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In the journal Brain, Behavior, and Immunity, researchers from the Karolinska Institute in Sweden published an evaluation of the gut microbiome among adults and children with attention-deficit/hyperactivity disorder (ADHD), including the effects of psychostimulant medication and synbiotic supplementation. This analysis utilized data from a randomized and controlled clinical trial published in 2020 that included 182 children and adults with ADHD. The 9-week trial compared a placebo to a mixture of probiotics and fibers (Synbiotic 2000), and though the 2020 publication did not indicate any overall significant difference in ADHD symptoms, it did improve sub-diagnostic autistic traits (restricted/repetitive behaviors) among children and emotion regulation among adults (note, participants with autism were excluded from the trial). Larger effects were observed among children and adults with an elevated baseline sVCAM-1 as well as among children not on ADHD medication (VCAM-1, expressed on epithelial cells and estimated by sVCAM-1 levels, is activated by pro-inflammatory cytokines, initiating the disruption of junction adhesion molecules, or tight junctions).
In this recent analysis, data from a subset of the 147 participants (106 completed randomized trial) were used for a secondary analysis of the fecal microbiome, with 52 receiving placebo (maltodextrin) and 54 receiving the probiotic/fiber mix daily for 9 weeks. A baseline microbiome analysis was also compared to 52 adult neurotypical controls, the case-control portion of this study. The probiotic was comprised of three lyophilized strains of lactic acid bacteria, including Pediococcus pentosaceus, Lactobacillus casei ssp paracasei, and Lactobacillus plantarum as well as an equal mixture of the fermentable fibers β-glucan, inulin, pectin, and resistant starch.
When comparing the adults with ADHD to neurotypical controls, four species were identified as differentially abundant; specifically, Streptococcus pasteurianus and Lachnospiraceae bacterium 3–1 were found in higher abundance in adults with ADHD compared to controls, and Bilophila wadsworthia and non-species-specific bacteria in the genus Bilophila were found in lower abundance among adults with ADHD. The decreased presence of B. wadsworthia among adults with ADHD is difficult to interpret, as this species is thought to be a pathobiont at higher levels and has also been associated with colitis in animal studies. It is the only known intestinal bacterium that uses taurine as an electron acceptor for anaerobic respiration, with hydrogen sulfide as the byproduct. As reported previously, plasma levels of short-chain fatty acids (formic acid and propionic acid) were significantly lower in adults with ADHD but were significantly increased with the synbiotic treatment compared to placebo.
There were also differences in the abundance of several species, as well as functional differences, when comparing children (but not adults) with ADHD taking psychostimulant medications to children not taking medications. Four different species of the Prevotella genus were all found in higher abundance among children taking stimulants, while the species Peptostreptococcus anaerobius was found at a lower abundance. An analysis of KEGG (Kyoto Encyclopedia of Genes and Genomes) modules was also carried out, providing insight into metabolic pathways not always captured by changes in bacterial abundance. A specific module related to vitamin B12 synthesis (M00122) was significantly reduced among children taking stimulant medications. A lower abundance of this module was also associated with looser stools among these children, suggesting a possible faster colonic transit time. A lower serum level of vitamin B12 was also observed among children taking stimulant medications, but not after adjustment for B vitamin supplementation, suggesting that supplementation was a possible explanation.
A looser stool consistency at baseline was also associated with less bacterial (Shannon) diversity, which was increased with probiotic supplementation. An increase in the abundance of each of the species provided in the synbiotic was observed compared to placebo, as well as an increase in the genus Lactobacillus, Anaerostipes hadrus, and Peptostreptococcus anaerobius, as well as a decrease in Eubacterium ramulus. Increases in 7 KEGG modules were also observed with synbiotic supplementation, primarily related to phosphotransferase systems, which are involved in the transportation and metabolism of several sugars.
Overall, this study raises several important questions that may be clinically important. It suggests (but does not clearly show) that B12 synthesis may be inhibited among children with ADHD taking stimulant medications, and that synbiotic supplementation may normalize this. There may also be a relationship between stimulant medications and colonic transit time, stool consistency, and B12 status, worth monitoring in future studies. However, given that most B12 is absorbed in the small intestine, the clinical significance of reduced B12 colonic synthesis is unclear.
Psychostimulants have been associated with a number of GI side effects, including increased acid production, reduced appetite, stomach pain, nausea, vomiting, and abdominal discomfort, and this study offers possible mechanistic insights. This and other studies suggest that there may be clinically meaningful differences in bacterial abundances among people with ADHD compared to neurotypical controls, and that probiotics may help to maintain microbial balance. The normalization of short-chain fatty acid levels with synbiotic supplementation is also worth noting, given their roles in immune, vascular, and nerve cell function. Lastly, the subset of people with the largest response to supplementation had looser stools at baseline, possibly providing a marker for clinical intervention.
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