International Journal of Microbiology & Advanced Immunology (IJMAI)    IJMAI-2329-9967-02-201

The Role of Intestinal Dysbiosis in the Pathogenesis of Autism: Minireview


Enzo Grossi*, Vittorio Terruzzi MD

Villa Santa Maria Institute, NeuropsychiatricRehabilitating Center, Tavernerio (Como), Italy.

*Corresponding Author

Enzo Grossi,
Villa Santa Maria Institute,
NeuropsychiatricRehabilitating Center,
Tavernerio(Como), Italy.
Tel: 0039031426042; Fax: 0039031360549
E-mail: enzo.grossi@villasmaria.org

Article Type: Review Article
Received: February 04, 2014; Accepted: March 19, 2014; Published: March 21, 2014

Citation: Grossi E, Terruzzi V (2014) The Role of Intestinal Dysbiosis in the Pathogenesis of Autism: Minireview. Int J Microbiol Adv Immunol. 2(2), 41-44. doi: dx.doi.org/10.19070/2329-9967-140007.

Copyright: Grossi E © 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.



Abstract

Autism spectrum disorder is a complex neurodevelopmental disease where gastrointestinal disturbance is commonly reported. Here we review the evidence suggesting that gut microbota my play a role in this disease and summarize comparative studies we found in international literature on the topic. Discussion of results, methodology of the data collection, bias of selection and behavioral interferences lead to the conclusion that changes in the gut microbiota is a significant piece of autism spectrum disorder but further studies are needed to understand this pathogenetic role.



1.Introduction
2.Material and Methods
3.Results
4.Discussion
5.References

Introduction


Human microbiota represents one of the most striking cultural revolution in medicine emerged in the last 20 years [1]. Many studies have revealed how the complexity and dynamics of gut microbiota influences normal physiology and contribute to a variety of diseases ranging from obesity to atherosclerosis, allergy and severe neurological disorders [2]. The latter topic is of particular relevance and really revolutionary and is specifically linked to the existence of so-called gut-brain axis: a physiological framework in which the gut microbiota communicates with the CNS and viceversa through neural, endocrine and immune pathways [3]. If this is true then is plausible to expect that the modulation gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders. Autism is definitely one of these disorders.

Autism encompasses a broad spectrum of heterogeneous neurodevelopmental disorders with a prevalence rate of 1:150 and a 4:1 male: female ratio, characterized by qualitative impairment in social communication area and restricted repetitive and stereotyped patterns of behavior interests and activities [4].

The possibility that autism is the consequence of an imperfect development of gut flora is supported by a number of observations like: the frequent coexistence of gastrointestinal symptoms in autistic children; the appearance of the disease after an incidental antimicrobic therapy and the increased levels of urinary biomarkers of specific pathogens of clostridium spp. in the urine of autistic children [2].

SCFAs represent a group of compounds derived from the host microbiome that can induce widespread effects on gut, brain, and behavior, contribute to various neurological processes and are plausibly linked to ASDs [5].

Since the literature about the role played by intestinal dysbiosis in autism is increasing, we felt interesting to summarize the present evidences in this mini review.


Material and Methods


We conducted a database search using Pubmed Plus, Ovid MEDLINE, CINAHL, ISIWeb of Science, PSYCinfo, The Cochrane Database, ALOIS, Google Scholar for the years 1980 to 2013 using the terms: autism, microbiota, dysbiosis, gut flora, gut-brain axis. From this search we reviewed clinical trials, case reports and qualitative observations that used these key words. We considered only comparative studies with a sizeable number of cases.At the end of our process we have identified nine articles fulfilling the selection criteria.


Results


Table1 one summarizes the fundamental features of the studies selected. We identifies nine studied published in the medical literature between 2005 and 2013.



Table 1. Comparative studies of intestinal microbiological profile in autism


All these studies have targeted fecal microbiota but two (ileal and cecal biopsies) using a wide range of techniques. Five studies have been carried out in USA, four in Australia and one in Italy. All the studies are case-control comparative studies with a small-medium sample size, ranging from 15 to 58 autistic children and from 10 to 53 typicals. The age of the children has a wide range: from 3 to 16 years. As expected there is a strong inhomogeneity as regards the microbiological assay method employed. One group has employed FISH analysis with specific 16SrRna oligonucleotide probes; other bacterial tag encoded FLX ampliconpyro sequencing (three studies). Four studies have been carried out using real-time PCR assays on CFX 384TM detection system and only one using bacterial and yeast culture using traditional techniques.

Only one study did not find any difference in microbiological pattern between autistic children and controls.

In the other eight significant differences have been found in increase or decrease of specific bacterial population. For example Parracho [6] et al found significantly increase incidence of Clostridium histoliticum in ASD group and intermediate non significant difference with sibling group. A significantly increase in bacteroidetes and decrease in Firmicutes has been described by Finegold [7]; while the opposite was true for Williams. This author by the way sampled the mucosa associated bacteria rather than fecal bacteria.

Significantly lower level of Bifidobacteria in autistics were found in two studies (Adams et al and Wang et al) [8, 9].

High level of Sutterella species have been found in intestinal biopsy samples by Williams, and in feces by Wang et al. and this seems particularly noteworthy since Sutterella species have never been described before in human gut. [11-14]

Significantly higher counts of Bacteroides and Prophyromon were found in fecal samples of ASD children by Italian group, and more important a higher median value of Clostridium spp. Enterococcus, Lactobacillus, Streptococcus Lactococcus and Staphylococcus were lower in autism [13].


Discussion


The studies on intestinal dysbiosis associated with ASD open new avenues in the understanding of this dramatic disease. The coexistence of ASD and gastrointestinal disturbances is often overlooked due to the difficulty in eliciting subjective symptoms in a disorder characterized by an impaired communication. It is not surprising therefore that a standardized diagnosis of GI symptoms in ASD is yet to be clearly defined.

In any case the high prevalence of the GI manifestations [16, 17] highlight the possibility that they might may be linked to gut dysbiosis.

There is an increasing body of knowledge pointing out that gut flora influences a variety of social emotional, and anxiety-like behaviors, and contribute to brain development and function in animals [18, 19] and humans [20]. In a recent study carried out by Hsiao et al. these authors demonstrated that a particular model of autistic mouse displays behavioral symptoms relevant to ASD and other neurodevelopmental disorders [21, 22], while also exhibiting defective GI integrity, dysbiosis of the commensal microbiota, and alterations in serum metabolites. The administration of a particular commensal (B. Fragilis) is able to reverse autistic symptoms and metabolic derangement These findings represent a major breakthrough in the microbiota hypothesis of ASD [23]. Unfortunately they have to be replicated in human being. B.Fragilis is not commonly found in foods, therefore clinical trials need special IND to be carried out.

The studies on intestinal microbiological profile in autism are more or less in their infancy. There are many methodological issues to be resolved, like the standardization of microbiological assay methods, of sampling protocols and mathematical analysis of the results.

An important issue to be addressed is the effect of diet on gut microbiota. The fact that autistic children display very often a “nutrition fixation”, i.e a reduced spectrum of food variety, implies that the differences seen in microbiota profile might depend more from particular dietary pattern related to autistic behavior rather than to an intrinsic defect of gut homeostasis. In most published studies authors were unable to make comparisons regarding the diets of the unaffected control children and autistic children since food records arerarely collected both for children with ASDs or controls. Therefore it is unclear if the differences observed in microbiota profile between case and control groups are reflective of their dietary intake or abnormal metabolism or both.

Further studies are therefore needed before the whole issue of gut microbiota can be considered as a hard end point in autism research. Comprehensive studies starting from behavior of mother during pregnancy, bacterial transolocation from mother intestine during pregnancy in fetus organs, early exposure to antibiotics after birth, quality and quantity of breast feeding and urinary metabolomic profile of the newborn in his early development are warranted to make a real step forward in this complex area of research and speculation.


References

  1. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in thehuman intestine. Science 307:1915–1920. PMID: 15790844
  2. Sekirov I, Russell SL, Antunes LCM, Finlay BB (2010). Gut Microbiota in Health and Disease. Physiol Rev 90: 859–904. doi:10.1152/physrev. 00045.2009
  3. Collins SM, Bercik P (2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinalfunction and disease. Gastroenterology 136: 2003–2014.
  4. APA (1994) Diagnostic and statistical manual of mental disorders. 4thedn DC: American Psychiatric Association: Washington
  5. MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP (2011) Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res 217: 47-54. doi:10.1016/j.bbr.2010.10.005. PubMed: 20937326.
  6. Parracho HM, Bingham MO, Gibson GR, McCartney AL (2005)Differences between the gut microflora of children with autisticspectrum disorders and that of healthy children. J Med Microbiol 54:987-991. doi:10.1099/ jmm.0.46101-0. PubMed: 16157555.
  7. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, et al. (2010) Pyrosequencing study of fecal microflora of autistic and control children.Anaerobe16(4):444-453. doi: 10.1016/j.anaerobe.2010.06.008. Epub 2010Jul9. PubMed PMID: 20603222.
  8. Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11: 22. doi:10.1186/1471-230X-11-22. PubMed: 21410934.
  9. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT , et al.(2011) Low relative abundances of the mucolytic bacteriumAkkermansiamuciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol 77(18): 6718-21. doi:10.1128/AEM.05212-11.
  10. Williams BL, Horning M, Buie T, Bauman ML, Cho Paik M, et al. (2011) Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLos ONE 6(9):e24585. doi:10.1371/journal.pone.0024585.
  11. Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, et al. (2012) Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5(6): 419-427. doi:10.1002/aur.1253. PubMed: 22997101.
  12. Williams BL, Hornig M, Parekh T, Lipkin WI (2012) Application of novelPCR- based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio 3:e00261-11. PubMed: 22233678.
  13. DeAngelis M, Piccolo M, Vannini L, Siragusa S, DeGiacomoA,et al.(2013) Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE 8: e76993.doi:10.1371/journal.pone.0076993
  14. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, et al. (2013) Increased abundance of Sutterella supp. And Ruminococcus torques in feces of children with autism spectrum disorder. Molecular Autism 4: 42. doi: 10.1186/2040-2392-4-42.
  15. Kang DW, Park JG, Ilhan ZE, Wallstrom G, LaBaer J et al. (2013) Reuced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.PLoS One 8 (7): e68322. doi: 10.1371/journal. pone.0068322
  16. Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, et al. (2010) Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125 (Suppl 1), S1–S18.
  17. Coury DL, Ashwood P,Fasano A, Fuchs G, Geraghty M, et al. (2012) Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl 2), S160–S168.
  18. Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Re Microbiol 10, 735–742.
  19. Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13, 701–712.
  20. Tillisch K, LabusJ, Kilpatrick L, Jiang Z, Stains J, et al. (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144, 1394–1401, e1–e4.
  21. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH (2012). Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain BehavImmun 26, 607–616.
  22. Shi L, Smith SE, Malkova N, Tse D, Su Y, et al. (2009) Activation of the maternal immune system alters cerebellar development in the offspring. Brain BehavImmun 23, 116–123.
  23. Hsiao EY, McBride SW, Hisien S, Sharon G, Embriette R et al. (2013)Microbiotamodulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell 155: 1-13 http://dx.doi.org/10.1016/j. cell.2013.11.024

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