Gut flora in autism

Normal gut flora This can vary widely between different people, and different groups. It appears shortly after birth, is often found to be similar in the different members of a household, and certain bacteria may well be found in the pets. It is not clear that gut flora is necessary at all in that, should the diet be right the body will continue well. However, development of the mucosal immune system, the absorption of complex macromolecules, the synthesis of amino acids and vitamins and the protection against pathogenic microorganisms. We should not expect to get rid of or modify immensely gut flora using antibiotics or probiotics in the community. It should be noted that the flora in different parts of the world and in different communities is quite wide, and this often varies with the diet of the person being tested e.g. vegans vs carnivorous diets. Literature on this is extremely wide. A review of gut flora in disease is available from Othman et al. Gut flora in inflammatory bowel disease There has been great argument as to the actual cause of crohns disease and ulcerative colitis. Gut flora has been pointed at but this is currently unclear. Gut flora in IBD . Significant in pathogenicity Probiotics and prebiotics: treatment Anti-inflammatory drugs and treatment: this is now wide and progressive. Antibodies to many inflammatory factors are shown to be successful. Gut flora in Autism The literature is poor and, because of the wide variation between people, and the lack of mouse models of the gut inflammatory condition, the involvement of the gut flora has been difficult to show but this does not mean that it is not involved following the work by Sandler. Gut flora abnormal? Use of vancomycin as a treatment Probiotics

A well considered pathway for the effect of bacterial flora on the inflammatory response of the gut wall in IBD. The inflammation response starts when the gut barrier is breeched and this causes a further inflammatory response.

Gut flora in IBD Enteric microflora profiles vary considerably between active inflammatory bowel diseases (IBD) and healthy conditions. Intestinal microflora may partake in the pathogenesis of IBD by one or some ways: specific pathogenic infection induces abnormal intestinal mucosal inflammation; aberrant microflora components trigger the onset of IBD; abnormal host immune response loses normal immune tolerance to luminal components; luminal antigens permeate through the defective mucosal barrier into mucosal lamina propria and induce abnormal inflammatory response. Animal models of IBD, which allow the effects above, show that changes in the gut flora will cause inflammation. However, the proof of the mechanism is not certain. As such there is some good evidence that the IBDs are an aggressive response by the body against certain gut microflora. The mechanism of the inflammatory response and the genetics of the patient are important in this respect. Cummings JH, Macfarlane GT, Macfarlane S. Intestinal bacteria and ulcerative colitis. Curr Issues Intest Microbiol. 2003 Mar;4(1):9-20. (No specific pathogen has been identified as causal and the disease is widely believed to occur as the result of a genetically determined, but abnormal immune response to commensal bacteria. When compared with healthy people, UC patients have increased levels of mucosal IgG directed against the normal microflora. Studies of mucosal bacterial populations in UC indicate that there may be increased numbers of organisms, but reduced counts of "protective" bacteria such as lactobacilli and bifidobacteria. In animal models of colitis, antibiotics, particularly metronidazole, clindamycin, ciprofloxacin and the combination of vancomycin/impinemem protect against UC, especially if given before the onset of inflammation. This to some degree is important in that it suggest that the inflammation is secondary to the gut flora changes rather than the other way around) Williams R. Review article: bacterial flora and pathogenesis in hepatic encephalopathy. Aliment Pharmacol Ther. 2007 Feb;25 Suppl 1:17-22. Review

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Inflammatory bowel disease: flora significance? The consideration has been that the inflammatory changes seen under the microscope in the gut wall of autistic children may have something to do with the gut flora. Attempts were made to see if this was true other IBDs but no evidence was found. The suggestion is not so much as to the flora breaking down the gut immune system (e.g. the mucus) but rather that altered bacterial antigens penetrate through the lamina propria to cause an inflammatory response. Kucharzik et al below explain this well. By using mouse models in which receptors, and other factors on the gut membrane, are altered it is possible to change the response to gut flora. Rhodes JM, Gallimore R, Elias E, Allan RN, Kennedy JF. Faecal mucus degrading glycosidases in ulcerative colitis and Crohn's disease. Gut. 1985 Aug;26(8):761-5. (it showed that the enzymes that break down the glycoside chains that are attached to the mucus chains are present and it is assumed that these are derived from the bacteria. However this does not seem to be associated with IBD relapse) Rhodes JM, Gallimore R, Elias E, Kennedy JF. Faecal sulphatase in health and in inflammatory bowel disease .Gut. 1985 May;26(5):466-9. (Similarly to the article above they found that the sulphatases that split the sulphates from mucus also seem to have nothing to do with IBD relapse) Kucharzik T, Maaser C, Lgering A, Kagnoff M, Mayer L, Targan S, Domschke W. Recent understanding of IBD pathogenesis: implications for future therapies. Inflamm Bowel Dis. 2006 Nov;12(11):1068-83. Review. (this is an excellent article indicating that flora changes may come before an inflammatory response in the gut wall: they show the data that There is now increasing evidence that the enteric flora plays a role not only in IBD animal models but also in the pathogenesis of IBD. This hypothesis is based on reports that suggest that intestinal content causes inflammation. It is also confirmed by data that report healing of distal Crohns lesions after surgery with diversion of the fecal stream.170,171) D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology. 1998 Feb;114(2):262-7. (in other words when gut flora was put into the ileum that had been excluded from human gut flora by surgery for Crohns disease, they saw inflammatory changes in the gut wall that was well described). Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of lipopolysaccharides from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.

Neuro Endocrinol Lett. 2008 Feb;29(1):117-24. (They explain why gut flora may induce psychiatric changes. However, to some degree this is a proposal rather than an answer but they have many useful references).
Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease. Baumgart DC, Thomas S, Przesdzing I, Metzke D, Bielecki C, Lehmann SM, Lehnardt S, Drffel Y, Sturm A, Scheffold A, Schmitz J, Radbruch A. Clin Exp Immunol. 2009 Sep;157(3):423-36. Inflammatory bowel disease (IBD) results
from a breakdown of tolerance towards the indigenous flora in genetically susceptible hosts. Failure of dendritic cells (DC) to interpret molecular microbial patterns appropriately when directing innate and adaptive immune responses is conceivable. Dendritic cells are the ones that are present in the wall of the gut that get hold of antigens and present them to the inflammatory cells in such a way as to create a response. The lipopolysaccharides are derived from bacterial wall and represent dead bacteria. What they found was that in IBD the cells, when presented with LPS, acted in an exaggerated manner in causing the production of cytokines.

The long-term health effects of neonatal microbial flora. Conroy ME, Shi HN, Walker WA. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):197-201. There is a complex interaction between
the bacteria within the developing gut and the immune system of the host. Colonization of the neonatal gut represents a critical window in this process. It appears clear that disruption within this flora has long-term health consequences as diverse as eczema, allergic rhinitis, and IBD.

Identification of the predominant antigenic epitopes in intestinal flora in IBD. Ergin A, Adam T, Bssow K, Thiel A, Sieper J, Duchmann R. Mucosal Immunol. 2008 Nov;1 Suppl 1:S19-23 Intestinal barrier dysfunction in inflammatory bowel diseases. McGuckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G. Inflamm Bowel Dis. 2009 Jan;15(1):100-13. inappropriate host responses to the complex commensal microbial flora in the gut, although an altered commensal flora is not completely excluded. A multifunctional cellular and secreted barrier separates the microbial flora from host tissues. Altered function of this barrier remains a major largely unexplored pathway to IBD. Although there is evidence of barrier dysfunction in IBD, it remains unclear whether this is a primary contributor to disease or a consequence of mucosal inflammation. This review article attempts to explain what appears to be happening and what comes first in order to create the pathology.

Also: see Hepatic Encephalopathy in the toxins page

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Inflammatory bowel disease: gut flora modification treatment Unfortunately many different probiotics have been used and few good trials have been carried out with high enough numbers. It may well not matter which of the probiotics is involved as all act in a similar manner. Sheil B, Shanahan F, O'Mahony L. Probiotic effects on inflammatory bowel disease. J Nutr. 2007 Mar;137(3 Suppl 2):819S-24S. link Bai AP, Ouyang Q. Probiotics and inflammatory bowel diseases. Postgrad Med J. 2006 Jun;82(968):376-82. Macfarlane S, Macfarlane GT, Cummings JH. Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther. 2006 Sep 1;24(5):701-14. Review. Mach T. Clinical usefulness of probiotics in inflammatory bowel diseases. J Physiol Pharmacol. 2006 Nov;57 Suppl 9:23-33. Prantera C, Scribano ML, Berto E, Zannoni F. Antibiotic use in Crohn's disease: why and how? BioDrugs. 1997 Oct;8(4):293-306. (Despite the fact that few controlled trials have been conducted, and have shown inconclusive results, antibiotics are widely employed for improving symptoms and for inducing remission of active phases. At present, a combination of metronidazole and ciprofloxacin, active against many enteric bacteria, has proved to be effective in the treatment of Crohn's disease complications.) Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, Luzi C. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol. 1996 Feb;91(2):328-32. (notably the treatment may be with a range of antibiotics e.g. clindamycin, vancomycin, also, but that when the antibiotics stop, there is expected to be a return of the condition) Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology. 1995 Jun;108(6):1617-21. (this showed that following surgery as ileocolonic resection it was expected that commonly there would be further ileoterminal lesions within 2 months. The use of metronidazole decreased this chance in a controlled trial. It must not be forgotten that metronidazole is absorbed to some degree by the gut, that it is not entirely active against all anaerobes, and has no activity against aerobic bacteria, microaerophillic bacteria or yeasts, whatsoever). Borruel N, Carol M, Casellas F et al. Increased mucosal tumour necrosis factor alpha production in Crohns disease can be downregulated ex vivo by probiotic bacteria. Gut 2002;51:659-664. The lactobacilli interacted with immunocompetent cells using the mucosal interface and modulate locally the production of proinflammatory cytokines. E. coli did not work. Rizzello CG, De Angelis M, Di Cagno R, Camarca A, Silano M, Losito I, De Vincenzi M, De Bari MD, Palmisano F, Maurano F, Gianfrani C, Gobbetti M. Highly efficient gluten degradation by lactobacilli and fungal proteases during food processing: new perspectives for celiac disease. Appl Environ Microbiol. 2007 Jul;73(14):4499-507. Saccharomyces boulardii: potential adjunctive treatment for children with autism and diarrhea. Linday LA. J Child Neurol. 2001 May;16(5):387.
Probiotics in experimental and human inflammatory bowel disease: discussion points. Pagnini C, Cominelli F. Dig Liver Dis. 2006 Dec;38 Suppl 2:S270-3. As a review it basically shows that many things have been shown in animal models but the data from humans have not been adequately carried out.

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Anti-inflammatory drugs and antibodies for the treatment of IBD Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: a review of medical therapy. World J Gastroenterol. 2008 Jan 21;14(3):354-77. A wide review of the literature on the treatment of IBD, involving steroids, thalidomide, 5-ASA, antibodies (against the inflammatory cytokines, adhesion molecules etc), probiotics, powerful anti-inflammatory drugs (methotrexate, cyclosporine, azothiaprine), interferons.
Future targets for immune therapy in colitis? Kristensen NN, Claesson MH. Endocr Metab Immune Disord Drug Targets. 2008 Dec;8(4):295-300.

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Gut flora in autism The literature on this is to some degrees quite poor. Samples are sent to the laboratory by post, often across the world and not refrigerated. Commonly the flora will have changed by the time they arrive. Only vancomycin has been used as a potential treatment antibiotic. There has been no report of a controlled trial using other antibiotics. William Shaw, Biological Basis of Autism and PDD, 1997. This tends to claim an excess of candida. However the findings have not been repeated and treatments of candida overgrowth with drugs such as fluconazole have also not been carried out in a controlled trial.

Bolte ER. Autism and Clostridium tetani. Med Hypotheses. 1998 Aug;51(2):133-44. (Suggesting that the odd clostridia produce toxins that cause the symptoms we see (and that the antibiotics are involved). W Walsh and W McGinnis show pyrrole elevations (compounds produced by bacteria, and then modified in the liver before excretion) 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. 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. Clostridial species numbers higher. 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. 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. (They looked for anaerobic bacteria using FISH and found an increase in clostridia but little else. They appeared to look to a much greater degree at the presence or lack of certain bacteria rather than the specific numbers of the bacterial species) Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Visnen 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. (a good graph showing advantages clinically during the period that the vancomycin was given and disappearing after it was stopped).
Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, Cain DP. Neuropharmacology. 2008 May;54(6):901-11

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Treatment of autism by direction against an IBD Almost all of the anti inflammatory drugs used against IBD have not been assessed in autism see treatment. Also possible are the ones below:

Pentosan polysulphate This is a heparan type compound which prevents the interaction of inflammatory compounds and cells with their adhesion sites. No adequate clinical studies have been carried out.

Thalidomide (also see Kosuch) Because of its anti-TNFa and anti-IL-12 properties, thalidomide has been studied in two small open-label trials in mixed IBD populations, with the majority of patients in each achieving either clinical response or remission use of this medication is severely restricted because of its well-known teratogenicity and it is further limited by side effects of sedation and mood disturbances. The reason why such a dangerous drug as thalidomide is even tried is because of its known activity against other T-cell associated inflammation (seen in leprosy). Bariol C, Meagher AP, Vickers CR, Byrnes DJ, Edwards PD, Hing M, Wettstein AR, Field A. Early studies on the safety and efficacy of thalidomide for symptomatic inflammatory bowel disease. J Gastroenterol Hepatol. 2002 Feb;17(2):135-9 (These data strongly suggest that thalidomide is an effective short-term treatment for symptomatic IBD.) Bauditz J, Wedel S, Lochs H. Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease. Gut. 2002 Feb;50(2):196-200.
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Treatment of autism using probiotics At the moment things have not been done well in that no controlled trials have been carried out in autism and published. Claims of Saccharomyces boulardii causing the release of an anti-inflammatory agent, the change in the gut flora etc are well published, however) Linday LA. Saccharomyces boulardii: potential adjunctive treatment for children with autism and diarrhea. J Child Neurol. 2001 May;16(5):387. (no good data) Probiotics: delineation of prophylactic and therapeutic benefits. Kaur IP, Kuhad A, Garg A, Chopra K. J Med Food. 2009 Apr;12(2):219-35. Considering that the purported claims about disease risk reduction are tentative, the review also encompasses various aspects regarding the safety of probiotics and their possible future role in disease prevention. Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases. Vanderpool C, Yan F, Polk DB. Inflamm Bowel Dis. 2008 Nov;14(11):1585-96. Clinical trials have shown beneficial effects of probiotics on several human diseases, such as inflammatory bowel diseases (IBDs), which are among the most-studied diseases testing probiotics as a potential therapy. However, a significant question regarding clinical use of probiotics is the mechanism underlying the wide range of actions. Studies discussed in this review suggest 3 distinct cellular and molecular mechanisms for probiotic regulation in IBD therapy: 1) Probiotics block pathogenic bacterial effects by producing bactericidal substances and competing with pathogens and toxins for adherence to the intestinal epithelium; 2) Probiotics regulate immune responses by enhancing the innate immunity and modulating pathogen-induced inflammation via toll-like receptor-regulated signaling pathways; and 3) Probiotics regulate intestinal epithelial homeostasis by promoting intestinal epithelial cell survival, enhancing barrier function, and stimulating protective responses.

Regulation of host homeostasis by probiotics. Probiotics induce several beneficial host responses. These include 1) blocking pathogenic bacterial effects by producing antibacterial substances and competing with pathogens for binding to epithelial cells; 2) defining the balance between necessary and excessive defense immunity by increasing innate immunity, upregulating antiinflammatory cytokine production, and inhibiting proinflammatory cytokine production; and 3) promoting intestinal epithelial cell homeostasis by increasing survival, barrier function, and cytoprotective responses. DC, dendritic cell; IL, interleukin; M, M-cell; Hsp, heat shock protein.

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