Effects of C-Terminal Domain of the Heavy Chain of Tetanus Toxin on Gut Microbiota in a Rat Model of Depression.

Background/aims: It is now well established that imbalance or dysbiosis in the gut microbiota (GM) plays a significant role in neuropsychiatric/neurodegenerative disorders. Recently it has been reported that the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) may not only act as a neuroprotectant but may also exhibit antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of treatment-resistant depression. The aim of this study was to determine whether Hc-TeTx may also interact with GM implicated in mood regulation in these rats.

Methods: Adult male WKY rats (5/group) were injected intramuscularly (IM) with 60 μg/kg Hc-TeTx or saline. Twenty-four hours after the injection, the animals were sacrificed, intestinal stools were collected and stored at -80°C. DNA was extracted from the samples for 16S rRNA gene-based microbiota analysis using 16S Metagenomics application.

Results: Abundance of several bacteria at different taxonomic levels were distinguished between Hc-TeTx group and the control. At species-level, 11 operational taxonomic units (OTUs), particularly Bifidobacterium cholerium, a bacterium with a strong ability to degrade resistant starch, were enriched (69 fold) in the Hc-TeTx group. In addition, 5 species of probiotic Lactobacillus, two butyrate-forming species Sarcina, Butyrivibro proteovlasticus and Roseburia faecis, were enhanced by a minimum of 2-fold in Hc-TeTx group. In contrast, 24 species including five species of pathogenic Provettela (5-14 fold), two mucin-degrading Akkermansia muciniphila and Mucispirillum schaedleri, and four species of pathogenic Ruminoccus were reduced by a minimum of 2-fold by Hc-TeTx treatment.

Conclusion: Hc-TeTx enhanced probiotic species and suppressed the opportunistic pathogens. Since overall effect of Hc-TeTx appears to be promoting GM associated with mood enhancement (e.g. Bifidobacterium, Butyrivibro, and Lactobacillus) and suppressing GM associated with mood dysregulation (e.g. Mucispirillum, Provettela, and Ruminoccus) a novel mechanism of beneficial effects of Hc-TeTx may involve normalization of dysbiosis.