A Possible Link Between Early Probiotic Intervention
and the Risk of Neuropsychiatric Disorders Later
in Childhood: A Randomized TrialThis section is compiled by Frank M. Painter, D.C.
Send all comments or additions to: Frankp@chiro.org
FROM: Pediatr Res. 2015 (Jun); 77 (6): 823–828
OPEN ACCESS Pärtty A, Kalliomäki M, Wacklin P, Salminen S, Isolauri E
Department of Pediatrics,
University of Turku and Turku University Hospital,
Turku, Finland
Finnish Red Cross Blood Service,
Helsinki, Finland.
Functional Foods Forum,
University of Turku,
Turku, Finland.BACKGROUND: Recent experimental evidence suggests that gut microbiota may alter function within the nervous system providing new insight on the mechanism of neuropsychiatric disorders.
METHODS: Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.
RESULTS: At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.
CONCLUSION: Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.
From the FULL TEXT Article:
Background
Psychiatric disorders are already ranked among the leading causes of disability in industrialized countries. With the current progressive increase in the incidence, they may be expected to assume the first place also globally within the next few years. [1, 2] Attention-deficit hyperactivity disorder (ADHD), characterized by inattention, impulsivity, and hyperactivity, affects three to seven percent of children worldwide. [3, 4] Moreover, symptoms of inattention and hyperactivity are frequent in children with Asperger syndrome (AS), which is characterized by stereotyped behavior and deficient social interaction and communication skills. [5] Besides the common behavioral features, shared biological pathways and neuroanatomical links between these diseases have been reported. [5, 6]
Despite intensive research on ADHD and AS, the precise chain of pathological events underlying them remains unknown. The available data indicate ADHD and AS to be multifactorial disorders, in which genetic risk predominates, reinforced by various environmental and biological factors such as fetal stress, prematurity, toxins, and diet. [7] Recently, the search for etiologies has been expanded both within the central nervous system and beyond. Experimental data are accumulating to suggest that the presence of gut microbiota as such, as compared with the absence of it, and especially its certain beneficial bacteria, probiotics, make for altered function within the nervous system. [8–12] As a recent empirical study indicates [13] probiotics may provide a tool to manipulate brain activity even in humans.
To test the hypothetical involvement of the gut brain-axis in the manifestation of ADHD and AS, we analyzed the association of compositional development of the gut microbiota, the blood group secretor type as an indirect evidence of gut microbiota involvement, and the impact of specific probiotic intervention on the emergence of these two neuropsychiatric disorders in a cohort followed until 13 y of age.
Discussion
The results of our preliminary study demonstrate for the first time that specific probiotics may reduce the risk of the development of ADHD and AS possibly by mechanisms not directly associated with gut microbiota composition, since no single constant microbiota composition or their difference could be distinctive in children with or without neuropsychiatric disorders.
These findings must be viewed in the light of some caution as preliminary and initial observation into this novel area. First, our probiotic intervention study was originally designed and statistically powered for prevention of atopic eczema, not for prevention of more uncommon neuropsychiatric disorders ADHD and AS. Regardless of that, it is interesting to notice that allergic disease has been shown to be associated with an increased risk of ADHD and differences in neurodevelopment [14, 15] suggesting a possibility for common environmental determinants. Second, the number of drop-outs was quite considerable during the follow-up. Therefore, we cannot discount the possibility that the issue would not have biased our findings. However the number of drop-outs was equally divided in the both intervention groups and base-line characteristics of the drop-outs and the study finishers were similar, except for the duration of exclusive breast-feeding, demonstrating that these two groups were unbiased in almost all of the known factors. On the other hand, the careful and prospective 13–y follow-up period is the strength of the study. A further strength of the study is that gut microbiota has been analyzed comprehensively by FISH and qPCR as well as indirectly by blood group secretor type analysis.
ADHD is a disease of substantial genetic predisposition, as suggested by a number of adoption, twins, and family studies. [7, 16, 17] This notwithstanding, recent studies document up to 20% discordance in identical twins, leaving room for environmental and epigenetic determinants of ADHD. Thus far, prenatal exposure to maternal smoking [18], low birth weight, prematurity [19, 20], and specific environmental exposures such as lead and organic pollutants [7] have been linked to ADHD. In contrast, research on dietary factors such as sugar, artificial food colorings, zinc, iron, and ω–3 fatty acids, has established only vague causality in ADHD [7], despite some hints of their therapeutic potential. [21, 22] An empirical elimination diet has indeed been shown to be effective in the treatment of ADHD. [22] Moreover, breastfeeding, as a potent inducer of Bifidobacteria in the gut microbiota [23], has proved to be associated with lower levels of conduct disorder symptoms in middle childhood, which is in line with our findings in this study [24] demonstrating defiencies in early Bifidobacterium composition in those with later ADHD or AS.
Although the precise possible mechanisms of action of the gut microbiota in the gut-brain axis are unclear, a previous experimental study offers an interesting clue. In the study in question, mice with experimentally induced chronic colitis showed anxiety-like behavior. Treatment with Bifidobacterium longum abolished such behavior. However, the anxiolytic effect of Bifidobacterium longum was absent in vagotomized mice, suggesting that the effect was transmitted to the central nervous system by activating vagal pathways at the level of the enteric nervous system. [9] It is thus intriguing to note that in our study the amount of the same species was found to be decreased in early life in children later developing ADHD or AS.
Our data demonstrate that early administration of Lactobacillus rhamnosus GG may reduce the risk of ADHD and AS. Lactobacillus rhamnosus GG has been shown to stabilize the gut permeability barrier by effects on tight junctions, mucin production and antigen-specific immunoglobulin A production. [25] In addition, a recent experimental study has demonstrated that Lactobacillus rhamnosus regulates, again via the vagus nerve, emotional behavior and the central GABAergic system, which is also associated with neuropsychiatric disorders. [11, 26] Of note, a recent study with healthy women demonstrated that a consumption of a mixture of probiotic bacteria had significant effects on brain regions that control central processing of emotion and sensation. [13] Probiotics had no significant effect on microbiota composition in the study suggesting that the effects on central nervous system were either induced by altered vagal afferent signaling or by systemic metabolic changes related to probiotic intake. [13] Furthermore, another experimental study with mice showed that pretreatment with probiotic Lactobacillus rhamnosus prevents learning and memory dysfunction in Citrobacter rodentium-infected mice. [27] It thus remains to be elucidated whether these effects of Lactobacillus rhamnosus are of importance in the development of neuropsychiatric disorders in humans. However, in accord with our clinical findings here it has been postulated that neural pathways may alter already early in development. If such an alteration takes place at a critical moment, the sequential dysfunction of the gut-brain axis may become relatively constant into adulthood. [28, 29]
Our findings demonstrate a possible preventive risk reducing effect of a probiotic LGG on later development of ADHD and AS. We also report an interconnection between the early gut microbiota and development of these neuropsychiatric disorders, although no single constant microbiota composition component or change was detected. However, keeping in mind the above-mentioned limitations of the study, we consider the findings preliminary but encouraging for further studies of the subject both in the area of well-powered clinical trials and experimental research.
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