From the AGA Journals

Unique, multi-omic profile found in children with autism and functional GI disorders

Publish date: March 1, 2017
By
Amy Karon
MDedge News

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Autism-spectrum disorder is a serious and increasingly prevalent developmental behavior disorder often accompanied and aggravated by a range of gastrointestinal and cognitive dysfunctions. Its etiology probably involves maternal diet and inflammatory events that alter central nervous system neurodevelopment critical to the cognition of social interaction. Candidate causal products of these events include the cytokines IL-6 and IL-17A, and certain bioactive amines, notably serotonin. Functional gastrointestinal disorders share these same molecules as biomarkers and disease modifiers, probably elicited in part by the intestinal microbiome. Hence, the comorbidity in ASD suggests these two disease processes are etiologically related.

The study by Luna and colleagues tightens the case for a microbial hub and serotonin and cytokine spokes in the gastrointestinal dysfunction of ASD: elevated mucosal tissue levels of select microbial taxa, mainly members of the genus Clostridium, and mucosal production of cytokines and serotonin-pathway bioamines associated with these and other select microbial species. Important and challenging questions loom ahead. What are the direct mucosal cell types and functions targeted of this network for the microbiota, and via what microbial products? Might they elicit epithelial or mucosal hematopoietic cell cytokine production that in turn causes mucosal bioamine secretion? And, what associated microbiota and products are just secondarily altered and not causally involved? The exciting study of Luna and colleagues raises confidence for this path ahead, and its promise for clarifying ASD pathogenesis and uncovering targetable elements for intervention.

Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine, UCLA David Geffen School of Medicine, UCLA Health System, Los Angeles. He has no conflicts of interest.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

The gut microbiomes of children with autism spectrum disorder (ASD) and functional gastrointestinal disorders (FGID) had significantly higher levels of several Clostridium species and lower concentrations of other bacteria compared with neurotypical children with and without FGIDs, which correlated with increases in inflammatory cytokines, decreased tryptophan, and increased serotonin, according to a small, single-center, cross-sectional study.

Children with ASD are at increased risk for FGIDs such as functional constipation, nonretentive fecal incontinence, functional abdominal pain, abdominal migraines, and irritable bowel syndrome, compared with their neurotypical peers. Changes in the gut microbiome can affect immunologic pathways and the balance between tryptophan and serotonin. This altered “microbial-gut-brain axis” has been reported in both ASD and FGID, suggesting “that altered gut-brain communications not only may play a role in the increased occurrence of FGIDs in ASD individuals, but could advance our understanding of potential risk factors for FGID in the ASD community,” the researchers wrote.

Previous studies of stool specimens have found higher levels of several species of Clostridium in pediatric ASD compared with neurotypical children. To confirm and expand on that work, the investigators examined microbial and neuroimmune markers in rectal biopsies and blood specimens from 14 children with ASD-FGID, 15 neurotypical children with FGID, and 6 asymptomatic neurotypical children. Participants were recruited from Nationwide Children’s Hospital in Columbus, Ohio. The researchers quantified microbial 16S ribosomal DNA community signatures, cytokines, chemokines, and serotonergic metabolites, and correlated results with parental responses to the Questionnaire on Pediatric Gastrointestinal Symptoms–Rome III version.

The ASD-FGID group had significantly higher numbers for ribosomal DNA sequences for Clostridium lituseburense (P = .002), Lachnoclostridium bolteae (P = .02), Lachnoclostridium hathewayi (P = .03), Clostridium aldenense (P = .04), and Oscillospira plautii (P = .04), compared with neurotypical children with and without FGID. Children with ASD-FGID also had significantly lower levels of Dorea formicigenerans (P = .006), Blautia luti (P = .02), and Sutterella species (P = .03). “Overall, our identification of clostridial species aligns with previous autism studies that have identified microbiome alterations,” the researchers noted.

They also looked specifically at abdominal pain. Children with ASD-FGID and abdominal pain had significantly higher gut mucosal levels of Turicibacter sanguinis (P = .03), Clostridium aldenense (P = .004), Clostridium lituseburense (P = .003), Oscillospira plautii (P = .01), Clostridium disporicum (P = .049), and Clostridium tertium (P = .045) than did any other subgroup, the investigators found. Patients with both ASD-FGID and abdominal pain also had significantly higher levels of C. aldenense (P = .03), O. plautii (P = .04), Tyzzerella species (P = .045), and Parasutterella excrementihominis (P = .04) than did ASD-FGID patients without abdominal pain.

Both C. disporicum and C. tertium correlated with increases in the proinflammatory cytokines IL6 and interferon-gamma. Levels of these cytokines were highest in patients with ASD-FGID, and IL6 was highest of all among children with ASD-FGID with abdominal pain. Another proinflammatory cytokine, IL17A, also correlated with Clostridia species that were enriched in children with ASD-FGID. Both IL6 and IL17A have been implicated in autism-like phenotypes in rodents, the researchers noted. Several other cytokines also were linked to ASD-FGID, and abdominal pain correlated significantly with increases in MCP-1 (P = .03) and eotaxin (P = .03).

Gut mucosal levels of tryptophan were significantly lower among children with ASD-FGID compared with neurotypical children, either with (P = .006) or without (P = .009) FGID. In contrast, gut mucosal levels of 5-HIAA, the primary metabolite of serotonin, were significantly higher among children with ASD-FGID compared with neurotypical children (P = .01). Increased 5-HIAA also correlated significantly with abdominal pain (P = .04). Six species of bacteria correlated significantly with tryptophan or serotonin, implicating the gut microbiome in the serotonin pathway.

“Although these initial findings are correlative, these data form the framework for future studies targeting tryptophan-serotonin metabolism and inflammatory pathways in FGID in ASD,” the researchers concluded.

The U.S. Department of Health and Human Services funded the work. The investigators had no relevant disclosures.

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