The Gut Microbiota and the Development of the Brain

http://www.ageofautism.com/2010/06/test-for-autism-measuring-gut-microbes.html
http://www.ageofautism.com/2010/06/test-for-autism-measuring-gut-microbes.html



The human gut host 1014 bacterial organisms, an amount that exceeds even the number of somatic cells within the body. When combined with the bacteria living both inside and on the human body (a community collectively known as microbiota, dwelling in the human microbiome), it is estimated that these (mostly) friendly intruders outnumber the somatic and germ cells of their human home by a factor of 10 (Neufeld, Turnbaugh). Specific to the human gut is the commensal microflora, the microbial community that enters into an important symbiotic association with the human host beginning with the colonization of the gastrointestinal (GI) tract by the bacteria within the first few postnatal days. The systematic takeover of the GI tract by this diverse array of microorganisms is actually a fairly useful and peaceful invasion, not the hostile takeover its numbers suggest it would be (Neufeld). Called “developmental processing,” the phenomenon begins at birth, continues through early development, and remains for life. Developmental processing is actually defined as a process by which environmental factors act during vulnerable or sensitive developmental periods and thus exert influences that impact the structure and function of organs that last throughout life (Heijtz). However, although the colonization of microbiota is due to postnatal environmental factors and is also affected by genetics, the relative abundance and distribution along the GI tract of the human microbiome is similar across healthy individuals, even those residing in different countries with different diets (Duff). The number and type of helpful bacteria is relatively consistent and is difficult to change. This stability is important because of the influences the microflora has on the development of a range of systems in the body. For example, the microbiota is essential to the proper development of the mucosal and systemic immune systems and in nutrient uptake and metabolism (Neufeld). In order to more fully understand the significance of these microorganisms, the Human Microbiome Project (HMP) has been launched worldwide. The HMP is an almost natural offshoot of the Human Genome Project and is hoped to not only bridge the gap between medical and environmental microbiology, but to reveal new insights into the world of health and diseases. Already, much has been found regarding the useful and important contributions these microbial symbionts make to an individual’s physiology (Turnbaugh, et al). Recent research regarding the HMP has revealed evidence that suggests these gut bacteria also influence the function of the central nervous system (CNS) and behavior (Neufeld). Of particular interest, though, is the impact on the functional development of the mammalian brain. Studies have shown the brain to be susceptible to internal and external cues during its perinatal life, an important point when considering the association between common neurodevelopmental disorders (e.g. autism, schizophrenia) and microbial pathogen infections during this same period. Related studies have shown support for this, at least in regards to mice; exposure to microbial pathogens within the perinatal period resulted in behavioral abnormalities such as anxiety-like behavior and impaired cognitive functions (Heijtz).

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http://www.nature.com/nature/journal/v449/n7164/fig_tab/nature06244_F1.html


Gut Feelings


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The relationship between the gut microflora and the brain, the so-called gut-brain axis, has been an important component for many years in gastrointestinal research. It is especially influential in such functional bowel disorders as Irritable Bowel Syndrome (IBS) and may play a part in ulcers. However, as with IBS, most of the studies have focused on a brain-to-gut control, a type of top-down relationship that examines mainly the impact of the brain on the function of the gut. New research in this field has also revealed that there may be close ties between the microbiota of the gut and the development and function of the central nervous system (CNS). This, in turn, has led to a discovery of a link between early life stress, altered stress activity later in life, and a change in the landscape of the microflora, all examined using the top-down approach. Further studies demonstrated the influence of microbiota over energy balance and their integral connections to the pathophysiology of obesity. Energy balance and the intake of food are both centrally mediated processes, and although the direct link between the gut microbiome and the central feeding circuits has not been discovered yet, it reveals the presence of the alternative bottom-up control, where the microbiota have an influence over the development and functionality of the brain. This discovery of bottom-up controls will be important in the research regarding the relationship between brain development and the establishment of the gut microbiota (Neufeld). It also brings into light the possible role of the human microbiome in the incidence of neurodevelopmental disorders (Heijtz).
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http://www.nyas.org/image.axd?id=b2487c81-5d3e-4bdc-a4bb-8b7102af2b5e&t=634164293398800000
mouse.jpgEvidence in Mice

In 2006, immunologist Sven Pettersson of the Karolinska Institute in Stockholm developed an interest in the bottom-up approach to the gut-brain axis when he and genomicist Shugui Wang of the Genome Institute of Singapore discovered that the key brain chemical was regulated by the microbes in the gut (Pennisi). This finding led him to collaboration with a neurobiologist at the Karolinska Institute, Rochellys Diaz Heijtz , in order to further study the effects of gut microbiota on brain development and function using mice (Heigtz).

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http://psyweb.vghtpe.gov.tw/Animal%20models%20of%20depression-detail.htm

For the study, they engineered germ-free (GF) mice that had no commensal intestinal microflora and therefore an underdeveloped immune system and specific pathogen free (SPF) mice with normal gut microbiota and put them through a series of tests in order to observe their exploratory activity and anxiety. Such tests included placing the mice in an open field box and measuring their spontaneous motor activity for an hour. Another test that assessed whether nonpathogenic gut microbiota could affect anxiety-like behavior involved both a light-dark box test and an elevated plus maze. In every case, the GF mice what are considered riskier behaviors, spending more time in the light box and in the open arms or end of the open arms of the elevated plus maze than the SPF mice. They also generated more spontaneous activity, traveling a greater total distance with more exploration of the open field than the SPF mice in the open field box. However, when the same battery of tests were performed with adult conventionalized offspring (CON) (offspring of GF mice that were exposed to the microbial pathogens early in their development), the CON mice displayed similar tendencies to the SPF mice instead of their GF parents. In order to check that this normalization of behavior patterns takes place only during a sensitive or critical period wherein the effects of the normal gut microbiota can occur, Heijtz et. al. then conventionalized adult GF mice and retested them. The new findings of the conventionalized adult GF mice showed no significant changes, displaying a failure to normalize their behavior at this late stage (Heijtz). Dr. Heijtz inferred from this data “that there is a critical period early in life when gut microorganisms affect the brain and change behavior in later life” (Pennisi).


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Elevated Plus Maze (http://btc.bol.ucla.edu/plus.htm)

Since anxiety-like behavior has been linked to alterations in monoamine neurotransmission, Heijtz et al also investigated the potential changes in the neurochemistry of the GF mice when compared to the SPF mice. Specific concentrations of brain chemicals associated with anxiety like noradrenaline (NA), dopamine (DA), and serotonin (5-HT) were measured in the frontal cortex, striatum, and hippocampus of both the SPF and GF mice (Heijtz). It was found that GF mice had a higher turnover rate of these anxiety-inducers in the striatum, breaking them down at a faster rate than the SPF mice. Additionally, two genes commonly linked to anxiety demonstrated reduced activity in GF mice. The microbiota seemed to increase the production of the synaptic plasticity-related gene, brain-derived neurotrophic factor (BDNF) and the immediate-early gene, nerve growth factor-inducible clone A (NGFI-A) in the hippocampus, amygdala, and cingulate cortex, which are to be key components of the neural circuitry that underlies fear and anxiety (Pennisi, Heijtz). As for how it does this, the presence of the microorganisms reduced the amount of two proteins significant in the maturation of the nerve-cell (Pennisi, Heijtz).
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http://www.clinicalexams.co.uk/images/functions_of_the_brain.jpg

This study clearly supports the hypothesis that the gut microbiota can have a significant impact on normal brain development and behavioral functions during a critical period early in the postnatal growth that lasts throughout life. It suggests also that during the course of evolution, microbiota colonization became an integral part of the development and programming of the brain with its effects extending to motor control and anxiety-like behaviors (Heijtz). However, Pettersson cautions that “it is important to note that this knowledge can be applied only to mice, and that it is too early to say anything about the effect of gut bacteria on the human brain” (“Bacteria in the gut…”).


Evidence in Autism

Even with such cautions, it is hard to ignore the implications to the world of neurodevelopmental disorders. In fact, many GI disorders have shown a high comorbidity with psychiatric illnesses (Neufeld). The most widely hoped for link is between the gut microbiota and schizophrenia or autism. Children with autistic spectrum disorders, particularly, demonstrate a high incidence of severe gastrointestinal problems, combined with an onset in early childhood, perhaps linking to the critical period discovered by Heijtz et al (Parracho). In addition to several bodily and behavioral changes and difficulties, there often is an inflammation of the intestinal lining, causing the gut to be more permeable. Some of these symptoms have even been linked to changes in the gut microbiota due to treatment with antibiotics (Duff).Several studies have been done hoping to find an association between the microbiota and autism in order to begin finding a cause and then a cure. One such study tested 86 children with autism and revealed a substantial change in the metabolism of amino acids and in the normal microorganisms that inhabit the gut of a healthy person. These major differences were mostly concerned with the aerobic bacteria Escherichia coli (E. coli) and Enterococcus, and with the anaerobic bacteria Bacteroides and Bifidobacteria. E. coli is the most common aerobe of the microflora, accounting for around 80-90% of all aerobic bacteria. The second, then, is Enterococcus which accounts for just 5% of aerobes. When interpreting the results of the Bioscreen faecal microbiology, it was found that the average amount of E. coli had considerably decreased, accounting for only 56% instead of its usual 90%. In 18 of the children, the amount of E. coli was actually less than 10%. Conversely, the amount of Enterococcus had risen to 40%, with a complete swap of the two aerobes in 19% of the children, as Enterococcus accounted for 95% of the aerobic bacteria. Relatedly, the anaerobes changed as well. There was a measurable decrease in Bacteroides whereas the Bifidobacteria increased (Duff).This study, however, is very basic and does not take into account many variables that would have to be considered in further examination of the role of the gut microorganisms in autism. For example, repeated microbial use (such as those commonly taken for autism) could cause disruptions in the indigenous microflora of the gut, accounting for some of the discrepencies. As Pettersson stated, at this point in the game, it is far too early to make any assumptions about the significance of the microbiota in the development of the human brain. In the future, who knows what will be discovered? Perhaps we will just have to listen to our guts.
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http://www.cartoonstock.com/directory/f/foreign_policies.asp


References
  1. Duff, Jacques. "Autism and ADHD: Intestinal Dysbiosis." ADHD,ADD, Attention Deficit Hyperactivity Disorder. Behavioural Neurotherapy Clinic. Web. <http://www.adhd.com.au/Intestinal_Dysbiosis.htm>.
  2. Heijtz, Rochellys Diaz, Shugui Wang, Farhana Anuar, Yu Qian, Britta Björkholm, Annika Samuelsson, Martin L. Hibberd, Hans Forssberg, and Sven Pettersson."Normal gut microbiota modulates brain development and behavior." PNAS 108.7 (2011): 3047-052. PNAS: Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 31 Jan. 2011. Web. <http://www.pnas.org/content/early/2011/01/26/1010529108.full.pdf+html>.
  3. Karolinska Institutet. "Bacteria in the gut may influence brain development." ScienceDaily, 1 Feb. 2011. Web.
  4. Neufeld, BSc, Karen-Anne, and Jane A. Foster, PhD. "Effects of gut microbiota on the brain: implications for psychiatry." Journal of Psychiatry & Neuroscience 34.3 (2009): 230-31. PubMed Central. Canadian Medical Association, May 2009. Web. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674977/>.
  5. Parracho, H. M. "Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children." Journal of Medical Microbiology 54.10 (2005): 987-91. PubMed.gov. National Center for Biotechnology Information, U.S. National Library of Medicine, Aug. 2005. Web. <http://www.ncbi.nlm.nih.gov/pubmed/16157555>.
  6. Pennisi, Elizabeth. "Do Gut Bugs Practice Mind Control?" Science/AAAS | News - Up to the Minute News and Features from Science. American Association for the Advancement of Science, 31 Jan. 2011. Web. <http://news.sciencemag.org/sciencenow/2011/01/do-gut-bugs-practice-mind-contro.html>.
  7. Turnbaugh, Peter J., Ruth E. Ley, Micah Hamady, Claire M. Fraser-Liggett, Rob Knight, and Jeffrey I. Gordon. "The Human Microbiome Project." Nature 449.7164 (2007): 804-10. Nature. Nature Publishing Group, 17 Oct. 2007. Web. <http://www.nature.com/nature/journal/v449/n7164/abs/nature06244.html>.