late-onset autism and clostridia


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(Updated 3/9/05)

Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A.
Gastrointestinal microflora studies in late-onset autism.
Clin Infect Dis. 2002 Sep 1;35(Suppl 1):S6-S16.
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. [Full Text]

Song Y, Liu C, Finegold SM
Real-time PCR quantitation of clostridia in feces of autistic children.
Appl Environ Microbiol. 2004 Nov;70(11):6459-65.
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 (CT) 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 x 10(8) CFU/g in autistic children and 4.8 x 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. [Abstract]

Martirosian G.
[Anaerobic intestinal microflora in pathogenesis of autism?]
Postepy Hig Med Dosw (Online). 2004 Sep 20;58:349-51.
The present study provides information on differences in the gastrointestinal microflora of children with autism compared with a control group. Special attention was paid to the microbiological characteristic of the new obligate anaerobic microorganisms: Clostridium bolteae sp.nov. and Cetobacterium somerae sp.nov. observed in stools of children with autism. In light of recent publications, the hypothesis of interactions between intestinal microflora - and the brain based on possible alterations in bacterial toxins and other metabolites in the pathogenesis of autism is discussed. [Abstract]

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 Jul;15(7):429-35.
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. [Abstract]

Whelan J.
Antibiotics: a possible treatment for regressive-onset autism.
Drug Discov Today. 2000 Nov 1;5(11):487-488. [PubMed Link]

Linday LA
Saccharomyces boulardii: potential adjunctive treatment for children with autism and diarrhea.
J Child Neurol. 2001 May;16(5):387. [Abstract]

Kotowska M, Albrecht P, Szajewska H.
Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial.
Aliment Pharmacol Ther. 2005 Mar 1;21(5):583-90.
Summary Background : Co-treatment with Saccharomyces boulardii appears to lower the risk of antibiotic-associated diarrhoea in adults receiving broad-spectrum antibiotics. Aim : To determine whether S. boulardii prevents antibiotic-associated diarrhoea in children. Methods : A total of 269 children (aged 6 months to 14 years) with otitis media and/or respiratory tract infections were enrolled in a double-blind, randomized placebo-controlled trial in which they received standard antibiotic treatment plus 250 mg of S. boulardii (experimental group, n = 132) or a placebo (control group, n = 137) orally twice daily for the duration of antibiotic treatment. Analyses were based on allocated treatment and included data from 246 children. Results : Patients receiving S. boulardii had a lower prevalence of diarrhoea (>/=3 loose or watery stools/day for >/=48 h occurring during or up to 2 weeks after the antibiotic therapy) than those receiving placebo [nine of 119 (8%) vs. 29 of 127 (23%), relative risk: 0.3, 95% confidence interval: 0.2-0.7]. S. boulardii also reduced the risk of antibiotic-associated diarrhoea (diarrhoea caused by Clostridium difficile or otherwise unexplained diarrhoea) compared with placebo [four of 119 (3.4%) vs. 22 of 127 (17.3%), relative risk: 0.2; 95% confidence interval: 0.07-0.5]. No adverse events were observed. Conclusion : This is the first randomized-controlled trial evidence that S. boulardii effectively reduces the risk of antibiotic-associated diarrhoea in children. [Abstract]

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Recent Late-onset Autism and Clostridia Research

1) Clayton TA
Metabolic differences underlying two distinct rat urinary phenotypes, a suggested role for gut microbial metabolism of phenylalanine and a possible connection to autism.
FEBS Lett. 2012 Apr 5;586(7):956-61.
A novel explanation is proposed for the metabolic differences underlying two distinct rat urinary compositional phenotypes i.e. that these may arise from differences in the gut microbially-mediated metabolism of phenylalanine. As part of this hypothesis, it is further suggested that elements of the mammalian gut microbiota may convert phenylalanine to cinnamic acid, either by means of an ammonia lyase-type reaction or by means of a three step route via phenylpyruvate and phenyllactate. The wider significance of such conversions is discussed with similar metabolism of tryptophan and subsequent glycine conjugation potentially explaining the origin of trans-indolylacryloylglycine, a postulated marker for autism. [PubMed Citation] [Order full text from Infotrieve]

2) Finegold SM, Downes J, Summanen PH
Microbiology of regressive autism.
Anaerobe. 2012 Apr;18(2):260-2.
This manuscript summarizes some of our earlier work on the microbiology of autism subjects' stool specimens, as compared with stools from control subjects. Our most recent data indicating that Desulfovibrio may play an important role in regressive autism is also presented. In addition, we present information on antimicrobial susceptibility patterns of Desulfovibrio using the CLSI agar dilution susceptibility technique. In addition, we summarize data from our earlier studies showing the impact of various antimicrobial agents on the indigenous bowel flora. This shows that penicillins and cephalosporins, as well as clindamycin, have a major impact on the normal bowel flora and therefore might well predispose subjects to overgrowth of such organisms as Clostridium difficile, and of particular importance for autism, to Desulfovibrio. [PubMed Citation] [Order full text from Infotrieve]

3) Iebba V, Aloi M, Civitelli F, Cucchiara S
Gut microbiota and pediatric disease.
Dig Dis. 2011;29(6):531-9.
[PubMed Citation] [Order full text from Infotrieve]

4) Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI
Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances.
PLoS One. 2011;6(9):e24585.
Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism. [PubMed Citation] [Order full text from Infotrieve]

5) Finegold SM
Desulfovibrio species are potentially important in regressive autism.
Med Hypotheses. 2011 Aug;77(2):270-4.
Autism is a complex disorder with no specific diagnostic test so the disease is defined by its characteristics including cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation. The incidence of this disease has increased remarkably in recent years and was 110/10,000 children (?1%) in multiple areas of the US in 2007. The financial burden on families and communities is enormous. In terms of predisposing factors, heredity plays a role in some subjects, but it is clear that environmental factors are also important. Environmental toxins can affect the immune system adversely. Intestinal bacteria are recognized by a few investigators as potentially important and we have proposed that certain antimicrobial drugs may be a key factor in modifying the intestinal bacterial flora adversely, selecting out potentially harmful bacteria that are normally suppressed by an intact normal intestinal flora. We had felt that clostridia in the gut might be involved in autism because they are virulent organisms and spore-formers; spores would resist antibacterial agents so that when antibiotics were discontinued the spores would germinate and by toxin production or another mechanism lead to autism. However, a recent study of ours employing the powerful pyrosequencing technique on stools of subjects with regressive autism showed that Desulfovibrio was more common in autistic subjects than in controls. We subsequently confirmed this with pilot cultural and real-time PCR studies and found siblings of autistic children had counts of Desulfovibrio that were intermediate, suggesting possible spread of the organism in the family environment. Desulfovibrio is an anaerobic bacillus that does not produce spores but is nevertheless resistant to aerobic and other adverse conditions by other mechanisms and is commonly resistant to certain antimicrobial agents (such as cephalosporins) often used to treat ear and other infections that are relatively common in childhood. This bacterium also produces important virulence factors and its physiology and metabolism position it uniquely to account for much of the pathophysiology seen in autism. If these results on Desulfovibrio are confirmed and extended in other studies, including treatment trials with appropriate agents and careful clinical and laboratory studies, this could lead to more reliable classification of autism, a diagnostic test and therapy for regressive autism, development of a vaccine for prevention and treatment of regressive autism, tailored probiotics/prebiotics, and important epidemiologic information. [PubMed Citation] [Order full text from Infotrieve]

6) Martirosian G, Ekiel A, Aptekorz M, Wiechuła B, Kazek B, Jankowska-Steifer E, Jˇźwiak J, Moskalewski S
Fecal lactoferrin and Clostridium spp. in stools of autistic children.
Anaerobe. 2011 Feb;17(1):43-5.
Stools from autistic and healthy children were studied for fecal lactoferrin, Clostridium difficile toxins, Clostridium perfringens enterotoxin and cultured for Clostridium spp. Elevated level of FLA was demonstrated in 24.4% stools, all from boys (31.25%). No toxins were detected. Clostridium spp. was isolated with similar frequency from all samples. C. perfringens were isolated significantly often from the autistic stools, intermediate sensitive strains to penicillin 19%, to clindamycin 11.3%, and to metronidazole 7.5% were detected. Further studies on fecal microflora and inflammatory mediators, with larger groups of patients, are required in order to explain their role in neurological deficits. [PubMed Citation] [Order full text from Infotrieve]

7) Ekiel A, Aptekorz M, Kazek B, Wiechuła B, Wilk I, Martirosian G
[Intestinal microflora of autistic children].
Med Dosw Mikrobiol. 2010;62(3):237-43.
Autistic behavior is often accompanied by numerous disturbing symptoms on the part of gastrointestinal system, such as abdominal pain, constipation or diarrhea. These problems are often connected with deregulation of physiological microflora in intestine. The aim of this study was to determine differences in intestinal microflora of autistic and healthy children. Strains of Clostridium spp. and enterococci were isolated more frequently from stool samples of autistic children and rarely lactobacilli. Quantitative differences were observed maliny among staphylococci, Candida spp. and Clostridium perfringens. Monitoring and stabilization of intestinal microflora and knowledge about role of particular strains in etiology of autistic disorders can increase the chances for appropriate therapy. [PubMed Citation] [Order full text from Infotrieve]

8) Shaw W
Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia.
Nutr Neurosci. 2010 Jun;13(3):135-43.
A compound identified as 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) was found in higher concentrations in urine samples of children with autism compared to age and sex appropriate controls and in an adult with recurrent diarrhea due to Clostridium difficile infections. The highest value measured in urine samples was 7500 mmol/mol creatinine, a value 300 times the median normal adult value, in a patient with acute schizophrenia during an acute psychotic episode. The psychosis remitted after treatment with oral vancomycin with a concomitant marked decrease in HPHPA. The source of this compound appears to be multiple species of anaerobic bacteria of the Clostridium genus. The significance of this compound is that it is a probable metabolite of m-tyrosine (3-hydroxyphenylalanine), a tyrosine analog which depletes brain catecholamines and causes symptoms of autism (stereotypical behavior, hyperactivity, and hyper-reactivity) in experimental animals. [PubMed Citation] [Order full text from Infotrieve]

9) Martirosian G
[Clostridium spp. spores in pathomechanism of autism].
Wiad Lek. 2009;62(2):119-22.
Autism is a syndrom with unknown etiology, however many hypothesis are described in medical publications. These hypothesis include clostridial spores as key elements. Exo- and also endogenous spores are possible cause of autism: antibiotics have lack of effects on spores, which germinate after discontinuation of antibiotic therapy to vegetative neurotoxin producing forms. In this paper we discuss possible role of gastrointestinal tract and intestinal microflora in pathomechanism of autism on the light of recent publications. [PubMed Citation] [Order full text from Infotrieve]

10) Martirosian G, Ekiel A, Aptekorz M, Kazek B, Marszał E, Jankowska-Steifer E, Moskalewski S
Intestinal anaerobic bacteria and autistic mind: is there some relations? Comment to: the autistic mind: a case study. Katarzyna Markiewicz, Bruce Duncan MacQueen. Med Sci Monit, 2009; 15(1): CS5-13.
Med Sci Monit. 2009 Mar;15(3):LE2-3.
[PubMed Citation] [Order full text from Infotrieve]

11) Boyd SD, Mobley BC, Regula DP, Arber DA
Features of hemolysis due to Clostridium perfringens infection.
Int J Lab Hematol. 2009 Jun;31(3):364-7.
Infection by Clostridium perfringens can be an unsuspected cause of hemolysis in emergency room patients. Historically, this condition has been associated with wound contamination and other tissue infections. We report the case of an autistic patient who presented to our emergency department with a distended abdomen and hemolysis of unknown etiology. The patient had no history of recent surgery. Exploration of the abdomen revealed a hepatic abscess. Blood cultures tested culture positive for C. perfringens. We present images demonstrating the salient features of the peripheral blood smear in cases of this uncommon but deadly cause of hemolysis. [PubMed Citation] [Order full text from Infotrieve]

12) Finegold SM
Therapy and epidemiology of autism--clostridial spores as key elements.
Med Hypotheses. 2008;70(3):508-11.
This manuscript reviews evidence indicating that intestinal bacteria, specifically clostridia, may play a role in certain cases of autism and hypothesizes that the clostridial spores (which are notably resistant to antimicrobial agents and commonly used germicides) are involved in: (1) relapse in the autistic subject after a response to an agent such as oral vancomycin, after the drug is discontinued, (2) the unexplained increased incidence of autism in recent years, and (3) the unexplained increase in numbers of multiple cases in the same family. Hypothesis (1), if established as valid, would spur research to find well-tolerated and safe agents that could be given together with vancomycin (or other appropriate antimicrobial agent) to eliminate spores; this would revolutionize the therapeutic approach. Hypotheses (2) and (3) relate to widespread use of antimicrobial agents, poor hygiene in young autistic children, and difficulty in removing spores from the home environment. These latter two hypotheses have major implications with regard to the epidemiology of this important and distressing disease and would encourage research into methods to eliminate clostridial spores from the home and other environments. [PubMed Citation] [Order full text from Infotrieve]

13) Fernell E, Fagerberg UL, Hellstr÷m PM
No evidence for a clear link between active intestinal inflammation and autism based on analyses of faecal calprotectin and rectal nitric oxide.
Acta Paediatr. 2007 Jul;96(7):1076-9.
[PubMed Citation] [Order full text from Infotrieve]

14) Dixon B
New worlds to explore.
Lancet Infect Dis. 2006 Feb;6(2):73.
[PubMed Citation] [Order full text from Infotrieve]

15) Parracho HM, Bingham MO, Gibson GR, McCartney AL
Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.
J Med Microbiol. 2005 Oct;54(Pt 10):987-91.
Children with autistic spectrum disorders (ASDs) tend to suffer from severe gastrointestinal problems. Such symptoms may be due to a disruption of the indigenous gut flora promoting the overgrowth of potentially pathogenic micro-organisms. The faecal flora of patients with ASDs was studied and compared with those of two control groups (healthy siblings and unrelated healthy children). Faecal bacterial populations were assessed through the use of a culture-independent technique, fluorescence in situ hybridization, using oligonucleotide probes targeting predominant components of the gut flora. The faecal flora of ASD patients contained a higher incidence of the Clostridium histolyticum group (Clostridium clusters I and II) of bacteria than that of healthy children. However, the non-autistic sibling group had an intermediate level of the C. histolyticum group, which was not significantly different from either of the other subject groups. Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects. Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients. [PubMed Citation] [Order full text from Infotrieve]