Mind-Altering Microbes: Probiotic Bacteria May Lessen Anxiety and Depression
Probiotic bacteria have the potential to alter brain neurochemistry and treat anxiety and depression-related disorders according to research published in the Proceedings of the National Academy of Sciences. The research, carried out by Dr Javier Bravo, and Professor John Cryan at the Alimentary Pharmabiotic Centre in University College Cork, along with collaborators from the Brain-Body Institute at McMaster University in Canada, demonstrated that mice fed with Lactobacillus rhamnosus JB-1 showed significantly fewer stress, anxiety and depression-related behaviours than those fed with just broth. Moreover, ingestion of the bacteria resulted in significantly lower levels of the stress-induced hormone, corticosterone.
"This study identifies potential brain targets and a pathway through which certain gut organisms can alter mouse brain chemistry and behaviour. These findings highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, the gut-brain axis, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for stress-related psychiatric disorders such as anxiety and depression," said John F. Cryan, senior author on the publication and Professor of Anatomy and Principal Investigator at the Science Foundation Ireland funded Alimentary Pharmabiotic Centre, at UCC. The APC researchers included Dr Hélène Savignac and Professor Ted Dinan.
The researchers also showed that regular feeding with the Lactobacillus strain caused changes in the expression of receptors for the neurotransmitter GABA in the mouse brain, which is the first time that it has been demonstrated that potential probiotics have a direct effect on brain chemistry in normal situations. The authors also established that the vagus nerve is the main relay between the microbiome (bacteria in the gut) and the brain. This three way communication system is known as the microbiome-gut-brain axis and these findings highlight the important role of bacteria in the communication between the gut and the brain, and suggest that certain probiotic organisms may prove to be useful adjunct therapies in stress-related psychiatric disorders.
The figure illustrates the molecular shape of a region of nucleosomal DNA when wrapped around the histone core, with the narrow minor groove in dark grey. The red mesh shows a surface with negative electrostatic potential. The shape of narrow minor groove regions induces an enhanced negative electrostatic potential, which is read by histone arginines. Such interactions between the protein and DNA contribute to the stabilization of the nucleosome core particle.
Most of us carry a mental picture of DNA in its iconic form – the famous double helix unveiled by Francis Crick and James Watson. But researchers are beginning to develop a new picture of DNA that shows the molecule’s more dynamic side, which is capable of morphing into a large number of complex shapes. This shape-shifting ability permits proteins to attach and read the right region of DNA so genes can be turned on or off at the proper time.
The findings show that proteins are adept at reading nuances in the shape of the double helix. Those variations in shape transmit information about where proteins need to bind to make sure the right genes are activated or silenced during development.
“The ideal double helix should not be viewed as a rigid entity but rather seen as a first approximation to a large set of more complex shapes that are recognized by proteins so as to bind to DNA in a sequence-specific fashion,” said Howard Hughes Medical Institute investigator Barry Honig at Columbia University.
Honig and his colleagues have discovered a new mechanism by which proteins recognize specific regions of DNA. Their research is reported in the October 29, 2009, issue of the journal Nature.
Even for seasoned biologists, the endless stream of A, T, G and C nucleotides in the genetic code can look like a string of letters in a long book that makes no sense. It can be easy to get lost. But proteins that bind to DNA to turn genes on or off have an innate intelligence -- they know how to read the book. One of their “secrets” is to follow a set of instructions that are hidden inside the DNA sequence.
Scientists have long known that specialized DNA-binding proteins, such as transcription factors that activate and repress genes, look for their docking sites on DNA by scanning the genome for a specific nucleotide sequence that says “bind here.” When proteins recognize that sequence, they bind to DNA and begin to do their jobs. But over the last 20 years, researchers have accumulated evidence that the physical shape of DNA can also influence where and when proteins attach to DNA.
The new studies published in Nature by Honig and his colleagues, Remo Rohs, Sean West, Alona Sosinsky, Peng Liu and Richard Mann, extend those results and describe a new recognition strategy that proteins use to identify and bind to DNA. The coiled, complementary strands of DNA form 'major' and 'minor' grooves, to which proteins can bind. The recognition strategy identified by Honig’s team depends on proteins’ ability to read DNA shape – specifically, the width of the minor grooves.
The work originated with an earlier study of how a particular transcription factor, known as a Hox protein, achieves DNA binding specificity. Hox proteins are important for determining the overall body plan in all animals and need to bind to their DNA targets with great specificity, so that they can control the activity of only the appropriate genes. Previous work from a number of labs had revealed common features that all Hox proteins share when they bind to DNA, but scientists did not know how individual Hox proteins distinguish between different binding sites.
In 2007, Honig and collaborators in the labs of geneticist Richard Mann and x-ray crystallographer Aneel Aggarwal compared the structures of two different DNA sequences bound to a Hox protein. One DNA sequence was highly selective for a particular Hox protein, while the other was able to bind multiple Hox proteins. They found that the selective DNA target had a narrower minor groove than is typical for double-helical DNA. In contrast, the less selective DNA sequence had a different, less narrow, minor groove shape.
“The question for us was, why is that important?” Honig says. “What we showed is that the electrostatic potential of the DNA – which is used to attract positive charges – is stronger when a groove is narrow.” Intriguingly, the width and shape of the grooves are affected by single-letter changes in the DNA sequence. In other words, the sequence of DNA determines its precise shape, which then provides a target for the proper protein to bind.
“It is quite surprising actually,” Honig says. “If you now realize that those nucleotides determine which proteins bind the DNA, and they do it in part through their effect on shape, you begin to understand how sensitive and subtle the DNA structure really is, and how this in turn affects how it's being read.”
With proof of this new type of DNA recognition strategy in hand, the team next set out to see whether their concept was generalizable – whether it would apply to proteins outside of the Hox family.
They probed a database of molecular structure information about DNA-protein complexes, looking at how the DNA’s sequence and structure matched up with each of the protein’s amino acid building blocks. They found that narrow minor grooves tended to attract parts of the protein that contained the amino acid arginine, which is positively charged. They saw that there are many arginine binding sites in DNA that have narrower minor grooves and that these have more negative electrostatic potentials that attract positively charged regions of proteins.
“The proteins are actually reading the shape of the DNA through its effect on electrostatic potential,” Honig says. “Sequence determines shape, which determines the affinity for arginines --a mechanism made possible because DNA does not form a perfect double helix.”
Honig’s group plans to examine RNA, the intermediate molecule produced when DNA’s information is translated into protein. He and his colleagues will be looking for similar relationships between sequence, shape and electrostatic potential. They also hope to use the relationship between DNA sequence and shape to predict which sequences of the DNA are bound by transcription factors and which proteins recognize these regulatory regions. Honig says he and other researchers are now thinking about DNA in new ways: A separate research group recently compared the shapes of DNA in different species and concluded that these molecular nuances are shaped by evolution. “Taken together with our studies, the results offer a new way to think about DNA,” Honig says.