Altered metabolism of mothers of young children with Autism Spectrum Disorder: a case control study.

BACKGROUND: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism. METHODS: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods. RESULTS: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules. CONCLUSIONS: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.

Evidence based recommendations for an optimal prenatal supplement for women in the US: vitamins and related nutrients.

The blood levels of most vitamins decrease during pregnancy if un-supplemented, including vitamins A, C, D, K, B1, B3, B5, B6, folate, biotin, and B12. Sub-optimal intake of vitamins from preconception through pregnancy increases the risk of many pregnancy complications and infant health problems. In the U.S., dietary intake of vitamins is often below recommended intakes, especially for vitamin D, choline and DHA. Many studies suggest that insufficient vitamin intake is associated with a wide range of pregnancy complications (anemia, Cesarean section, depression, gestational diabetes, hypertension, infertility, preeclampsia, and premature rupture of membranes) and infant health problems (asthma/wheeze, autism, low birth weight, congenital heart defects, intellectual development, intrauterine growth restriction, miscarriage, neural tube defects, orofacial defects, and preterm birth). The primary goal of this paper is to review the research literature and propose evidence-based recommendations for the optimal level of prenatal supplementation for each vitamin for most women in the United States. A secondary goal was to compare these new recommendations with the levels of vitamins in over 180 commercial prenatal supplements. The analysis found that prenatal supplements vary widely in content, often contained only a subset of essential vitamins, and the levels were often below our recommendations. This suggests that increasing prenatal vitamin supplementation to the levels recommended here may reduce the incidence of many pregnancy complications and infant health problems which currently occur.

Evidence-Based Recommendations for an Optimal Prenatal Supplement for Women in the U.S., Part Two: Minerals.

The levels of many essential minerals decrease during pregnancy if un-supplemented, including calcium, iron, magnesium, selenium, zinc, and possibly chromium and iodine. Sub-optimal intake of minerals from preconception through pregnancy increases the risk of many pregnancy complications and infant health problems. In the U.S., dietary intake of minerals is often below the Recommended Dietary Allowance (RDA), especially for iodine and magnesium, and 28% of women develop iron deficiency anemia during their third trimester. The goal of this paper is to propose evidence-based recommendations for the optimal level of prenatal supplementation for each mineral for most women in the United States. Overall, the evidence suggests that optimal mineral supplementation can significantly reduce a wide range of pregnancy complications (including anemia, gestational hypertension, gestational diabetes, hyperthyroidism, miscarriage, and pre-eclampsia) and infant health problems (including anemia, asthma/wheeze, autism, cerebral palsy, hypothyroidism, intellectual disability, low birth weight, neural tube defects, preterm birth, rickets, and wheeze). An evaluation of 180 commercial prenatal supplements found that they varied widely in mineral content, often contained only a subset of essential minerals, and the levels were often below our recommendations. Therefore, there is a need to establish recommendations on the optimal level of mineral supplementation during pregnancy.

Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota.

Many studies have reported abnormal gut microbiota in individuals with Autism Spectrum Disorders (ASD), suggesting a link between gut microbiome and autism-like behaviors. Modifying the gut microbiome is a potential route to improve gastrointestinal (GI) and behavioral symptoms in children with ASD, and fecal microbiota transplant could transform the dysbiotic gut microbiome toward a healthy one by delivering a large number of commensal microbes from a healthy donor. We previously performed an open-label trial of Microbiota Transfer Therapy (MTT) that combined antibiotics, a bowel cleanse, a stomach-acid suppressant, and fecal microbiota transplant, and observed significant improvements in GI symptoms, autism-related symptoms, and gut microbiota. Here, we report on a follow-up with the same 18 participants two years after treatment was completed. Notably, most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment. Important changes in gut microbiota at the end of treatment remained at follow-up, including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella. Our observations demonstrate the long-term safety and efficacy of MTT as a potential therapy to treat children with ASD who have GI problems, and warrant a double-blind, placebo-controlled trial in the future.

Reply to "Comment on: Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial, Nutrients 2018, 10, 369".

We thank Vorland et al [...].

Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial.

This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3-58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. -0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.

Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study.

BACKGROUND: Autism spectrum disorders (ASD) are complex neurobiological disorders that impair social interactions and communication and lead to restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. The causes of these disorders remain poorly understood, but gut microbiota, the 1013 bacteria in the human intestines, have been implicated because children with ASD often suffer gastrointestinal (GI) problems that correlate with ASD severity. Several previous studies have reported abnormal gut bacteria in children with ASD. The gut microbiome-ASD connection has been tested in a mouse model of ASD, where the microbiome was mechanistically linked to abnormal metabolites and behavior. Similarly, a study of children with ASD found that oral non-absorbable antibiotic treatment improved GI and ASD symptoms, albeit temporarily. Here, a small open-label clinical trial evaluated the impact of Microbiota Transfer Therapy (MTT) on gut microbiota composition and GI and ASD symptoms of 18 ASD-diagnosed children. RESULTS: MTT involved a 2-week antibiotic treatment, a bowel cleanse, and then an extended fecal microbiota transplant (FMT) using a high initial dose followed by daily and lower maintenance doses for 7-8 weeks. The Gastrointestinal Symptom Rating Scale revealed an approximately 80% reduction of GI symptoms at the end of treatment, including significant improvements in symptoms of constipation, diarrhea, indigestion, and abdominal pain. Improvements persisted 8 weeks after treatment. Similarly, clinical assessments showed that behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended. Bacterial and phagedeep sequencing analyses revealed successful partial engraftment of donor microbiota and beneficial changes in the gut environment. Specifically, overall bacterial diversity and the abundance of Bifidobacterium, Prevotella, and Desulfovibrio among other taxa increased following MTT, and these changes persisted after treatment stopped (followed for 8 weeks). CONCLUSIONS: This exploratory, extended-duration treatment protocol thus appears to be a promising approach to alter the gut microbiome and virome and improve GI and behavioral symptoms of ASD. Improvements in GI symptoms, ASD symptoms, and the microbiome all persisted for at least 8 weeks after treatment ended, suggesting a long-term impact. TRIAL REGISTRATION: This trial was registered on the ClinicalTrials.gov, with the registration number  NCT02504554.