Wednesday, October 5, 2016

Antibiotics in the first year of life and subsequent neurocognitive outcomes

Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, Mitchell EA.
Antibiotics in the first year of life and subsequent neurocognitive outcomes.
Acta Paediatr. 2016 Oct 4.

There may be a link between disruption to the gut microbiota in early life and later neurocognitive outcomes. We hypothesised that antibiotic use in early life is associated with a detrimental effect on later neurocognitive outcomes.
871 European mothers and their children enrolled in the Auckland Birthweight Collaborative Study at birth. Information on antibiotic use during the first year of life and between 12 months and 3.5 years of age was gathered via maternal interview. Intelligence test scores and measures of behavioural difficulties were obtained when children were 3.5, 7 and 11 years of age.
Antibiotic use in the first year of life was reported in 70% of the 526 children with antibiotic data assessed at age 3.5 years. Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up. Results were consistent across all standardised psychologist administered tests, as well as parent rated, teacher rated and self-report measures.

This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood. If confirmed by further research these findings could have implications for the use of antibiotics for minor illnesses in infancy. 

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From the article:

After adjustment for SGA status, sex, maternal school leaving age, maternal smoking in pregnancy,
method of delivery and breastfeeding duration, the following outcome variables remained statistically
significantly associated with antibiotic use: higher parent rated total behavioural difficulty score at age of 3.5 and 11 years (in particular conduct problems), higher self-rated peer difficulties, lower self-rated prosocial behaviour scores at age 11, higher parent rated ADHD symptoms at age 11, higher teacher reported symptoms of ADHD at age 11 and higher depression symptom scores at age 11.

Antibiotic use between the ages of 12 months and 3.5 years was not significantly associated with any
of the outcomes measures.   Furthermore, maternal antibiotic use during pregnancy  was not
significantly associated with any of the outcome measures. Information about the timing,
dosage and type of antibiotic given to mothers during pregnancy was not available. Admission to
hospital in the first 3.5 years of life was not significantly associated with any of the outcome measures ...

The finding that it is antibiotic use in the first year of life (as opposed to antibiotic use between 12
months and 3.5 years of life) that is associated with behavioural, mood and cognitive outcomes later
in childhood is consistent with the theoretical underpinnings of the development of the gut-brain axis.
This argues against the explanation that the confounding influence of chronic otitis media associated
with antibiotic use and deafness is the cause of poorer neurodevelopmental outcomes. The early
development and stabilisation of the gut microbiome in postnatal life and the concomitant continued
rapid development of the central nervous system implies that disruptions to the gut-brain axis during
this critical period are the most likely to have a long term impact on development.

Potential mechanisms by which the gut microbiota affects CNS function include altered microbial
composition, immune inactivation, vagal nerve activation, tryptophan metabolism, gut hormone
response, and through bacterial metabolites . Studies have linked early disruptions to the
development of the gut microbiota and development of the stress-response system particularly the
hypothalamic pituitary adrenal axis (HPA axis). The function of the HPA axis has been implicated in
emotional and behavioural outcomes later in life such as depression  and the link between
antenatal maternal stress and later anxiety and depression in offspring. Foster and McVey
Neufeld (2013) provide a review of the growing evidence that microbiota are involved in the early
development of the HPA axis and thus the later functional outcomes associated with the function of
the stress response system.  In short, animal models indicate that the function of the HPA axis
differs according to the composition of the gut microbiota in mice. In 2004 it was reported that the
stress reactivity of the HPA axis was linked to the microbiota of rodents. Germ free mice (who have no commensal bacteria) had exaggerated stress responses when restrained compared with house-
specific pathogen free mice. Germ free mice have also been found to have more anxiety like
behaviour on measures such as the elevated plus maze and the forced swim test.  As an
alternative to using germ free mice the effect of antibiotic exposure on the gut microbiota and
observable behavioural outcomes have also been modelled in mice.  A recent study investigated the
effects of antibiotic induced gut dysbiosis in adult mice.  In addition to demonstrating disruption to
the gut microbiota, antibiotic treated mice had impaired novel object recognition memory which is
consistent with previous reports.  Changes in circulating metabolites, cerebral signalling
molecules and expression of neuropeptides such as brain derived neurotrophic factor (BDNF) were
also demonstrated posing a plausible pathway connecting antibiotic induced dysbiosis to cognitive

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