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Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.

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Based on the hypothesis that intestinal clostridia play a role in late-onset autism, we have been characterizing clostridia from stools of autistic and control children. We applied the TaqMan real-time PCR procedure to detect and quantitate three Clostridium clusters and one Clostridium species, C. bolteae, in stool specimens. Group-and species-specific primers targeting the 16S rRNA genes were designed, and specificity of the primers was confirmed with DNA from related bacterial strains. In this procedure, a linear relationship exists between the threshold cycle (C T ) fluorescence value and the number of bacterial cells (CFU). The assay showed high sensitivity: as few as 2 cells of members of cluster I, 6 cells of cluster XI, 4 cells of cluster XIVab, and 0.6 cell of C. bolteae could be detected per PCR. Analysis of the real-time PCR data indicated that the cell count differences between autistic and control children for C. bolteae and the following Clostridium groups were statistically significant: mean counts of C. bolteae and clusters I and XI in autistic children were 46-fold (P ‫؍‬ 0.01), 9.0-fold (P ‫؍‬ 0.014), and 3.5-fold (P ‫؍‬ 0.004) greater than those in control children, respectively, but not for cluster XIVab (2.6 ؋ 10 8 CFU/g in autistic children and 4.8 ؋ 10 8 CFU/g in controls; respectively). More subjects need to be studied. The assay is a rapid and reliable method, and it should have great potential for quantitation of other bacteria in the intestinal tract.Autism is a complex disease with unclear causes. Many autistic subjects exhibit a range of gut disorders, which include constipation, diarrhea, retention of gas, and abdominal pain and discomfort. Abnormal gut microflora may play a role in these problems. Research into the characteristics of the gut flora in autism has been limited. In our initial studies that characterized the fecal bacterial composition by culturing, we noted abnormalities in the fecal bacterial composition of children with autism compared to age-and sex-matched controls. We found higher counts of clostridia overall and more species of clostridia in stools of autistic children than in healthy children (11). In particular, Clostridium bolteae, a novel species that we described previously (29; called Clostridium clostridioforme in reference 11), caught our attention because it was cultured from 5 of 15 autistic children, but none of 8 controls. However, it is well known that traditional culture-based methods, while very important, result in a significant underestimation of bacteria present in fecal samples (14,19,30).Molecular techniques introduced in microbial ecology have made it possible to study the composition of intestinal flora in a culture-independent way based on the detection of rRNA genes. Although these methods, such as fluorescent in situ hybridization (12,13,19), denaturing gradient gel electrophoresis, temperature gradient gel electrophoresis (8,10,28), and the 16S rRNA gene clone library method (15,27,30), have been applied successfully for studying the eco...

Colon and rectal cancer together account for an estimated 92,500 new cancer cases in the U.S. annually, more than any other organ site; large bowel cancer results in an estimated annual mortality of 47,400, being second only to lung cancer in this regard (1). The median survival time for colon cancer patients is only 2.2 years. Recent epidemiologic studies are of great interest since they offer prospects of preventing this very serious form of cancer. Japan is one of a number of countries with a low incidence of large bowel cancer. However, Japanese migrating to the U.S. and adopting the western diet develop this cancer with increased frequency, approaching that of native Amencans (1). Hill et al. (2) have postulated that intestinal

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