  Image courtesy of: http://thatsugarfilm.com/blog/2016/07/05/the-microbiome-and-the-gut-brain-axis/. In a world buzzing with political and economic uncertainty, anxiety and depression have run rampant in our society; the most recent studies estimate that 40 million Americans — or roughly 18% of the American population — are affected by the detrimental affects of anxiety (1). And with increasing research and curiosity surrounding the mysterious microbial inhabitants of our gut, ongoing research continues to unravel their not-so-subtle involvement in our well-being.
It is well established in the research community that our microbiome has profound affects on our weight, the production of vitamins and food digestion. But is it too far-fetched to believe that microscopic life-forms living in our intestines influence our brain functions? Can bacteria communicate with our brains to determine our moods, feelings and emotions? It seems likely. Physiologically speaking, there is no reason why this communication can’t happen. Of the billions of nerves that thread through our bodies, one of them — termed the “vagus nerve” — serves as a direct connection between the intestines and the brain. This connection, which is formally referred to as the “gut-brain axis”, has been a critical area of research for more than a decade. What we have discovered in that time is that the vagus nerve seems to be bi-directional, meaning that while the brain can act on on the gastrointestinal tract to shape its bacterial composition, at the same time gut microbes can produce certain chemicals that act on the brain (2). Initial excitement was sparked in 2004, when a landmark study observed that mice that were devoid of bacteria (i.e. “sterile” or, more formally, “germ-free” mice) demonstrated heightened levels of stress hormones in their blood (compared to normal, bacteria-carrying mice) when placed in stressful conditions (3). What’s really interesting is that while the stress response was clearly dysfunctional in germ-free mice, researchers could induce a more normal hormonal response by simply treating the mice with one single microbe: a bacterium called Bifidobacterium infantis. This served as the first clue that our gut bacteria are doing something that influences our mood. Likely, gut bacteria produce chemicals that influence the brain to reduce psychological stress. These chemicals have since been coined as “psychobiotics”. Further experimentation continued to shed light on the great influence our bacteria has on our mood. Prominent researchers Premsyl Bercik and Stephen Collins working out of McMaster University discovered that behaviour can be transferred between mice simply by transferring their gut bacteria. They discovered that if they took one species of bacteria from the intestines of a mouse, and gave that single strain to a germ-free mouse (such that the intestines of the recipient mouse only contained that single bacterial species), then the recipient mouse would also take on aspects of the donor mouse’s personality. For example, mice that were naturally timid/shy before receiving bacteria became more exploratory if they received bacteria from a naturally exploratory donor mouse. As another example, naturally daring mice would become more shy once they received the bacteria from a naturally shy mouse (4). While this is only the beginning steps in what promises to be a long journey of intensive, complex research, these kinds of tendencies hint that microbial interactions could very well influence the brain to induce anxiety and other mood disorders. References
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  Image Courtesy of Sarah C.P. Williams, Howard Hughes Medical Institute It is Aristotle that once famously remarked how “man is by nature a social animal”. Of course, we need only reflect on our past experiences for a short while to understand the truth in Aristotle’s words. Our very existence as a species depended on our ancestor’s abilities to interact and help one another. Seeing as how social skills often (but not universally) serve as a prerequisite for a fulfilled life, social psychologists and neuroscientists alike have dedicated large resources to deciphering the mechanisms behind our social nature. A major breakthrough came at the turn of the 20th century, when Henry Dale discovered “Oxytocin”, a chemical that has earned the reputation of the “love hormone” for its role in encouraging social bonding, prosocial behaviours, “maternal instincts”, fear reduction and in antagonizing the effects of depression (learn more here: 1). But oxytocin alone cannot explain the entirety of our social behaviour.
We’re missing something. In natural sciences, one will often hear the phrase “paradigm shift” to describe a series of scientific findings that radically alters our basic understanding of a scientific phenomenon (the most notable example, for instance, is Charles Darwin’s Evolutionary Theory, which rigorously challenged the way in which we perceived our very origin as a species). With a wealth of studies demonstrating new ways in which our intestinal bacteria dictates our health and behaviour (a great review can be found here: 2), the gut microbiome is primed to give way to the next great paradigm shift – particularly in relation to the extent to which the gut-brain axis influences our mood and behaviour. If you are familiar with my previous blog post Life on The Spectrum – An Abnormal Microbiome and…Autism?, you may recall the three characteristic behavioural autism-like symptoms: limited social interactions, a tendency for repetitive behaviour and reduced overall communication (3). Autism patients are also known to possess an altered gut microbiome composition (4). Up until recently, this observation was merely an association; an altered gut microbiome in autistic patients was associated with disruption in social development, but was never shown to be a cause of social disruption. However, recent evidence emerging from the lab of Dr. JF Cryan at University College Cork in Ireland (5) suggests that an altered gut microbiome does indeed impede normal social development. To support his claim, Cryan’s team studied the social behaviour of mice using a “three-chambered sociability test” (6). This test includes a three-chambered box with openings between the chambers. In brief, this setup assesses social behavior in the form of general sociability as well as interest in social novelty. Cryan’s group performed two experiments:
The results of this study have potentially large implications in the realm of autism. In addition to symptoms of reduced social motivation, children with autism exhibit poor communication skills as well as repetitive behaviours. Since it is well understood that many autism patients have a dysregulated gut microbiome, is it a far-stretched hypothesis that the impaired social behaviour observed among autistic patients is at least a partial result of an abnormal microbiome? If so, could we substantially decrease autism-like symptoms and increase social development by focusing our treatments and efforts on re-balancing the gut microbiome? And how about introverts? Approximately 50% of the population identify themselves as introverted (7). Do they house a microbiome that differs from those of extroverts? Cryan’s results spur a whole new set of questions concerning our social behaviour as a species. A final question that may come to mind is why gut bacteria are dictating our social behaviour. We have a fairly clear idea as to how – via the gut-brain axis. But why have humans and microbes co-evolved in such a way? Although we cannot know for certain, it is worth noting that microbes have lived on Earth for far longer than humans have. In that time, microbes have yearned for one ultimate evolutionary goal: to reproduce and spread throughout the planet. Is it possible, then, that bacteria, in a parasitic way, are purposefully encouraging our social drive? By encouraging us to interact with other humans, bacteria can jump to our neighbors, who then go their own way. Just like that, bacteria figured out a way long ago to use mammals as vehicles to spread across the globe… Although this idea is difficult to prove, what a remarkable mechanism that would be – microbes stimulate our social development for their benefit, to promote their spread. And if that’s true, what other behaviours are being manipulated by microscopic organisms? If our gut microbiome is controlling our social development, who’s to say they don’t play a role in other cognitive functions? Are we really in control of our own thoughts and actions, or are we merely the puppets in a microbe-dominated world? References 1. Ishak, W. W., M. Kahloon, and H. Fakhry. 2011. Oxytocin role in enhancing well-being: a literature review. J. Affect. Disord. 130: 1-9. 2. Shreiner, A. B., J. Y. Kao, and V. B. Young. 2015. The gut microbiome in health and in disease. Current opinion in gastroenterology 31: 69-75. 3. Prevention, C. f. D. C. a. 2012. Autism Spectrum Disorder — Data & Statistics. 4. Kang, D. W., J. B. Adams, A. C. Gregory, T. Borody, L. Chittick, A. Fasano, A. Khoruts, E. Geis, J. Maldonado, S. McDonough-Means, E. L. Pollard, S. Roux, M. J. Sadowsky, K. S. Lipson, M. B. Sullivan, J. G. Caporaso, and R. Krajmalnik-Brown. 2017. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5: 10. 5. Desbonnet, L., G. Clarke, F. Shanahan, T. G. Dinan, and J. F. Cryan. 2014. Microbiota is essential for social development in the mouse. Mol. Psychiatry 19: 146-148. 6. Yang, M., J. L. Silverman, and J. N. Crawley. 2011. Automated three-chambered social approach task for mice. Curr. Protoc. Neurosci. Chapter 8: Unit 8.26. 7. Myers, I. B., McCaulley, M. H., Quenk, N. L., & Hammer, A. L. (1998). MBTI Manual: A guide to the development and use of the Myers-Briggs Type Indicator (3rd ed.). Palo Alto, CA: Consulting Psychologists Press.   Image courtesy of: https://www.autismspeaks.org/science/science-news/year-autism-epidemiology The past several decades have been met with a roaring increase in the discussions surrounding autism and related disorders that fall within the Autism Spectrum. And with good reason.
First coined in 1910, autism quickly emerged as a notoriously difficult condition to diagnose, given its eerie similarity to other neurodevelopment disorders, specifically childhood schizophrenia. Indeed, it took nearly 70 years of intense research for autism to be diagnosed as a separate disorder (2). Since then, autism prevalence has skyrocketed in Western society; prior to 1980, 1 in 5000 children were diagnosed with autism. Today, an astounding 1 in 68 children possess autism-like symptoms, which include limited social interactions, a tendency for repetitive behaviour and reduced overall communication (3). Which begs us to ask the question: why? An enormous array of controversial explanations have been put forward to explain the worrying increase in autism prevalence. The most notorious of which is Andrew Wakefield’s “vaccine hypothesis”, which singled-out the MMR vaccine (Measles, Mumps & Rubella) as the cause of rising autism prevalence (note: Wakefield’s findings have since proven to be falsified and have been retracted from the scientific literature. Read more here: (4)) It was only in the mid 1980s that researchers uncovered that autism had a strong genetic component, wherein certain gene mutations were found to associated with autism (5). The genetic basis became even more clear by the 1990s, when it was discovered that a child was 25-times more likely to be diagnosed with autism if one of their siblings was also diagnosed (6). Since then, an impressive amount of research, made possible by advances in genetic technologies, has identified numerous genes linked to autism (which are summarized in this article: (7)). While genetics undoubtedly play a role in the development of autism, the last decade saw scientists explore an alternative hypothesis — one that included the microbiome. For years, researchers couldn’t explain the seemingly-odd data that showed — quite conclusively — that women who suffered a high, prolonged fever during pregnancy were seven times more likely to have a child with autism. In 2007, Paul Patterson was able to reproduce this result in mice, such that if he induced a prolonged fever in pregnant mice, then their offspring would display all three features of human autism, including limited social interactions, a tendency for repetitive behaviour and reduced overall communication (8). Patterson also showed that the offsprings also had leaky intestines, which is a critical detail here because anywhere from 40 to 90% of human children with autism also suffer gastrointestinal issues (9). Then, in 2013, Dr. Sarkis Mazmanian and his research team made the remarkable discovery that these mice had abnormal microbiomes compared to non-autistic mice (10). This finding suggested that the autistic-like behaviour of these mice — and perhaps by extension autistic behaviour in humans — might be partially rooted in the gut rather than entirely in the brain. If this is true, then treating the gut bacteria should also treat the autism-like symptoms. And indeed, Mazmanian’s research team was able to show that by simply restoring a normal microbiota, the mice also displayed better communication and a decreased tendency towards repetitive behaviour. This heavily implicates our gut bacteria as one of the culprits of autism, and — at least in mice — shows that some features of autism can be reversed by treating an abnormal gut microbiome. There remains one more twist to this story. Earlier, it was mentioned that a sharp rise in autism prevalence was observed at the end of the 1970s. It turns out that the same can be said for obesity. That is, the rates of both autism and obesity among Westerners seem to have taken off around the same time — the end of the 1970s. This may seem like a simple coincidence (and it very well might be) but consider this: it was during the 1970s that Westerns began to adopt a diet rich in processed foods, sugar-sweetened drinks and a mostly sedentary lifestyle (11). That’s important here because, as we have spoken about in previous blogs, it’s already very well appreciated that our gut bacteria influence our weight (You can read that blog here: http://www.thegutguys.com/myhealth/category/obesity). Given that our gut bacteria have already been shown to influence weight, and given that autism prevalence spiked once the Western diet was introduced in the late 1970s, is it too far-fetched to assume that they also contribute to autism? Has our adoption of the Western diet molded a “bad” microbiome conducive to both obesity and autism? Although further research is required to fully understand the answer to that question, it definitely deserves its fair share of discussion, as autism prevalence among our children continues to increase at an alarming rate. References 1. Muir, H. 2003. Einstein and Newton showed signs of autism. In New Scientist. 2. Wilson, M. 1993. DSM-III and the transformation of American psychiatry: a history. Am. J. Psychiatry 150: 399-410. 3. Centers for Disease Control and Prevention. 2012. Autism Spectrum Disorder — Data & Statistics. 4. Rao, T. S. S., and C. Andrade. 2011. The MMR vaccine and autism: Sensation, refutation, retraction, and fraud. Indian J. Psychiatry 53: 95-96. 5. Blomquist, H. K., M. Bohman, S. O. Edvinsson, C. Gillberg, K. H. Gustavson, G. Holmgren, and J. Wahlstrom. 1985. Frequency of the fragile X syndrome in infantile autism. A Swedish multicenter study. Clin. Genet. 27: 113-117. 6. Jorde, L. B., S. J. Hasstedt, E. R. Ritvo, A. Mason-Brothers, B. J. Freeman, C. Pingree, W. M. McMahon, B. Petersen, W. R. Jenson, and A. Mo. 1991. Complex segregation analysis of autism. Am. J. Hum. Genet. 49: 932-938. 7. Miles, J. H. 2011. Autism spectrum disorders--a genetics review. Genet. Med. 13: 278-294. 8. Malkova, N. V., C. Z. Yu, E. Y. Hsiao, M. J. Moore, and P. H. Patterson. 2012. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain. Behav. Immun. 26: 607-616. 9. Erickson, C. A., K. A. Stigler, M. R. Corkins, D. J. Posey, J. F. Fitzgerald, and C. J. McDougle. 2005. Gastrointestinal factors in autistic disorder: a critical review. J. Autism Dev. Disord. 35: 713-727. 10. Hsiao, E. Y., S. W. McBride, S. Hsien, G. Sharon, E. R. Hyde, T. McCue, J. A. Codelli, J. Chow, S. E. Reisman, J. F. Petrosino, P. H. Patterson, and S. K. Mazmanian. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155: 1451-1463. 11. Popkin, B. M., L. S. Adair, and S. W. Ng. 2012. NOW AND THEN: The Global Nutrition Transition: The Pandemic of Obesity in Developing Countries. Nutr. Rev. 70: 3-21.  
Image Courtesy of https://www.senioradvisor.com/blog/wp-content/uploads/2017/03/New-Alzheimer’s-Research-Could-Gut-Bacteria-Play-a-Role-.png
Alzheimer’s disease (AD) is the most common form of dementia (disorder affecting the brain) in the western world. However, there is no cure available for this devastating neurodegenerative disorder. This disease is characterized by proteins called beta amyloid (Aβ) which build up in the brain to form structures called ‘plaques’ and ‘tangles’ (1). This leads to the loss of connections between nerve cells, and eventually to the death of nerve cells and loss of brain tissue. Since Alzheimer’s is a progressive disease, this means that gradually, over time, more parts of the brain will be damaged. As this happens, more symptoms develop and become more severe. Some of the symptoms of Alzheimer’s are memory loss, confusion, inability to learn new things, hallucinations and impulsive behavior (2). But what does Alzheimer’s disease have to do with the gut microbiota? Increasing evidence suggests that the gastro-intestinal tract is the bridge between microbiota and the central nervous system. As a matter of fact, a growing body of clinical and experimental evidence suggests that gut microbiota may contribute to aging and influence brain disorders (3). For instance, a new connection between gut microbiota and Parkinson’s disease has been reported in humans. In mouse models, studies report a role for the microbiota in the modulation of stress-related behaviors relevant to psychiatric disorders as mentioned in one of our previous blogs (You can read that blog here http://www.thegutguys.com/myhealth/the-worried-gut-can-gut-bacteria-influence-our-mood). Similarly, recent studies have showed marked differences in the gut bacteria composition between mice suffering from Alzheimer's and healthy mice (4). Researchers also studied Alzheimer’s disease in mice that completely lacked bacteria to further test the relationship between intestinal bacteria and the disease. The results showed that mice without bacteria had a significantly smaller amount of beta amyloid plaques in the brain (recall: Beta-amyloid plaques are the lumps that form at the nerve fibres in cases of Alzheimer's disease). Furthermore, in order to clarify the link between intestinal bacteria and the occurrence of the disease, the researchers transferred intestinal bacteria from diseased mice to germ-free mice (meaning mice free of bacteria), and discovered that the mice developed more beta-amyloid plaques in the brain compared to if they had received bacteria from healthy mice (4). Overall, that’s all a very scientific way to say that a healthier gut appears to lead to both a lower incidence of Alzheimer’s and a less severe form of the disease when it does occur. These are very promising results and they have the potential for opening new area for the treatment and prevention of Alzheimer’s disease and ultimately other neurodegenerative disorders. In fact, researchers will continue to study the role of bacteria in the development of Alzheimer's disease, and test entirely new types of preventive and therapeutic strategies based on the modulation of the gut microbiota through diet and new types of probiotics. References 1. Park, Laibaik, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pitstick, Linda H. Younkin, Steven G. Younkin, Ping Zhou, Geroge A. Carlson, Josef Anrather, and Costantino Iadecola. "Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides." Circulation Research (2017): n. pag. 2. Society, Alzheimer's. "Alzheimer's Disease." Alzheimer's Society. Alzheimer's Society, 11 Nov. 2016. Web. 3. O’Toole, P. W. & Jeffery, I. B. Gut microbiota and aging. Science 350, 1214–1215, (2015). 4. Harach, T., N. Marungruang, N. Duthilleul, V. Cheatham, K. D. Mc Coy, G. Frisoni, J. J. Neher, F. FÃ¥k, M. Jucker, T. Lasser, and T. Bolmont. "Reduction of Abeta Amyloid Pathology in APPPS1 Transgenic Mice in the Absence of Gut Microbiota." Scientific Reports 7 (2017): 41802. |
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