Fecal Transplantation Can Alleviate Tic Severity in a Tourette Syndrome Mouse Model by Modulating Intestinal Flora and Promoting Serotonin Secretion
Tourette syndrome (TS) is a chronic neurological disorder characterized by recurrent motor and vocal tics, typically emerging in childhood. Despite various therapeutic interventions, the management of TS remains challenging due to inadequate control of tics and adverse side effects associated with current treatments. The exact etiology of TS is not fully understood, but evidence suggests dysfunctions in dopaminergic pathways, cortical inhibition deficits, and abnormalities in cortico-basal ganglia-thalamo-cortical loops. Recent research has highlighted the role of the gut microbiota in neurological and psychiatric disorders through the microbiota-gut-brain axis. This study explores the potential of fecal microbiota transplantation (FMT) as a therapeutic intervention for TS, using a mouse model to investigate its effects and underlying mechanisms.
Introduction
TS is a neuropsychiatric disorder with a complex and multifactorial etiology. While current therapies, including pharmacological and behavioral interventions, provide some relief, they often fall short of adequately managing symptoms. The gut microbiota has emerged as a critical player in brain function and behavior, influencing conditions such as depression, autism spectrum disorder, and Parkinson’s disease. The microbiota-gut-brain axis, a bidirectional communication system between the gut and the brain, offers a novel avenue for therapeutic exploration. FMT, which involves transferring fecal microbiota from a healthy donor to a recipient, has shown promise in treating conditions like autism and epilepsy. This study aims to investigate whether FMT can alleviate TS symptoms in a mouse model and elucidate the mechanisms involved.
Methods
Ethical Approval
The study was conducted in compliance with ethical standards and approved by the biomedical research ethics committee of Cheeloo Children’s Hospital of Shandong University. All procedures adhered to institutional guidelines and international standards for animal use, with efforts made to minimize animal suffering.
Animal Model
A total of 200 Kunming-specific pathogen-free (SPF) healthy mice were used in the study. After acclimatization, 160 mice were randomly divided into healthy control (CONH) and TS model (TSMO) groups. The TSMO group was further subdivided into four groups: those receiving FMT from healthy children (MFHC), FMT from healthy mice (MFHM), probiotics (MPro), and no treatment (MCon). The TS model was established using 3,30-iminodipropionitrile (IDPN), which induced abnormal behaviors and activities in the mice.
Fecal Transplantation and Probiotic Administration
Fecal specimens were collected from TS and healthy children, as well as from CONH and TSMO mice. The fecal samples were processed into bacterial suspensions and administered to the recipient mice via gavage. Probiotics, a complex of seven probiotics and two prebiotics, were also administered to the MPro group. Behavioral observations and fecal specimen collections were conducted three weeks post-FMT.
Serotonin (5-HT) Assay
Serum 5-HT levels were measured using chromatographic analysis. Blood samples were collected from the orbital sinus, and serum was separated and stored at -80°C until analysis. The 5-HT levels were quantified to assess the impact of FMT and probiotics on serotonin secretion.
Microbiota Analysis
Fecal samples were collected two weeks post-FMT for 16S rRNA sequencing. DNA was extracted using the cetyltrimethylammonium bromide method, and the V3-V4 region of the 16S rRNA gene was amplified. Sequencing was performed using the Illumina HiSeq 2500 platform. The data were analyzed using QIIME software to identify differences in microbial communities between groups.
Statistical Analysis
Differences between groups were analyzed using the Mann-Whitney U test and Kolmogorov-Smirnov (KS) test. Behavioral and 5-HT data were expressed as mean ± standard error (SE). Statistical significance was set at P < 0.05.
Results
Microbiota Differences Between TS and Healthy Mice
The gut microbiota of TSMO mice differed significantly from that of CONH mice. Analysis of β diversity based on unweighted UniFrac distances revealed distinct microbial communities between the two groups. Linear discriminant analysis (LDA) identified 18 discriminative microbial signatures that varied significantly between TSMO and CONH mice. Notably, the relative abundance of Turicibacteraceae and Ruminococcaceae was significantly higher in TSMO mice compared to CONH mice.
Therapeutic Effects of FMT
FMT demonstrated a significant therapeutic effect on TS symptoms. Mice transplanted with feces from healthy donors (MFHM and MFHC groups) showed a reduction in tic severity compared to untreated TSMO mice (MCon group). The behavioral scores of MFHM mice were significantly lower than those of MCon mice, indicating an alleviation of TS symptoms.
Changes in Gut Microbiota Post-FMT
FMT altered the gut microbiota composition in both CONH and TSMO mice. Mice receiving FMT from TS donors (HTSM group) showed a decrease in Firmicutes and Actinobacteria and an increase in Bacteroidetes and Proteobacteria compared to CONH mice. Conversely, TSMO mice receiving FMT from healthy donors (MFHM group) exhibited a shift in microbiota composition, suggesting a rebalancing effect of FMT on the gut microbiome.
Impact on Serotonin Levels
Serum 5-HT levels were significantly lower in TSMO mice compared to CONH mice. However, FMT and probiotic administration led to a significant increase in 5-HT levels in TSMO mice. The MFHM and MPro groups showed higher 5-HT levels than the MCon group, indicating that FMT and probiotics promote serotonin secretion.
Discussion
This study provides compelling evidence that FMT can alleviate TS symptoms in a mouse model by modulating the gut microbiota and promoting serotonin secretion. The findings align with previous research highlighting the role of the gut-brain axis in neuropsychiatric disorders. The increased abundance of Turicibacteraceae and Ruminococcaceae in TSMO mice suggests a potential link between these bacterial taxa and TS pathogenesis. The therapeutic effects of FMT, as evidenced by reduced tic severity and increased 5-HT levels, underscore the potential of microbiota-based interventions for TS.
The study also highlights the importance of serotonin in TS. Reduced 5-HT bioavailability has been associated with the severity of TS and related disorders. The gut microbiota plays a crucial role in tryptophan metabolism, a precursor to 5-HT, suggesting that FMT may enhance serotonin production through microbial modulation. These findings open new avenues for exploring the molecular mechanisms underlying FMT’s therapeutic effects and its potential application in clinical settings.
Limitations
While the study provides valuable insights, it has several limitations. Blood markers of the microbiota-gut-brain axis, such as lipopolysaccharides and inflammation markers, were not assessed. Additionally, neurotransmitter levels in the brain were not measured, limiting the understanding of the direct effects of FMT on central nervous system function. Future studies should address these gaps to provide a more comprehensive understanding of FMT’s mechanisms.
Conclusion
This study demonstrates that FMT can alleviate tic severity in a TS mouse model by modulating the gut microbiota and promoting serotonin secretion. The findings support the hypothesis of a microbe-intestine-brain axis in TS and provide a foundation for developing microbiota-based therapies. Further research is needed to explore the underlying mechanisms and evaluate the efficacy of FMT in clinical trials. The study underscores the potential of FMT as a novel therapeutic approach for TS, offering hope for improved management of this challenging disorder.
doi.org/10.1097/CM9.0000000000001885
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