed to alcohol. On the other hand, it was decreased in
the case of CUMS. Consequently, this proved that A. muciniphila enlarges the serotonin pool independently
of this limiting bio-catalyzer. A. muciniphila gavage also inhibited the expression of serotonin transporter in
the gut but not in the brain for both stress model mice, which can further be responsible for elevated
serotonin pool. A. muciniphila also decreased the expression of cFos in enteric nerves, pointing out that
[98]
such intervention impacts gut-to-brain signaling through these nerves. To add, a very recent study
pointed out that modified Amuc_1100 (Amuc_1100Δ80 without 80 N-terminal amino acids with higher
affinity for TLR2 as compared to Amuc_1100) in a mouse model of CUMS also upregulated a tryptophan
hydroxylase 1 (Tph1) limiting serotonin expression in the gut. Furthermore, as evidenced by this group
previously , the intervention downregulated the 5-HTR1A-CREB-BDNF signal pathway and restored gut
[96]
microbiota composition post CUMS exposure. Interestingly, Amuc_1100Δ80 diminished the inflammatory
state and downregulated the HPA axis, consequently improving rodent depressive-like behavioral deficits.

In a study by Sun et al., depressive and anxious behaviors were induced via an antibiotic cocktail (ABX;
[8]
Ampicillin, Streptomycin, and Clindamycin;1 g/L) administration lasting three weeks . One study group
9
received A. muciniphila (1.5 × 10 CFU/200 μL) per day, while the other was gavaged with the Amuc_1100
protein (100 μg/200 μL) per day, and these periods lasted two weeks. ABX was administered continuously
during the intervention period. During a series of behavioral tests, it was shown that A. muciniphila/
Amuc_1100 alleviated depression-like behavioral deficits induced by the ABX. Specifically, in an OFT, the
number of entries into the center and time spent there were significantly elevated in Amuc_1100-treated
mice as compared to the group treated with ABX only. The similar observation was recorded in the case of
time spent in a lightbox; however, in the case of the entries into the lightbox, a significant improvement was
also found for the A. muciniphila-treated group compared to solely ABX-treated mice. As for immobility in
the TST, similar improvements were noted, but in the FST, only Amuc_1100 treatment significantly