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Misera et al. Microbiome Res Rep 2024;3:48 https://dx.doi.org/10.20517/mrr.2023.81 Page 9 of 19

Ruminiclostridium. This study concluded that CRS-induced dysbiosis damages colonic mucus and induces
the development of colitis along with a depressive phenotype and that A. muciniphila might inhibit the
aggravation of colitis and improve the behavioral deficits associated with depression in mice.

Another study in an animal model by Ding et al. was conducted using C57BL/6 male mice aged 6-8
weeks . Three groups of rodents were analyzed: mice subjected to CRS (3 weeks), mice not subjected to
[95]
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CRS, and mice treated with A. mucinphila after CRS (3 weeks, 5 × 10 CFU/mL via oral gavage). After the
treatment protocol, mice were subjected to behavioral tests and hippocampal biospecimens were collected
to analyze hormones, neurotransmitters, and brain-derived neurotrophic factor (BDNF) RNA expression.
Blood was taken to evaluate serum untargeted metabolome and hepatic and renal biochemical parameters.
Additionally, cecal microbiota was analyzed using the next generation sequencing (NGS) amplicon-based
technique. It was observed that mice treated with A. muciniphila exhibited a significant improvement in the
OFT, TST, and FST behavioral tests compared to mice with CRS exposure only. In gene expression
analyses, A. muciniphila intervention diminished the level of corticosterone release after CRS exposure,
along with elevation in serum dopamine and hippocampal BDNF but not serum serotonin levels.

The differences were significant regarding the CRS exposure group. As far as gut microbiota composition is
concerned, differences in structure were found (A. muciniphila vs. CRS-only groups: higher abundance of
Verrucomicrobia, lower of Epsilonbacteraeota, Patescibacteria, Chloroflexi, and Acidobacteria; genus level:
lower of Helicobacter, Candidatus_Saccharimonas, Eubacterium_brachy_group, and Lachnoclostridium).
However, the principal component analysis revealed no differences between the groups. In a functional
prediction approach, pathways linked to neurodegenerative diseases were inhibited in the CRS +
A. muciniphila compared to the CRS-only group. Additionally, the CRS + A. muciniphila group exhibited a
lowered abundance of genes involved in tryptophan metabolism, geraniol degradation, caprolactam
degradation, fluorobenzoate degradation, and Parkinson’s disease. Metabolites between all three groups
clustered differently. CRS and CRS + A. muciniphila groups differed in metabolites linked to cholinergic
synapse, fat digestion and absorption, degradation of aromatic compounds, fatty acid degradation, vitamin
digestion and absorption, butanoate metabolism, carbon metabolism, pantothenate and CoA biosynthesis,
metabolic pathways, and digestion and absorption. In correlation analyses, it was found that A. muciniphila
abundance in the gut positively correlated with β-alanyl-3-methyl-l-histidine, edaravone, and 2”,3”,6”-Tris-
O-(3,4,5-trihydroxybenzoyl)-3’-glucosyl-2’,4’,6’-trihydroxyacetophenone. In addition, a negative correlation
with respect to 2-pyrrolidineacetic acid and amino pyrrolnitrin was observed. β-Alanyl-3-methyl-l-histidine
and edaravone were upregulated in CRS + A. muciniphila group; thus, in the final part of this study, these
agents were administered to CRS mice to observe the effects. In two out of three behavioral tests, this
administration significantly improved the results compared to the CRS-only group. β-Alanyl-3-methyl-l-
histidine lowered the corticosterone level while edaravone serum elevated serotonin concentration. Both
metabolites improved hippocampal BDNF expression but not significantly compared to the CRS-only
group. The study further supported that A. muciniphila can abolish the effect of CRS via the regulation of
hormones, neurotransmitters, and BDNF levels, as well as modifications in gut microbiota and serum
metabolism.

The effects of the Amuc_1100 protein, located on the outer membrane of the A. muciniphila, in mouse
[96]
models of depression were investigated in another experiment . Depression-like behavior was induced in
C57BL/6 mice by exposure to six-week-long chronic unpredictable mild stress (CUMS), which is meant to
mimic daily life stressors. Four groups were analyzed: control, CUMS, CUMS + antidepressant fluoxetine
(FLX) (20 mg/kg), and CUMS + Amuc_1100 (80 µg/day). Treatments were administered by oral gavage
during or after CUMS. Treatment with Amuc_1100 at both time points improved the CUMS-induced