Different Alterations in Gut Microbiota between Bifidobacterium longum and Fecal Microbiota Transplantation Treatments in Propionic Acid Rat Model of Autism.

Autism spectrum disorders (ASD) consist of a range of neurodevelopmental conditions accompanied by dysbiosis of gut microbiota. Therefore, a number of microbiota manipulation strategies were developed to restore their balance. However, a comprehensive comparison of the various methods on gut microbiota is still lacking. Here, we evaluated the effect of Bifidobacterium (BF) treatment and fecal microbiota transplantation (FT) on gut microbiota in a propionic acid (PPA) rat model of autism using 16S rRNA sequencing. Following PPA treatment, gut microbiota showed depletion of Bacteroidia and Akkermansia accompanied by a concomitant increase of Streptococcus, Lachnospiraceae, and Paraeggerthella. The dysbiosis was predicted to cause increased levels of porphyrin metabolism and impairments of acyl-CoA thioesterase and ubiquinone biosynthesis. On the contrary, BF and FT treatments resulted in a distinct increase of Clostridium, Bifidobacterium, Marvinbryantia, Butyricicoccus, and Dorea. The taxa in BF group positively correlated with vitamin B12 and flagella biosynthesis, while FT mainly enriched flagella biosynthesis. In contrast, BF and FT treatments negatively correlated with succinate biosynthesis, pyruvate metabolism, nitrogen metabolism, beta-Lactam resistance, and peptidoglycan biosynthesis. Therefore, the present study demonstrated that BF and FT treatments restored the PPA-induced dysbiosis in a treatment-specific manner.

The Efficacy of Fecal Transplantation and Bifidobacterium Supplementation in Ameliorating Propionic Acid-Induced Behavioral and Biochemical Autistic Features in Juvenile Male Rats.

Gut microbiota plays a major role in neurological disorders, including autism. Modulation of the gut microbiota through fecal microbiota transplantation (FMT) or probiotic administration, such as Bifidobacteria, is suggested to alleviate autistic symptoms; however, their effects on the brain are not fully examined. We tested both approaches in a propionic acid (PPA) rodent model of autism as treatment strategies. Autism was induced in Sprague-Dawley rats by administering PPA orally (250 mg/kg) for 3 days. Animals were later treated with either saline, FMT, or Bifidobacteria for 22 days. Control animals were treated with saline throughout the study. Social behavior and selected brain biochemical markers related to stress hormones, inflammation, and oxidative stress were assessed. PPA treatment induced social impairments, which was rescued by the treatments. In the brain, Bifidobacteria treatment increased oxytocin relative to control and PPA groups. Moreover, Bifidobacteria treatment rescued the PPA-induced increase in IFN-γ levels. Both treatments increased GST levels, which was diminished by the PPA treatment. These findings indicate the potential of gut microbiota-targeted therapeutics in ameliorating behavioral deficit and underlying neural biochemistry.

Fecal Transplant and Bifidobacterium Treatments Modulate Gut Clostridium Bacteria and Rescue Social Impairment and Hippocampal BDNF Expression in a Rodent Model of Autism.

Autism is associated with gastrointestinal dysfunction and gut microbiota dysbiosis, including an overall increase in Clostridium. Modulation of the gut microbiota is suggested to improve autistic symptoms. In this study, we explored the implementation of two different interventions that target the microbiota in a rodent model of autism and their effects on social behavior: the levels of different fecal Clostridium spp., and hippocampal transcript levels. Autism was induced in young Sprague Dawley male rats using oral gavage of propionic acid (PPA) for three days, while controls received saline. PPA-treated animals were divided to receive either saline, fecal transplant from healthy donor rats, or Bifidobacterium for 22 days, while controls continued to receive saline. We found that PPA attenuated social interaction in animals, which was rescued by the two interventions. PPA-treated animals had a significantly increased abundance of fecal C. perfringens with a concomitant decrease in Clostridium cluster IV, and exhibited high hippocampal Bdnf expression compared to controls. Fecal microbiota transplantation or Bifidobacterium treatment restored the balance of fecal Clostridium spp. and normalized the level of Bdnf expression. These findings highlight the involvement of the gut-brain axis in the etiology of autism and propose possible interventions in a preclinical model of autism.

The role of sex-differentiated variations in stress hormones, antioxidants, and neuroimmune responses in relation to social interaction impairment in a rodent model of autism.

Males are more likely to develop autism as a neurodevelopmental disorder than females, but the mechanisms underlying male susceptibility are not fully understood. In this paper, we used a well-characterized propionic acid (PPA) rodent model of autism to study sex differences in stress hormones, antioxidants' status, and the neuroimmune response that may contribute to the preponderance of autism in males. Sprague Dawley rats of both sexes were divided into a saline-treated group as controls and PPA-treated groups, receiving 250 mg/kg of PPA per day for three days. Animals' social behavior was examined using the three-chamber social test. Hormones (ACTH, corticosterone, melatonin, and oxytocin), oxidative stress biomarkers (glutathione, glutathione-S-transferase, and ascorbic acid), and cytokines (IL-6, IL-1α, IL-10, and IFNγ) were measured in the brain tissue of all the animals. The results showed a sex dimorphic social response to PPA treatment, where males were more susceptible to the PPA treatment and exhibited a significant reduction in social behavior with no effects observed in females. Also, sex differences were observed in the levels of hormones, antioxidants, and cytokines. Female rats showed significantly higher corticosterone and lower oxytocin, antioxidants, and cytokine levels than males. The PPA treatment later modulated these baseline differences. Our study indicates that the behavioral manifestation of autism in PPA-treated males and not females could be linked to neural biochemical differences between the sexes at baseline, which might play a protective role in females. Our results can contribute to early intervention strategies and treatments used to control autism, an increasingly prevalent disorder.