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The results of a 12-week randomized and placebo-controlled trial evaluating the use of a specific strain of the probiotic Bifidobacterium bifidum (Bf-688) for ADHD symptoms were recently published in Nutrients. Just over 100 Taiwanese children (85% boys and 15% girls) between the ages of 6 and 10 with clinician-confirmed ADHD (who were also receiving a stable dose of methylphenidate for ADHD prior to study onset) were randomized 1:1 to receive 2 daily doses of either placebo or probiotic (Bf-688) for a total daily dose of 5 × 109 CFUs. Multiple assessments were made every 4 weeks during the study, including standardized assessments of ADHD symptoms, specifically the Swanson, Nolan, and Pelham Rating Scale (SNAP-IV, completed by parents) and the ADHD rating scale (ADHD-RS, completed by clinicians), along with the Barkley’s Side Effects Rating Scale (SERS, also completed by parents). Gut microbiome analysis, along with assessments of visual and auditory attention abilities (Conners’ Continuous Performance Test (CPT) and Conners’ Continuous Auditory Test of Attention (CATA)), were also conducted at baseline and at the study’s conclusion (week 12).
Although both groups had significant decreases (improvement) in both SNAP-IV and ADHD-RS assessments, the probiotic group had significantly greater improvements in several categories, including a decrease in omission errors and an increase in response rates (Hit reaction time) in both CPT and CATA scores, indicative of improvements in both visual and auditory attention. Additionally, the children receiving the probiotic had a significant increase in the Firmicutes to Bacteroidetes (F/B) ratio over the 12-week study, as well as significant changes in the abundance of 20 bacterial species. A number of potential microbial pathways were examined that might explain the mechanism for clinical benefit, including riboflavin metabolism, Lipopolysaccharide (LPS) and LPS protein biosynthesis, protein digestion and absorption, and N-Glycan biosynthesis. Significant correlations were made between reaction times and N-Glycan biosynthesis, which in turn was positively correlated with Bacteroidetes, Bacteroidia, and Bacteroidales, and negatively correlated with Firmicutes, Clostridia, Clostridiales, and the F/B ratio.
The authors highlight several potential mechanisms by which the microbiome may influence ADHD. For example, previous research describes the importance of N-glycosylation for multicellular life and estimates the complexity of the “glycoproteome” to be several-fold greater than the proteome itself. Difficulty in measuring and evaluating the impact of the glycoproteome has limited research in this field, but several studies point to anomalies in N-glycosylation among children with ADHD. This includes a previously published study with 99 children with ADHD, who were found to have “increased A2FG2 and decreased tri- and tetraantennary glycans” compared to a control group of children, changes which indicate a decrease in the branching of plasma glycans. Increased glycan branching has been linked to cell membrane stability and a longer half-life in membrane-bound receptors. Thus, it’s quite plausible that membrane branching could influence neural signaling. A more recent paper published in the International Journal of Molecular Sciences also describes significant differences in protein glycosylation between 10 children with ADHD and controls. In line with the previous analysis, a decrease in triantennary N-glycans was observed, as well as decreases in α2-3 sialylation and diantennary N-glycans, along with an increase in antennary fucosylation. Although it’s difficult to interpret the importance of these small studies in a growing field, it’s worth noting that these types of changes in glycosylation have been linked to memory and neuronal function as well as other aspects of brain development.
Probiotic supplementation may influence other neuronal pathways as well. A review published in the European Journal of Nutrition describes a number of mechanisms by which the gut microbiota may influence neuronal pathways related to ADHD, including metabolic pathways, a vagus nerve pathway, and immune pathways. Regarding the metabolic pathway, Bifidobacterium spp. has been shown to produce dopamine precursors, gamma-aminobutyric acid (GABA), and increase the circulating availability of tryptophan (which can cross the blood-brain barrier), a precursor for serotonin. Microbial pathways also influence both vitamin B6 (pyridoxal phosphate) and short-chain fatty acid (SCFA) synthesis, also implicated in ADHD. For example, an experimental animal study suggested that a strain of Bifidobacterium bifidum (BBG9-1) could improve constipation by preventing a decrease in butyrate levels in the gut, while modulating serum levels of dopamine and serotonin. The strain used in the controlled trial (Bf-688) most recently published (in Nutrients) was also utilized in an open-label trial, and found to improve participants’ inattention and hyperactivity/impulsive symptoms, as well as modify the gut microbiome.
It’s also worth noting that the assessment scale used to assess side effects (SERS) suggested an improvement in GI symptoms between weeks 4 and 12 among the children receiving Bf-688 in the recent trial, while those receiving placebo had a brief improvement followed by a return to baseline. All children in this study were receiving methylphenidate, known to cause a variety of gastrointestinal symptoms in children. Although a recently published systematic review suggests likely benefits to probiotic supplementation among children with ADHD, larger trials of longer duration, as well as comparisons between species and doses, are needed to confirm these benefits.
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