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autism spectrum disorder (asd) is a widespread neurodevelopmental disorder characterized by speech and social impairment, narrow interests, and repetitive stereotyped behaviors [1]. in recent years, the prevalence of asd in my country has increased year by year, reaching 1% [2]. the efficacy of educational rehabilitation training is currently limited, and there is a lack of more effective treatments. the intestinal microbiome has been reported to participate in the pathogenesis of asd through the microbiota-gut-brain axis [3], affecting its gastrointestinal function and behavior [4,5]. recently, a randomized, double-blind, placebo clinical trial conducted by the department of clinical nutrition of the second affiliated hospital of guangzhou medical university found that the use of the self-developed strain bacteroides fragilis bf839 in my country can effectively intervene in autism with high safety, which brings hope to autistic patients and their families.

in this randomized, double-blind, placebo-controlled trial, the research team recruited 60 autistic patients aged 2-10 years old and gave them bf839 or placebo for 16 weeks without changing the routine rehabilitation training of the two groups of patients. the autism behavior checklist (abc), childhood autism rating scale (cars), social responsiveness scale (srs), normal development of social skills from infant to junior high school children (sm), gastrointestinal symptom rating scale (gsrs) were evaluated and adverse reactions were monitored on day 0, week 8, and week 16, respectively. at the same time, feces of asd patients were collected on day 0 and week 16 for intestinal flora analysis.

result

(i) bf839 can significantly improve abnormal behaviors and gastrointestinal symptoms in children with asd, especially motor skills that reflect stereotyped behaviors. children under 4 years old may be the effective window period for probiotic intervention.

compared with the placebo group, the bf839 group significantly improved the abc motor ability score at 16 weeks (-4.68±6.29 vs -1.07±5.73, p＜0.05). further subgroup analysis: in children with asd younger than 4 years old, the bf839 group significantly improved the abc motor ability score at 16 weeks compared with the placebo group (-4.85±4.60 vs 1.50±3.87, p＜0.05). the improvement in the total abc score was also significantly higher than that in the placebo group by 3 times (-20.23±23.92 vs -6.42±15.96, p=0.106), which was close to statistical significance; in children older than 4 years old, the bf839 group improved slightly better than the placebo, but not significantly (-11.27 ± 11.74 vs -8.88 ± 14.93, p= 0.623). in asd children with cars ≥ 30 points, compared with the placebo group, the bf839 group could significantly improve the abc total score (-19.71±24.12 vs -5.05±16.58, p＜0.05), abc motor ability score (-5.71±8.26 vs -0.32±5.88, p＜0.05) and cars score (-5.57±5.79 vs -2.11±3.70, p＜0.05) at 16 weeks. compared with the placebo group, the bf839 group could significantly improve the gsrs score at 8 and 16 weeks [8w, -3.50(-7.36,-1.25) vs 0.00(-3.00,3.00), p＜0.05; 16w, -3.50(-7.13,-1.25) vs 0.00(-3.00,3.00), p＜0.05]. 2.00(-3.00,3.00), p<0.05].

2. high security

only 2 patients (6.67%) in the bf839 group withdrew due to mild diarrhea, and no other adverse reactions were observed in the remaining patients.

3. bf839 can promote the growth of bifidobacterium in the intestines of asd children

the placebo group and the bf839 group did not show significant differences in abundance at 0 days, but compared with the placebo group at 16 weeks, the abundance of bifidobacterium pseudocatenulatum, bifidobacterium longum, and bifidobacterium bifidum in the bf839 group increased significantly after 16 weeks of intervention, and the metabolic function of related neuroactive compounds was significantly improved.

an increasing number of animal studies [6-10] and clinical trials [11-21] have reported that single or compound strain probiotics can improve asd behavioral manifestations and gastrointestinal symptoms to a certain extent. the results of this study suggest that bf839 shows a relatively good efficacy in improving the behavioral symptoms of asd children. zhao's study [18] showed that after 2 months of fecal microbiota transplantation (fmt), the cars score decreased by 10.8% compared with the baseline (the control group only decreased by 0.8%, p < 0.001). after 16 weeks of intervention in this study, in asd children with a baseline cars score of ≥ 30, bf839 decreased by 14.50% (the control group decreased by 5.93%, p = 0.044). the results of this study are similar to the efficacy of fmt.

previous studies have shown that compared with healthy children, bifidobacterium[22-24] and veillonella[25] were found to be significantly decreased in children with asd. it is known that some bifidobacteria can produce γ-aminobutyric acid (gaba)[26], so gaba concentrations are also lower in children with asd. gaba is closely related to glutamate metabolism, which is the main excitatory neurotransmitter in the brain[27]. some studies have shown that lower glutamate concentrations are associated with the severity of typical anxiety and social and behavioral disorders in asd[28-29]. based on this, some people believe that gaba/glutamate abnormalities may play an important role in asd pathology[28-30]. amino acid imbalances have also been reported in children with autism[31], and new evidence emphasizes the role of the gut microbiota in amino acid metabolism. in addition, bifidobacterium longum ncc3001 can normalize anxiety-like behavior and hippocampal brain-derived neurotrophic factor (bdnf) in mice with infectious colitis through the vagus nerve pathway [32]. this study found that compared with the placebo group and before intervention, the abundance of bifidobacterium pseudocatenulatum, bifidobacterium longum, and bifidobacterium bifidum increased significantly after 16 weeks of bf839 intervention. our intestinal flora results suggest that bf839 can promote the growth of bifidobacteria in the intestines of asd children, resulting in significant changes in the metabolic function of some neuroactive compounds, which may be one of the reasons why bf839 can effectively improve the symptoms of asd children.

the results of this study have important practical and theoretical significance for the use of intestinal microecological preparations to treat neurodevelopmental disorders. since bf839 is a human-derived intestinal bacteria preparation with independent intellectual property rights in china and has been on the market for many years, this research result can be quickly applied to clinical practice.

this clinical study also confirmed the results of animal experiments conducted by our team [33, 34] and abroad from cell [35]: bacteroides fragilis can improve some symptoms of autistic mice. 30% of autistic children have epileptic seizures, and our previous clinical studies have also found that bf839 can also reduce epileptic seizures and effectively treat refractory and immune-related epilepsy [36-38]. this further shows that intestinal microecological imbalance is one of the common causes of neurodevelopmental disorders. using beneficial microorganisms to correct children's microecological imbalance is of great help to children. however, our research found that children under 4 years old may be the effective window period for microecological intervention. therefore, we call for time to be brain!