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   Mental Health: Thinking from the Gut    
      
   Charles Schmidt    
   Nature 518, S12-S15 (26 February 2015) doi:10.1038/518S13a    
   Published online 25 February 2015    
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   The microbiome may yield a new class of psychobiotics for the treatment of   
   anxiety, depression and other mood disorders    
      
   Subject terms: Microbiology Microbiome    
      
   Illustration by Jessica Fortner    
   The notion that the state of our gut governs our state of mind dates back more   
   than 100 years. Many 19th- and early 20th-century scientists believed that   
   accumulating wastes in the colon triggered a state of "auto-intoxication,"   
   whereby poisons emanating    
   from the gut produced infections that were in turn linked with depression,   
   anxiety and psychosis. Patients were treated with colonic purges and even   
   bowel surgeries until these practices were dismissed as quackery.    
      
   The ongoing exploration of the human microbiome promises to bring the link   
   between the gut and the brain into clearer focus. Scientists are increasingly   
   convinced that the vast assemblage of microfauna in our intestines may have a   
   major impact on our    
   state of mind. The gut-brain axis seems to be bidirectional--the brain acts on   
   gastrointestinal and immune functions that help to shape the gut's microbial   
   makeup, and gut microbes make neuroactive compounds, including n   
   urotransmitters and metabolites    
   that also act on the brain. These interactions could occur in various ways:   
   microbial compounds communicate via the vagus nerve, which connects the brain   
   and the digestive tract, and microbially derived metabolites interact with the   
   immune system, which    
   maintains its own communication with the brain. Sven Pettersson, a   
   microbiologist at the Karolinska Institute in Stockholm, has recently shown   
   that gut microbes help to control leakage through both the intestinal lining   
   and the blood-brain barrier, which    
   ordinarily protects the brain from potentially harmful agents.    
      
   Microbes may have their own evolutionary reasons for communicating with the   
   brain. They need us to be social, says John Cryan, a neuroscientist at   
   University College Cork in Ireland, so that they can spread through the human   
   population. Cryan's research    
   shows that when bred in sterile conditions, germ-free mice lacking in   
   intestinal microbes also lack an ability to recognize other mice with whom   
   they interact. In other studies, disruptions of the microbiome induced mice   
   behavior that mimics human    
   anxiety, depression and even autism. In some cases, scientists restored more   
   normal behavior by treating their test subjects with certain strains of benign   
   bacteria. Nearly all the data so far are limited to mice, but Cryan believes   
   the findings provide    
   fertile ground for developing analogous compounds, which he calls   
   psychobiotics, for humans. "That dietary treatments could be used as either   
   adjunct or sole therapy for mood disorders is not beyond the realm of   
   possibility," he says.    
      
   Personality shifts    
   Scientists use germ-free mice to study how the lack of a microbiome--or   
   selective dosing with particular bacteria--alters behavior and brain function,   
   "which is something we could never do in people," Cryan says. Entire colonies   
   of germ-free mice are    
   bred and kept in isolation chambers, and the technicians who handle them wear   
   full bodysuits, as if they were in a biohazard facility. As with all mice   
   research, extrapolating results to humans is a big step. That is especially   
   true with germ-free mice    
   because their brains and immune systems are underdeveloped, and they tend to   
   be more hyperactive and daring than normal mice.    
      
   A decade ago a research team led by Nobuyuki Sudo, now a professor of internal   
   medicine at Kyushu University in Japan, restrained germ-free mice in a narrow   
   tube for up to an hour and then measured their stress hormone output. The   
   amounts detected in the    
   germ-free animals were far higher than those measured in normal control mice   
   exposed to the same restraint. These hormones are released by the   
   hypothalamic-pituitary-adrenal axis, which in the germ-free mice was clearly   
   dysfunctional. But more important,    
   the scientists also found they could induce more normal hormonal responses   
   simply by pretreating the animals with a single microbe: a bacterium called   
   Bifidobacterium infantis. This finding showed for the first time that   
   intestinal microbes could    
   influence stress responses in the brain and hinted at the possibility of using   
   probiotic treatments to affect brain function in beneficial ways. "It really   
   got the field off the ground," says Emeran Mayer, a gastroenterologist and   
   director of the Center    
   for Neurobiology of Stress at the University of California, Los Angeles.    
      
   Meanwhile a research team at McMaster University in Ontario led by   
   microbiologist Premsyl Bercik and gastroenterologist Stephen Collins   
   discovered that if they colonized the intestines of one strain of germ-free   
   mice with bacteria taken from the    
   intestines of another mouse strain, the recipient animals would take on   
   aspects of the donor's personality. Naturally timid mice would become more   
   exploratory, whereas more daring mice would become apprehensive and shy. These   
   tendencies suggested that    
   microbial interactions with the brain could induce anxiety and mood disorders.    
      
   Bercik and Collins segued into gut-brain research from their initial focus on   
   how the microbiome influences intestinal illnesses. People who suffer from   
   these conditions often have co-occurring psychiatric problems such as anxiety   
   and depression that    
   cannot be fully explained as an emotional reaction to being sick. By   
   colonizing germ-free mice with the bowel contents of people with irritable   
   bowel syndrome, which induces constipation, diarrhea, pain and low-grade   
   inflammation but has no known cause,    
   the McMaster's team reproduced many of the same gastrointestinal symptoms. The   
   animals developed leaky intestines, their immune systems activated, and they   
   produced a barrage of pro-inflammatory metabolites, many with known nervous   
   system effects.    
   Moreover, the mice also displayed anxious behavior, as indicated in a test of   
   their willingness to step down from a short raised platform.    
      
   Autism connection?    
      
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