BACKGROUND supplementation on gut microbiota, fecal and urinary


Autism spectrum disorders (ASDs)
are a series of fast growing neurodevelopmental disorders clinically evident
from early childhood. With their rates of diagnosis dramatically increasing in
the past few decades, they now account for a substantial health loss across
lifespan, estimated to effect about one in every 68 children.  As genetics alone doesn’t explain the exact pathology
and etiology of ASD, the attention is now towards environmental factors as
potential etiologic agents. Gastrointestinal disorders are a common comorbidity
in ASD patients and clinical studies have shown that GI disturbances in ASD
might be linked to gut dysbiosis representing the observable phenotype of the
microbiota-gut-brain axis disruption which is emerging as a prominent factor in
the generation of autistic behaviors.  While a handful of reports show that the use of
potential probiotics as adjuvant treatments for ASD, can restore normal gut
microbiota and reduce the gut production and absorption of toxins, definitive
evidence that this non-pharmacological complementary alternative therapy
improves behavioral symptomology in ASD patients is lacking. Studies with larger data sets are needed for
side-by-side comparisons of gut microbiota and toxins (Fecal and urinary
analysis) in ASD patients with and without GI symptoms and those who have
received or not probiotic treatment. As there are no longitudinal studies with
repeated analysis, more studies that are done over time to see the correlation
of disease symptomatology in ASD to microbiome /metabolic parameters are needed.
There is no solid evidence on reports of environmental transmission, further
studies on microbial changes in ASD children in comparison to unaffected
children are also needed.



Aim of
the Study:

The general aim
of this prospective interventional study is to determine the effects of probiotic
mixture supplementation in ASD children on GI symptoms, autism severity
symptoms, cognition, language development, behavioral symptomology and on brain
function & connectivity. The specific aims of the study will be

To determine the
relation of child’s Delivery, Neonatal & breastfeeding history to the
current microbiota composition, GI symptoms and autism symptoms severity.

To study if the
observed microbial changes in ASD are due to variation in dietary habits &
directly correlate to ASD symptomatology in comparison to unaffected siblings
or healthy subjects.

To study possible
effects of probiotic supplementation on gut microbiota, fecal and
urinary analysis for toxins which have been
previously linked to ASD.

To evaluate possible
effects of probiotic supplementation on GI symptoms and in turn their
correlation to gut microbiota. 

To evaluate possible
effects of probiotic supplementation on improvement in cognitive, language development and behavioral symptomology in
children with ASD. 



The study design will be prospective interventional study, that
includes infants and preschool children diagnosed with ASD. Various demographic
details, maternal history, child’s Delivery, Neonatal & breastfeeding
history will be elucidated. The study population with be grouped into a GI
group or to a Non-GI (NGI) group based on the symptom severity index specific
to GI disorders. Obtaining 4 arms in the study, the subjects belonging to the
GI and NGI group will be randomized 1:1 into to a interventional and a control
group. Along with their regular diet, the intervention group will be given
probiotics and the control group with a placebo for 6 months. The main
variables in the study will be GI Symptoms, autism symptoms severity,
neurophysiological patterns, cognitive, language development and
behavioral symptomology. Secondary
variables include patient demographic profile, gut microbiota, Plasmatic, fecal and urinary biomarkers for toxins
related to abnormal intestinal function and altered microbiota-gut-brain axis.
Assessment will be done at baseline, after three months and after six months from baseline in order to
evaluate the possible changes.


and multivariate regression analysis will be performed to analyze the
associations.  Univariate
analysis uses Fisher’s exact test, two sample t-tests, or ?2-test
wherever appropriate. For comparisons with baseline assessments, Wilcoxon
signed-rank test will be used and Pearson’s correlation will be used to
examine the correlations. Kaplan-Meier Survival
analysis curves will be calculated and compared using the log-rank test. Linear
regression models will be used in comparison of variables between the groups
and among sub cohorts adjusted for possible confounding variables.


Implications of results and further scope of study :

This study could give us
valuable preliminary information on the mechanisms of microbiota-gut-brain axis in ASD. This information will help in
stratifying ASD patients risk and in appropriately targeting interventions for
specific sub set of ASD patients, leading to further clinical trials,
establishment of clinical practice guidelines and new therapeutic frontiers. To establish causation and determine the temporal
order of events, further longitudinal studies with analysis of fecal and
urinary samples of all babies (including those who will develop ASD and healthy
individuals) since at the time of birth would be needed.


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