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A meta-analysis evaluating the efficacy of probiotics/prebiotics among people with cognitive impairment was published in PLoS One. A plausible link occurring via the microbiota-gut-brain axis raises the possibility of benefit with supplementation, and this meta-analysis included 10 randomized and controlled clinical trials to discern the strength of this connection. Combined, this was a total of nearly 800 participants, though all of the included studies were rather small. For example, the largest among them was comprised of 117 participants (half taking placebo) while the smallest enrolled 28. Nearly all of the studies were conducted in China or Japan, with one taking place in Iran. The control groups also varied, receiving either a placebo, milk, donepezil, etc. The quality of each study was rated as either Grade A or B, with lower quality studies excluded.
The overall finding was that probiotic/prebiotic supplementation was associated with improved cognitive function among people with cognitive impairment, with a standardized mean difference of 0.52, generally considered a medium effect size. Subgroup analysis found that the use of single-species probiotics was associated with a greater effect than multi-species formulations, and studies with a duration of ≤ 12 weeks found a greater effect than those of more than 12 weeks.
There are some questions about the conclusions of this study, specifically regarding the limited availability of the studies cited in the meta-analysis. For example, the specific species used in the randomized trials were not reported in the meta-analysis, including the two studies that reported using a single-species supplement. Unfortunately, neither of these two studies was indexed on PubMed or available on Google Scholar (despite being cited as available on Google Scholar), so the species used are unknown, as is any type of detailed methodology.
Additionally, the title of one of these two single-species studies suggests that the “Si Mo decoction” was used among participants with Alzheimer’s disease in both the control and experimental groups, in combination (in the experimental group) with an “intestinal tract micro-ecosystem preparation.” This preparation is described as “Jin Shuangqi Oral Treatment” (per table 2), sometimes referred to as “Golden Bifid.” Rather than a single species, this appears to be a combination of B. Longum, L. bulgaricus, and S. thermophilus. It’s also plausible that the ingredients of the Si Mo decoction, including Fructus aurantii (citrus fruit), Radix aucklandiae (a type of tree), Semen arecae (areca nut), and Radix linderae (a type of shrub), have prebiotic properties or otherwise interact with the probiotic supplement to affect treatment outcomes. One of the ingredients (areca nut) has a variety of alkaloids listed among its active ingredients, as well as the neurotransmitter acetylcholine. This single study had the largest effect size of any of the 10 studies included in the meta-analysis, and the very small effect size associated with the eight multi-species probiotic trials suggests that this study alone may be driving an effect size not broadly applicable.
One of the other studies with a positive effect may not be broadly applicable either. This study, indexed on Google Scholar, evaluated low-frequency repetitive transcranial magnetic stimulation with or without probiotic supplementation. But the population included only people with post-stroke depression, which may not represent other groups with generalized cognitive impairment.
Yet there were some encouraging studies mixed into this meta-analysis. One controlled trial with 42 participants diagnosed with mild cognitive impairment (MCI) was published in Geriatric Nursing, describing a 12-week trial of placebo vs. an 18 multi-species combination of Lactobacillus, Lactococcus, and Bifidobacterium. Significant improvements were observed in cognitive function (assessed by the Mini-Mental State Examination and Montreal Cognitive Assessment Scale scores) with probiotic supplementation, accompanied by significant increases in serum BDNF levels, as well as improvements in both gastrointestinal symptoms and sleep quality and duration. This last improvement alone, i.e., improving sleep, is certainly a plausible mechanism by which cognitive function could be improved (or at least a slowing of the decline) among people with MCI.
Another encouraging controlled trial included in this meta-analysis was published in the Journal of Alzheimer’s disease, describing the effect of supplementation with the single species B. breve A1, compared to placebo, among 79 people with MCI (for an unknown reason, this study was included with the multi-species probiotics in the meta-analysis’ subgroup analysis). After 16 weeks, a significant improvement in cognitive function was observed among people receiving the probiotic compared to placebo (assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Japanese version of the MCI Screen (JMCIS)). This included improvements in specific scores, such as immediate memory, visuospatial/constructional, and delayed memory. The 11.3 point increase in RBANS between groups is considered substantial, with over a 50% increase in total score from baseline.
Lastly, one study not captured by the meta-analysis was a randomized trial published in Clinical Nutrition in 2022. This was a 3-month trial enrolling 169 middle-aged and older adults with MCI or neurologically healthy, who received either Lactobacillus rhamnosus GG or placebo. This study also included a microbiome analysis, which found some species more prevalent at baseline among people with MCI, such as Prevotella ruminicola and two species of Bacteroides. In this study, there was an improvement in cognitive function which correlated with a decrease in the relative abundance of the genus Prevotella and Dehalobacterium following probiotic supplementation. While there are still questions, evidence is growing for a cognitive benefit of probiotic supplementation, likely mediated via several mechanisms.
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