Autism-Gut Connection
Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Phil D, Berelowitz M and Walker-Smith JA.
Introduction
We have recently described a characteristic pattern of intestinal inflammation in a cohort of children with developmental disorders (1). In these children, the majority of whom had autism, a period of initial normal development was followed by developmental regression and loss of acquired skills, sometimes occurring precipitously over a period of days to weeks. Long-standing intestinal symptoms, as described previously (1), were typical of this group of children. These symptoms had often started at around the same time as the behavioral changes.
Ileocolonic lymphoid nodular hyperplasia (LNH) was a consistent feature of this condition, an observation that has been reported subsequently in children with attention deficit hyperactivity disorder (ADHD) and non-IgE-mediated food allergy (2). There is an anecdotal impression that LNH is a common finding in children undergoing ileocolonoscopy, although this has not been subjected to systematic analysis in a controlled study.
It cannot be assumed that LNH is a normal finding in children, as aymptomatic children are not subjected to ileocolonoscopy, and LNH may produce symptoms in its own right (3). Chronic intestinal LNH is a feature of either congenital or acquired immunodeficient states (4, 5, 6, 7, 8, 9, 10) and has been described in congenital B cell abnormalities (5, 6), and common variable immunodeficiency (7, 8). In its persistent acquired form, ileal LNH has been reported in association with infection with human immunodeficiency virus (HIV) before the development of AIDS (10).
The other consistent feature of the intestinal lesion was a mild-to-moderate colitis that lacked the specific diagnostic features of either Crohn's disease or ulcerative colitis (1). This combination of features, i.e., LNH and nonspecific colitis, indicates the possibility of chronic mucosal and/or systemic immune dysregulation. Systemic immunological abnormalities are not infrequent in children with autistic spectrum disorders (11, 12, 13, 14), although the origin and significance of the findings are uncertain. These immune changes, plus the presence of myelin basic protein (MBP) antibodies (15) and inhibition of macrophage migration to MBP (16), have led some workers to suggest that the behavioural syndrome may be associated with cerebral damage due to an autoimmune response to myelin or other structural components of the CNS (15, 16).
As part of our initial study (1) we undertook cerebral magnetic resonance imaging, EEG, and biochemical analysis of cerebrospinal fluid; none of these investigations indicated cerebral inflammation that would be consistent with autoimmune demyelination, although a more subtle lesion remains a possibility. Alternatively, others have proposed that some forms of autism may arise from the toxic effects of intestinal products on the developing brain (17, 18, 19), a situation that may have some overlap with hepatic enephalopathy. An early childhood enterocolitis would be more consistent with the latter mechanism.
This study sought to describe some of the characteristic endoscopic and histopathological features of this syndrome in a larger cohort of children with developmental disorders and intestinal symptoms, and to compare the findings with those in developmentally normal children undergoing ileocolonoscopy.
Materials and Methods
This study involved the analysis of data from 60 consecutive children with developmental disorders (affected children) including those 12 children described in a preliminary report (1). The median age of the children was 6 yr (range 3-16 yr) and 53 were boys, consistent with the male bias of developmental disorders (20). Developmental diagnoses in the affected children were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), and schizophrenia (one). The latter child was the oldest in the cohort, at 14 yr of age. The remaining child in this cohort, a girl 8 yr of age, had dyslexia and learning difficulties: she underwent developmental regression from approximately 54 months of age, which was associated with mouth ulcers, conjunctivitis, and severe constipation. Her developmental status is currently under investigation.
Autism is a behavioral syndrome that consists of qualitative impairments in social interaction and communication, with restrictive, repetitive, and stereotypic patterns of behavior. Delays or abnormal functioning in at least one of these areas occurs before the age of 3 yr. Asperger's syndrome is a high-functioning autistic spectrum disorder, and disintegrative disorder is a regressive condition occurring at age >3 yr in a previously normal child. Loss of acquired skills may occur precipitously or over a period of months. The behavioral features are similar to those of autism but may be accompanied by loss of bowel and bladder control (20).
The majority of affected children were white (57), but two were of Middle-Eastern origin, and one child had an Indian father and a white mother.
All but three affected children had a developmental disorder that was associated with a clear history of regression, with loss of acquired skills after 1 year of documented normal development (general practitioner/health visitor records). In three cases, affected children who had been developmentally normal failed to progress beyond a certain point, but did not regress. All but one of the affected children had current intestinal symptoms consisting of abdominal pain, constipation, diarrhea (or alternating constipation and diarrhea), and bloating.
The one affected child who did not have current intestinal symptoms was investigated at his parents' and general practitioner's request. Affected children were consistently fastidious in their eating habits, with a diet limited largely to cereals, potato crisps, and bread. Despite this, they typically seemed well nourished, with anthropomorphic indices within normal limits. Certain foodstuffs such as dairy products were reported by parents to produce deterioration in behavior, whereas withholding such foods apparently produced behavioral improvement -- in particular, for aggression, eye contact, and sleep pattern. According to parental reports, recognizably undigested food was often seen in stools.
Discussion
These data both confirm and extend our original observations (1), and indicate a subtle and consistent pattern of intestinal pathology in this cohort of consecutively referred children. The combination of ileocolonic LNH and colitis in children with developmental disorders distinguished them from developmentally normal children with similar symptoms (including abdominal pain and constipation) in whom LNH and histopathological change were uncommon. These observations, in a broader diagnostic group of children with developmental/psychiatric disorders, and the recent report of Sabra et al. (2) of similar intestinal pathology in children with ADHD, suggests that the findings may be relevant more widely to childhood developmental disorders.
This study provides a quantitative assessment of a qualitative interpretation of histopathological changes in the ileocolonic mucosa. We have previously reported the quantitative assessment of cellular infiltration of the mucosa in biopsies from these children, employing immunohistochemistry and cell counting (22). That study confirmed the presence of a statistically significant increase in mucosal macrophage infiltrate and cells expressing class-II MHC antigen in biopsies from affected children, compared with normal controls.
Further quantitative studies have shown a statistically significant excess of CD3+, CD8+, and T cells, and of Syndecan-1+ plasma cells in the lamina propria, and evidence of increased epithelial proliferation in affected children compared with both normal children and those with chronic constipation (R. Furlano et al., submitted for publication). The pathology seems to reflect a subtle new variant of inflammatory bowel disease that lacks the specific diagnostic features of either Crohn's disease (e.g., granulomata) or ulcerative colitis (e.g., contiguous distal to proximal colonic inflammation).
The inflammatory features were accompanied by endoscopic changes and included a patchy, mild-to-moderate pancolitis, where (with the proviso that only mucosal biopsies were studied) they were confined to the upper lamina propria/epithelium. It is of possible clinical relevance that active disease in the ileum and colon was reflected systemically in a raised ESR and a neutrophil leucocytosis, respectively.
In view of the presenting symptoms in the affected children, the majority underwent ileocolonscopy rather than investigation of the upper gastrointestinal tract. However, Horvath et al. have recently reported compelling evidence of inflammatory changes in the esophagus, stomach, and duodenum in a majority of autistic children with symptoms similar to those described here (23). Where it is indicated, we have included upper endoscopy and biopsy in our protocol. Our initial findings are consistent with those of Horvath et al. and will be reported later.
The median age of affected children was lower than that in either of the two control groups. However, within the controls groups there was no relationship between age and either endoscopic or histopathological features of disease, indicating that the comparisons made here are valid. The natural history of this condition -- autistic enterocolitis -- is not known; because Crohn's disease and ulcerative colitis are rare in this age group, it is too soon to say whether or not the pathology will progress to a typical IBD phenotype.
It is notable that 68% of affected children had a lymphopenia. Immunological abnormalities are a recurring feature in studies of children with autism (25, 26), and detailed immunological studies of affected children will be reported as a follow-up to this report. Reactive follicular hyperplasia is an antigen-driven response (9). In a preliminary study, we have reported evidence of measles virus nucleocapsid protein in follicular dendritic cells of the reactive ileal lymphoid tissue and raised serum measles IgG immunoreactivity in some affected children (26). An association between measles virus, immunodysregulation, and autism was also suggested by the recent study by Singh et al. (27). Measles virus is recognized not only for its ability to establish persistent infection, but also to induce prolonged T helper cell, type II immune skewing and immunosuppression (28). The follicular dendritic cell would be an ideal location from which to mediate such a response (29).
It is tempting to suggest that a gut-brain interaction may be responsible for some of the behavioral features of this syndrome. Although the opioid excess hypothesis for autism was first proposed by Panksepp (17) in 1979, and reiterated independently by Reichelt et al. (18) and Shattock et al. (19), it has only recently found increasing acceptance in the pediatric psychiatry community. Opioid peptides of dietary origin, i.e., gliadomorphine and bovine casomorphine, have been identified in the urine of some of these children with autistic enterocolitis (unpublished observations), and the possible significance of these findings is under investigation.
In summary, an endoscopically and histologically consistent pattern of ileocolonic pathology has been identified in a cohort of children with developmental disorders. Reactive follicular hyperplasia, particularly prominent in the ileum, provides a focus for investigating the nature of antigen(s) that may be driving the intestinal inflammation in these children. This syndrome may reflect a subset of children with developmental disorders with distinct etiological and clinical features.
American Journal of Gastroenterology September 2000; 95: 2285-2295.