Sydney M. Finegold, MD | Studies on Bacteriology of Autism

Dr. Sydney Finegold
Autism
The incidence of autism is increasing continuously and, in the latest survey, is one case in every 88 births and one per every 54 boys born (Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 2012;61:1-19.). Most of the increase appears to be in the regressive form of autism which currently accounts for two-thirds of all cases (Personal communication, Stephen Edelson, Autism Research Institute). To our knowledge, no one has offered a reasonable explanation for this striking phenomenon. Autism research to date has mainly focused on finding a genetic association, as autism has been considered a neurobiologically based genetic disorder. However, while there is evidence of genetic predisposition to autism, genetic studies have not uncovered genes of strong effect and evidence of systemic abnormalities (e.g., gastrointestinal and immune), and increasing rates of the disease support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. There is evidence indicating in utero or early postnatal environmental, infections, seizure, or autoimmune insult will trigger an immune response leading to autism. A number of autistic children manifest gastrointestinal abnormalities, with an apparent over-representation of a regressive history in those with GI symptoms. Among the GI abnormalities that have been noted are abdominal pain or discomfort, bloating, and constipation with or without diarrhea. MacFabe stresses the importance of the gut-brain connection and the probable role of diet, gut function, and enzymes in autism (MacFabe D. Autism and the digestive system. EP Magazine 2008;55-57.). We feel that regressive autism is primarily caused by overgrowth of certain bacteria in the bowel of these children, in turn related to use of antimicrobial agents that have little or no activity against these pathogens but suppress other elements of the normal bowel flora, permitting overgrowth of the resistant pathogens.

Vancomycin study
Our studies indicate that intestinal bacteria are a factor in autism in that autistic children improved after oral vancomycin, an antibiotic which is essentially not absorbed from the gut. We observed good clinical response in children with regressive autism receiving oral vancomycin in an open label trial (Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 2000;15:429-435.). In the study, patients ranged from 43 to 84 months in age, they had not received any antimicrobial for at least two months prior to entry into the study, had been clinically stable for at least 3 months, met the criteria for autistic disorder, and had no other significant medical problems. By the Childhood Autism Rating Scale, six children met the criteria for severe autism, two for moderate autism, and three for mild autism. Presence of intestinal pathogens that might be implicated in the gastrointestinal difficulties was ruled out by appropriate studies. Vancomycin was given orally as a liquid (500 mg/6 ml) divided into three 2 ml doses per day for 8 weeks.
There was evidence of a good clinical response in 8 of 10 evaluable children receiving oral vancomycin in this open label trial. The response included improved behavior, communication, and social skills. Behavior and communication analog rating scales were not done in blinded fashion, but paired videotapes (30 minutes in a playroom environment) made before and during therapy were evaluated in blinded fashion by a clinical child psychologist who had no personal contact with the children. Patients relapsed to their pre-treatment state within a few weeks, often within two weeks, of discontinuation of the vancomycin. A brief period (1 to 4 days) of hyperactivity, followed by lethargy for one day in one subject, was noted in 6 children within 3 days of initiating the vancomycin treatment. It is important to note that, anecdotally, several individual patients have responded to antimicrobials such as oral vancomycin and metronidazole on several occasions, relapsing each time after discontinuation and then responding again to reinstitution of these antimicrobials.

Microbiological studies
We have further studied the gut bacteria-autism connection. Our microbiological studies reveal that that the geometric mean count of clostridial species in the stools of children with autism was higher than in the stools of control children (P = 0.0393) and more clostridial species were found in autistic children. This finding was confirmed by using real-time PCR subsequently; we found that cell count differences of Clostridium bolteae and Clostridium clusters I and XI were statistically significantly higher in autistic than in age- and sex-matched control children. We have hypothesized what may be the critical involvement of clostridial spores in the bowel contaminating the local environment of children with autism as explanations for the increased incidence of autism in recent years and the incidence of multiple cases in families. We further examined the fecal microbial flora of 33 subjects with various severities of regressive autism with gastrointestinal symptoms, 7 siblings not showing autistic symptoms and eight non-sibling control subjects, using a bacterial tag encoded FLX amplicon pyrosequencing procedure. We found statistically significant differences in the gut flora of autistic and control subjects with statistically significant p values ranging from less than 0.001 to 0.009 indicating that autistic subjects have an altered intestinal flora. Autistic children had an increased level of Bacteroidetes whereas in controls, the Firmicutes dominated. Of particular interest was a statistically significantly greater presence of sulfate-reducing bacteria of the genus Desulfovibrio in severely autistic children as compared to unrelated control children, with higher counts of the organism in the most severe cases. Desulfovibrio produces hydrogen sulfide (H2S), a major toxic product, and endotoxin which is found in increased amounts in autistic children and correlates negatively with cognition.
An organism in the bowel responsible for the manifestations of autism would readily contaminate the environment (and, if a spore-former such as Clostridium sp. or an organism like Desulfovibrio known to go into a prolonged resting state in presence of hostile environment), would persist for extended periods). Very young siblings and visiting children, not being very hygienic yet, would readily acquire the organism(s) in question and, if predisposed by an inadequate immune system and/or antimicrobial therapy, might develop autism. A group of investigators from Columbia University in New York City (Williams, B. et al.) found a microaerophilic organism, Sutterella, in bowel mucosal biopsies of autistic children, but not in control children. We have found this organism in stools of autistic children in statistically significant numbers compared to control, non-autistic children. These findings underscore the important role of gut bacteria in autism.


Dr. Finegold is on the Emeritus faculty of the VA Medical Center, WLA in the Infectious Diseases Section and is Emeritus Professor of Medicine and of Microbiology, Immunology and Molecular Genetics at the UCLA School of Medicine. He trained in internal medicine before the subspecialty of infectious diseases was established, first with Wesley Spink, MD, and Wendell Hall, MD, at the University of Minnesota and later with William L. Hewitt, MD, at UCLA. His principal research interests over the past sixty years (the last 12 years as a "retiree") have been anaerobic bacteria and their role in disease and the intestinal flora of man and its role in health and disease.
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