Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin

Abstract

Increasing evidence suggests that the gut microbiota plays a key role in the central nervous system (CNS), and alterations of the gut microbiota composition due to environmental factors can contribute to neurodevelopmental disorders. Animal modeling may help to identify drugs that can normalize the altered gut microbiota and thereby ameliorate abnormal brain signaling pathways. The purpose of the present study was to investigate the therapeutic potency of probiotics such as Bifidobacteria and Lactobacilli on glutamate excitotoxicity as a neurotoxic effect induced by clindamycin and propionic acid (PPA) in juvenile hamsters. Fifty young golden Syrian hamsters weighing between 60 and 70 g were enrolled in the study. The hamsters were randomly divided into five groups, each with ten hamsters. The hamsters in the control group only received phosphate-buffered saline orally. The PPA-treated group received a neurotoxic dose of 250 mg PPA/kg body weight (BW)/day for three days. The clindamycin-treated group received 30 mg clindamycin/kg BW as a single orogastric dose on the day the experiment started. The two therapeutic groups received the same doses of PPA and clindamycin followed by 0.2 g probiotic/kg BW for three weeks. Biochemical parameters related to glutamate excitotoxicity were investigated in brain homogenates from each group of hamsters. Additionally, the development of pathogenic bacteria was monitored in stool samples from all groups. The microbiology results of the present study revealed descriptive changes in the fecal microbiota and the appearance of Clostridium species in the hamsters treated with clindamycin and PPA. Additionally, the effectiveness of the probiotic in the restoration of the normal gut microbiota was demonstrated. Moreover, clindamycin and PPA were found to induce a significant depletion of Mg and γ-aminobutyric acid (GABA) and a remarkable increase in the Na/Mg and glutamate/GABA ratios but non-significant changes in the absolute levels of K, Na and glutamate. The bacteria overgrowth induced by PPA and clindamycin in the present study effectively showed signs of neuronal toxicity. The study indicates that probiotics can be used safely to ameliorate glutamate excitotoxicity mostly through increasing depleted GABA and Mg and decreasing the excitatory neurotransmitter, glutamate.

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Chromatolysis is often considered as the preapoptotic stage or specific apoptotic process, where the Nissl substance disintegrates. Therefore, present data coincide with the results of our previous and other studies, where the proapoptotic effect of high dose of PPA was proposed (Choi et al, ; El‐Ansary et al, ; Lobzhanidze et al, ). CA1 is the first region in the hippocampus circuit, from which a major output pathway projecs to enthorinal cortex.…”

“…Brains from PPA‐treated rodents show micro‐ and astroglial activation, mitochondrial and fatty acid dysfunction, increased the levels of neurotoxic cytokines and oxidative stress markers, and other alterations, consistent with the findings in human ASD (Choi et al, ; El‐Ansary et al, ; MacFabe et al, ; Mepham et al, ; Nankova et al, ; Shams et al, ). In addition to animal models, autism‐like biochemical alterations were found on PPA‐treated human lymphoblast cell lines (Frye et al, , ; Nankova et al, ; Rose et al, ) and human stem cells (Abdelli, Samsam, & Naser, ; Yang et al, , Neurochemistry, accepted for publication).…”

“…Further to this we (Lobzhanidze et al, ; MacFabe, ; MacFabe et al, ; Shams, Foley, Kavaliers, MacFabe, & Ossenkopp, ; Shultz et al, , ), and others (Aabed et al, ; Choi et al, ; El‐Ansary et al, ) have used the exposure of PPA and related short chain fatty acid administration in rodents as an acceptable animal model of autism. It was shown that the rats, treated with PPA (intracerebroventricular, intraperitoneal, subcutaneous injections, intragastric gavage), exhibit many autism‐like behaviours, like repetitive, antisocial, anxiety‐like and repetitive behaviours, including dystonia and seizures.…”

Could Gut Modulation through Probiotic Supplementation Be Beneficial in Autism Spectrum Disorder?

“…A role for probiotics has been suggested for children with ASD as well, as preliminary findings from experimental animals studies provide some evidence that administration of selected probiotics may be effective in reducing neurologic signs and symptoms associated with gut dysbiosis. In a summary of studies to date, several probiotic strains, i.e., [18,[89][90][91][92]. In a mouse model of ASD induced by maternal immune activation, oral administration of human commensal B. fragilis corrected intestinal permeability, restored GM, improved GI physiology, and abolished ASD-like behavioral disruptions [18].…”

“…Treatment with L. reuteri resulted also in reduction of stress-induced corticosterone, and stimulation of the production of oxytocin, a key regulator of social behaviors, involved in the mesolimbic dopamine reward system, which is thought to be dysregulated in ASD [94]. On another hand, a recent study performed on hamsters in which autistic-like behaviors were induced by propionic acid and clindamycin administration studied the therapeutic effect of a 3-week oral treatment with a mixture of bifidobacteria and lactobacilli strains (Protexin ® ) [91]. Protexin ® administration was effective in rebalancing GM, ameliorating oxidative stress, and counteracting behavioral deficits.…”