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      The gut: a triggering place for autism – possibilities and challenges

      review-article
      , MD, PhD *
      Microbial Ecology in Health and Disease
      Co-Action Publishing
      autism, intestine, microbiota, Clostridium, Desulfovibrio, Sutterella

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          Abstract

          Background

          During the recent years, a substantial amount of new data has underlined the importance of the gut as a triggering place for autism. Temporary improvements in clinical status following dietary alterations and the same that may occur after an antibiotic therapy are reported. Additionally, increasing numbers of bacteria belonging to certain groups, such as clostridia, desulfovibrios, and sutterella, have been reported. So far, however, presence of any bacterial group has never been causatively linked to autism, and every time a new candidate organism is introduced the same questions have to be asked: What is the cause? What is the consequence? What is the confounder? The possibilities of answering these questions are hampered by difficulties in obtaining adequate samples. Therefore, more efforts have been made to those biochemical methods that probe possible functional alterations in the gastrointestinal (GI) microbiota in autistic children.

          Conclusion

          Autism is a disorder involving many organs and their functions, including the GI microbiota. More knowledge about the GI microbiota and its cross-talks with the host creates possibilities for future diagnostic and therapeutic improvements.

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          Most cited references18

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          Autistic disturbances of affective contact.

          L Kanner (1968)
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            A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

            Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.
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              Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders

              Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastrointestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs). Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derived from the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements, repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitine profiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment in carnitine-dependent pathways, consistent with findings in patients with ASDs. Of note, common antibiotics may impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and by directly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPA are more common than previously thought. PPA has further bioactive effects on neurotransmitter systems, intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function, and alteration of gene expression that warrant further exploration. These findings are consistent with the symptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in rats as a valid animal model of the condition. Collectively, this offers further support that gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine.
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                Author and article information

                Journal
                Microb Ecol Health Dis
                Microb. Ecol. Health Dis
                MEHD
                Microbial Ecology in Health and Disease
                Co-Action Publishing
                0891-060X
                1651-2235
                24 August 2012
                2012
                : 23
                : 10.3402/mehd.v23i0.18982
                Affiliations
                Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
                Author notes
                [* ] Tore Midtvedt, Department of Microbiology, Tumor and Cell Biology (MTC), Nobels v 16, Karolinska Institutet, Stockholm, S 171 77, Sweden. Email: @ 123456tore.midtvedti.se
                Article
                18982
                10.3402/mehd.v23i0.18982
                3747739
                23990818
                3ec15db8-f0ec-42d7-9dbe-30889e4ec23d
                © 2012 Tore Midtvedt

                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 work is properly cited.

                History
                Categories
                Thematic Cluster: Focus on Autism Spectrum Disorders

                Microbiology & Virology
                autism,intestine,microbiota,clostridium,desulfovibrio,sutterella
                Microbiology & Virology
                autism, intestine, microbiota, clostridium, desulfovibrio, sutterella

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