Kent C. Williams

Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, and Associated Factors

The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. One hundred twenty‐one children were recruited into three groups: co‐occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their childs behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% confidence interval 2.54–56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by health‐care providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.

Rigid–Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder

Based on clinical experience, we hypothesized that rigid–compulsive behaviors are associated with severe constipation and co-occurring diarrhea or underwear staining in children with autism spectrum disorder. Using data from the Autism Treatment Network, we evaluated the association between these gastrointestinal symptoms and measures of rigid compulsive behavior in children ages 2–17. Following statistical correction, four of five primary measures were significantly associated with constipation and diarrhea or underwear staining, including parental report of repetitive behavior, parental report of compulsive behavior, clinician diagnosis of obsessive–compulsive disorder, and report of rituals observed on the autism diagnostic observation schedule. This association could point to a causal connection between these symptoms or to a common biological pathway that impacts both gut and brain.

Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder

Background & Aims Emerging data on the gut microbiome in autism spectrum disorder (ASD) suggest that altered host–microbe interactions may contribute to disease symptoms. Although gut microbial communities in children with ASD are reported to differ from individuals with neurotypical development, it is not known whether these bacteria induce pathogenic neuroimmune signals. Methods Because commensal clostridia interactions with the intestinal mucosa can regulate disease-associated cytokine and serotonergic pathways in animal models, we evaluated whether microbiome-neuroimmune profiles (from rectal biopsy specimens and blood) differed in ASD children with functional gastrointestinal disorders (ASD-FGID, n = 14) compared with neurotypical (NT) children with FGID (NT-FGID, n = 15) and without abdominal pain (NT, n = 6). Microbial 16S ribosomal DNA community signatures, cytokines, and serotonergic metabolites were quantified and correlated with gastrointestinal symptoms. Results A significant increase in several mucosa-associated Clostridiales was observed in ASD-FGID, whereas marked decreases in Dorea and Blautia, as well as Sutterella, were evident. Stratification by abdominal pain showed multiple organisms in ASD-FGID that correlated significantly with cytokines (interleukin [IL]6, IL1, IL17A, and interferon-γ). Group comparisons showed that IL6 and tryptophan release by mucosal biopsy specimens was highest in ASD children with abdominal pain, whereas serotonergic metabolites generally were increased in children with FGIDs. Furthermore, proinflammatory cytokines correlated significantly with several Clostridiales previously reported to associate with ASD, as did tryptophan and serotonin. Conclusions Our findings identify distinctive mucosal microbial signatures in ASD children with FGID that correlate with cytokine and tryptophan homeostasis. Future studies are needed to establish whether these disease-associated Clostridiales species confer early pathogenic signals in children with ASD and FGID.

Detecting Biochemical Changes in the Rodent Cervix During Pregnancy Using Raman Spectroscopy

The goal of this research is to determine whether Raman spectroscopy (RS), an optical method that probes the vibrational modes of tissue components, can be used in vivo to study changes in the mouse cervix during pregnancy. If successful, such a tool could be used to detect cervical changes due to pregnancy, both normal and abnormal, in animal models and humans. For this study, Raman spectra were acquired before, during and after a 19-day mouse gestational period. In some cases, after Raman data was obtained, cervices were excised for structural testing and histological staining for collagen and smooth muscle. Various peaks of the Raman spectra, such as the areas corresponding to fatty acid content and collagen organization, changed as the cervix became softer in preparation for labor and delivery. These findings correspond to the increase in compliance of the tissue and the collagen disorganization visualized with the histological staining. The results of this study suggest that non-invasive RS can be used to study cervical changes during pregnancy, labor and delivery and can possibly predict preterm delivery before overt clinical manifestations, potentially lead to more effective preventive and therapeutic interventions.

Age- and Ethnic-Specific Elevation of ALT Among Obese Children at Risk for Nonalcoholic Steatohepatitis (NASH): Implications for Screening

The objectives are to: (1) characterize ethnic-specific differences in alanine aminotransferase (ALT) elevation among obese children, (2) investigate the earliest ages at which significant ALT elevation occurs, and (3) determine associations between ALT and biochemical parameters. A cohort of 134 multiethnic obese children and adolescents was analyzed retrospectively. ALT levels ≥45 U/L or <45 U/L, denoting high or normal risk, were used to categorize obese childrens risk for developing nonalcoholic steatohepatitis. In all, 60% of Hispanics had high-risk ALT levels compared with 12% of whites and 8% of blacks. A significantly higher proportion of boys had ALT ≥ 45 U/L (49.4%, vs 37.9% for girls, P = .002); 17.5% were Hispanic boys less than 7 years old. Obese Hispanic children, particularly boys, not only have higher ALT levels but present alarmingly young with high-risk levels. This study highlights a discrete subgroup of children who may present with fatty liver at a younger age and should be screened earlier.

The Brain-Gut-Microbiome Axis: What Role Does it Play in Autism Spectrum Disorder?

The brain-gut-microbiome axis refers to the interactions between the central nervous system, gastrointestinal (GI) system, and microorganisms that live in the gastrointestinal tract. Exploring these interactions provides a rationale for why gastrointestinal disorders commonly occur in children with autism spectrum disorders (ASD). Signs of altered brain-gut interactions that are closely associated with functional GI disorders (FGIDs) commonly occur in children with ASD. Studies of microbiome in ASD suggest that changes in the gut microbiome may be associated with ASD and with GI disorders in children with ASD. Further studies into the brain-gut-microbiome axis could lead to new techniques for identifying GI disorders in children with ASD and novel therapies for treating ASD behaviors.

Association of Rigid-Compulsive Behavior with Functional Constipation in Autism Spectrum Disorder.

Based upon checklist data from the Autism Speaks Autism Treatment Network, we hypothesized that functional constipation (FC) would be associated with rigid-compulsive behavior in children with autism spectrum disorder (ASD). We used the Questionnaire on Pediatric Gastrointestinal Symptoms—Rome III to assess FC symptoms in 108 children with ASD. As hypothesized, FC was associated with parent ratings on the Repetitive Behavior Scales—Revised (RBS-R) Compulsive, Ritualistic, and Sameness subscales in the overall population. Of note, FC was less common in children who were not taking medications that target behavior or treat FC. In the medication-free children, rigid-compulsive behavior was not significantly associated with FC. More research is needed to understand the mechanisms underlying these associations.

Constipation in Children with Autism Spectrum Disorder Associated with Increased Emergency Department Visits and Inpatient Admissions

Objective To evaluate whether constipation in children with autism spectrum disorder (ASD) is associated with increased emergency department (ED) visits and inpatient admissions compared with constipation in children without ASD. Study design The Nationwide Emergency Department Sample was used to retrospectively examine demographic data, clinical characteristics, and outcomes of children with ASD and children without ASD who visited the ED for constipation between 2006 and 2014. Results ED visits by children with ASD were more likely to be constipation‐related compared with visits by children with other chronic conditions or children with no chronic conditions (1.9% vs 0.6% vs 0.9%; P < .001). Children with ASD were more likely than children with other chronic conditions or no chronic conditions to be admitted to the hospital after an ED visit for constipation (15.0% vs 10.6% vs 1.2%; P < .001). Hospital charges were higher in children with ASD than in those without chronic conditions. Conclusions Constipation is responsible for a large proportion of ED visits and more inpatient admissions resulting from these ED visits. These findings suggest a need for developing more effective outpatient therapies for constipation in children with ASD.