A Home for the Microbiome

 Biologists Identify How Beneficial Bacteria Reside and Thrive in Gastrointestinal Tract

A section of mouse colon is shown with gut bacteria (outlined in yellow) residing within the crypt channel. (Credit: Caltech / Mazmanian Lab)

The human body is full of tiny microorganisms -- hundreds to thousands of species of bacteria collectively called the microbiome, which are believed to contribute to a healthy existence. The gastrointestinal (GI) tract -- and the colon in particular -- is home to the largest concentration and highest diversity of bacterial species. But how do these organisms persist and thrive in a system that is constantly in flux due to foods and fluids moving through it? A team led by California Institute of Technology (Caltech) biologist Sarkis Mazmanian believes it has found the answer, at least in one common group of bacteria: a set of genes that promotes stable microbial colonization of the gut.

A study describing the researchers' findings was published as an advance online publication of the journal Natureon August 18.

"By understanding how these microbes colonize, we may someday be able to devise ways to correct for abnormal changes in bacterial communities -- changes that are thought to be connected to disorders like obesity, inflammatory bowel disease and autism," says Mazmanian, a professor of biology at Caltech whose work explores the link between human gut bacteria and health.

The researchers began their study by running a series of experiments to introduce a genus of microbes called Bacteriodesto sterile, or germ-free, mice. Bacteriodes, a group of bacteria that has several dozen species, was chosen because it is one of the most abundant genuses in the human microbiome, can be cultured in the lab (unlike most gut bacteria), and can be genetically modified to introduce specific mutations.

"Bacteriodes are the only genus in the microbiome that fit these three criteria," Mazmanian says.

Lead author S. Melanie Lee (PhD '13), who was an MD/PhD student in Mazmanian's lab at the time of the research, first added a few different species of the bacteria to one mouse to see if they would compete with each other to colonize the gut. They appeared to peacefully coexist. Then, Lee colonized a mouse with one particular species, Bacteroides fragilis, and inoculated the mouse with the same exact species, to see if they would co-colonize the same host. To the researchers' surprise, the newly introduced bacteria could not maintain residence in the mouse's gut, despite the fact that the animal was already populated by the identical species.

"We know that this environment can house hundreds of species, so why the competition within the same species?" Lee says. "There certainly isn't a lack of space or nutrients, but this was an extremely robust and consistent finding when we tried to essentially 'super-colonize' the mice with one species."

To explain the results, Lee and the team developed what they called the "saturable niche hypothesis." The idea is that by saturating a specific habitat, the organism will effectively exclude others of the same species from occupying that niche. It will not, however, prevent other closely related species from colonizing the gut, because they have their own particular niches. A genetic screen revealed a set of previously uncharacterized genes -- a system that the researchers dubbed commensal colonization factors (CCF) -- that were both required and sufficient for species-specific colonization by B. fragilis.

But what exactly is the saturable niche? The colon, after all, is filled with a flowing mass of food, fecal matter and bacteria, which doesn't offer much for organisms to grab onto and occupy.

"Melanie hypothesized that this saturable niche was part of the host tissue" -- that is, of the gut itself -- Mazmanian says. "When she postulated this three to four years ago, it was absolute heresy, because other researchers in the field believed that all bacteria in our intestines lived in the lumen -- the center of the gut -- and made zero contact with the host…our bodies. The rationale behind this thinking was if bacteria did make contact, it would cause some sort of immune response."

Nonetheless, when the researchers used advanced imaging approaches to survey colonic tissue in mice colonized with B. fragilis, they found a small population of microbes living in miniscule pockets -- or crypts -- in the colon. Nestled within the crypts, the bacteria are protected from the constant flow of material that passes through the GI tract. To test whether or not the CCF system regulated bacterial colonization within the crypts, the team injected mutant bacteria -- without the CCF system -- into the colons of sterile mice. Those bacteria were unable to colonize the crypts.

"There is something in that crypt -- and we don't know what it is yet -- that normal B. fragilis can use to get a foothold via the CCF system," Mazmanian explains. "Finding the crypts is a huge advance in the field because it shows that bacteria do physically contact the host. And during all of the experiments that Melanie did, homeostasis, or a steady state, was maintained. So, contrary to popular belief, there was no evidence of inflammation as a result of the bacteria contacting the host. In fact, we believe these crypts are the permanent home ofBacteroides, and perhaps other classes of microbes."

He says that by pinpointing the CCF system as a mechanism for bacterial colonization and resilience, in addition to the discovery of crypts in the colon that are species specific, the current paper has solved longstanding mysteries in the field about how microbes establish and maintain long-term colonization.

"We've studied only a handful of organisms, and though they are numerically abundant, they are clearly not representative of all the organisms in the gut," Lee says. "A lot of those other bacteria don't have CCF genes, so the question now is: Do those organisms somehow rely on interactions with Bacteroides for their own colonization, or their replication rates, or their localization?"

Suspecting that Bacteroides are keystone species -- a necessary factor for building the gut ecosystem -- the researchers next plan to investigate whether or not functional abnormalities, such as the inability to adhere to crypts, could affect the entire microbiome and potentially lead to a diseased state in the body.

"This research highlights the notion that we are not alone. We knew that bacteria are in our gut, but this study shows that specific microbes are very intimately associated with our bodies," Mazmanian says. "They are living in very close proximity to our tissues, and we can't ignore microbial contributions to our biology or our health. They are a part of us."

Funding for the research outlined in the Nature paper, titled "Bacterial colonization factors control specificity and stability of the gut microbiota," was provided by the National Institutes of Health and the Crohn's and Colitis Foundation of America. Additional coauthors were Gregory Donaldson and Silva Boyajian from Caltech and Zbigniew Mikulski and Klaus Ley from the La Jolla Institute for Allergy and Immunology in La Jolla, California.

Source : California Institute of Technology.

By Science and Universe

Honk If You Think Geese Are Good Guard Dogs

Some cops in China now use feathered friends instead of canine companions.

Domestic geese in a Norwegian pasture menace a photographer. (Photograph by Sindre Ellingsen, Alamy)

Police in rural parts of China's Xinjiang Province are no longer turning to dogs to stand guard at police stations at night. They're using geese instead. And it works.

According to a recent report, a guy tried to break into a police station to take back a motorbike confiscated by the cops. The guard geese sounded the alarm, awakening the sleeping officers.

But ... really? Guard geese?

To gain insights into goose behavior, we spoke with Patrick Cumins, director of bird conservation at Audubon Connecticut, who has seen barnyard geese in action at a neighborhood park.

Would geese make good guards?

They have amazing hearing. And almost all birds have amazing eyesight. Not only do they see better at a distance than humans do, they can also see things up close [better than we do].

Our eyes have three different color sensors that combine to build the picture in our brain. Birds add a fourth—ultraviolet. They have a much wider range of wavelengths they can view. Things are going to look sharper. And they can pick out smaller things [as well as movement].

And I guess they're not shy when an intruder is sighted?

In terms of alerting people to activity, yeah, they're very vigilant. They're territorial. And certain species can be quite loud, especially the barnyard varieties.

Besides guarding a police station, are there any other things geese might guard?

I understand people in this country are using geese to guard their free-range chicken flocks.

So they're just really good watchdogs.

That's the beauty of it: It's instinct for them. They're territorial. They could fly off anywhere they want to, but they hang around their home. That's just the way a lot of geese act. Certain of them can be rather vigilant in defending their territory.

Would the same be true of swans?

I haven't heard of anybody using guard swans, but they can even be more aggressive than geese [when it comes to] defending their territory. There are stories of them knocking people out of kayaks, tangling with people and actually injuring them.

Is there any danger a guard goose would turn on a cop?

I don't think so. They seem to recognize you as part of the flock. If a new person came, the uniform might help the geese to acclimate [to that person]. People might all look the same [to a goose] if they're wearing uniforms.

Could a criminal distract a guard goose?

Dogs you can give some steak and they might be a little distracted. It's pretty hard to give geese something that's going to distract them enough where they wouldn't make noise. They might make more noise if you throw something yummy at them. And once they get going, they're hard to quiet down.

What would you feed them, anyway?

Geese are fairly easy to take care of. Feeding them is relatively inexpensive. There are specific [feed] mixes for geese, but they're happy eating cracked corn and grazing on grass.

Do geese have any other police-like traits?

The barnyard geese that live in our park are used to lots of people. They're not afraid of cars. They can be brazen. A major road goes right by [the park where the geese live]. Every once in a while all traffic stops as the geese walk across the road.

So a goose might also apply for a job as a crossing guard?

Yeah. You see one of the more dominant geese stop and stare down the cars while the others are crossing.

Source: National Geography

Neuroscientists Plant False Memories in Mice: Location Where Brain Stores Memory Traces, Both False and Authentic, Pinpointed

MIT neuroscientists identified the cells
(highlighted in red) where memory traces are stored in the
mouse hippocampus.
(Credit: Steve Ramirez and Xu Liu)

The phenomenon of false memory has been well-documented: In many court cases, defendants have been found guilty based on testimony from witnesses and victims who were sure of their recollections, but DNA evidence later overturned the conviction.

In a step toward understanding how these faulty memories arise, MIT neuroscientists have shown that they can plant false memories in the brains of mice. They also found that many of the neurological traces of these memories are identical in nature to those of authentic memories.

“Whether it’s a false or genuine memory, the brain’s neural mechanism underlying the recall of the memory is the same,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the July 25 edition of Science. 

The study also provides further evidence that memories are stored in networks of neurons that form memory traces for each experience we have — a phenomenon that Tonegawa’s lab first demonstrated last year. 

Neuroscientists have long sought the location of these memory traces, also called engrams. In the pair of studies, Tonegawa and colleagues at MIT’s Picower Institute for Learning and Memory showed that they could identify the cells that make up part of an engram for a specific memory and reactivate it using a technology called optogenetics. 

Lead authors of the paper are graduate student Steve Ramirez and research scientist Xu Liu. Other authors are technical assistant Pei-Ann Lin, research scientist Junghyup Suh, and postdocs Michele Pignatelli, Roger Redondo and Tomas Ryan. 

Seeking the engram

Episodic memories — memories of experiences — are made of associations of several elements, including objects, space and time. These associations are encoded by chemical and physical changes in neurons, as well as by modifications to the connections between the neurons.

Where these engrams reside in the brain has been a longstanding question in neuroscience. “Is the information spread out in various parts of the brain, or is there a particular area of the brain in which this type of memory is stored? This has been a very fundamental question,” Tonegawa says.

In the 1940s, Canadian neurosurgeon Wilder Penfield suggested that episodic memories are located in the brain’s temporal lobe. When Penfield electrically stimulated cells in the temporal lobes of patients who were about to undergo surgery to treat epileptic seizures, the patients reported that specific memories popped into mind. Later studies of the amnesiac patient known as “H.M.” confirmed that the temporal lobe, including the area known as the hippocampus, is critical for forming episodic memories. 

However, these studies did not prove that engrams are actually stored in the hippocampus, Tonegawa says. To make that case, scientists needed to show that activating specific groups of hippocampal cells is sufficient to produce and recall memories.

To achieve that, Tonegawa’s lab turned to optogenetics, a new technology that allows cells to be selectively turned on or off using light. 

For this pair of studies, the researchers engineered mouse hippocampal cells to express the gene for channelrhodopsin, a protein that activates neurons when stimulated by light. They also modified the gene so that channelrhodopsin would be produced whenever the c-fos gene, necessary for memory formation, was turned on. 

In last year’s study, the researchers conditioned these mice to fear a particular chamber by delivering a mild electric shock. As this memory was formed, the c-fos gene was turned on, along with the engineered channelrhodopsin gene. This way, cells encoding the memory trace were “labeled” with light-sensitive proteins.

The next day, when the mice were put in a different chamber they had never seen before, they behaved normally. However, when the researchers delivered a pulse of light to the hippocampus, stimulating the memory cells labeled with channelrhodopsin, the mice froze in fear as the previous day’s memory was reactivated. 

“Compared to most studies that treat the brain as a black box while trying to access it from the outside in, this is like we are trying to study the brain from the inside out,” Liu says. “The technology we developed for this study allows us to fine-dissect and even potentially tinker with the memory process by directly controlling the brain cells.” 

Incepting false memories

That is exactly what the researchers did in the new study — exploring whether they could use these reactivated engrams to plant false memories in the mice’s brains. 

First, the researchers placed the mice in a novel chamber, A, but did not deliver any shocks. As the mice explored this chamber, their memory cells were labeled with channelrhodopsin. The next day, the mice were placed in a second, very different chamber, B. After a while, the mice were given a mild foot shock. At the same instant, the researchers used light to activate the cells encoding the memory of chamber A. 

On the third day, the mice were placed back into chamber A, where they now froze in fear, even though they had never been shocked there. A false memory had been incepted: The mice feared the memory of chamber A because when the shock was given in chamber B, they were reliving the memory of being in chamber A. 

Moreover, that false memory appeared to compete with a genuine memory of chamber B, the researchers found. These mice also froze when placed in chamber B, but not as much as mice that had received a shock in chamber B without having the chamber A memory activated.

The researchers then showed that immediately after recall of the false memory, levels of neural activity were also elevated in the amygdala, a fear center in the brain that receives memory information from the hippocampus, just as they are when the mice recall a genuine memory. 

These two papers represent a major step forward in memory research, says Howard Eichenbaum, a professor of psychology and director of Boston University’s Center for Memory and Brain.

“They identified a neural network associated with experience in an environment, attached a fear association with it, then reactivated the network to show that it supports memory expression. That, to me, shows for the first time a true functional engram,” says Eichenbaum, who was not part of the research team.

The MIT team is now planning further studies of how memories can be distorted in the brain. 

“Now that we can reactivate and change the contents of memories in the brain, we can begin asking questions that were once the realm of philosophy,” Ramirez says. “Are there multiple conditions that lead to the formation of false memories? Can false memories for both pleasurable and aversive events be artificially created? What about false memories for more than just contexts — false memories for objects, food or other mice? These are the once seemingly sci-fi questions that can now be experimentally tackled in the lab.”

Article Source : Massachusetts Institute of Technology

By Science & Universe

Red bacteria fighting cholesterol for you

What started as a food that astronauts could grow themselves is showing potential for lowering cholesterol levels around the world: space research has found a bacterium that can reduce cholesterol by half.

The origin of this discovery is ESA’s research into self-contained eco systems recycling mission waste into oxygen, food and water. Why take bulky supplies into space when you can engineer your own using the right mix of plants and microorganisms?

The ESA-led Micro-Ecological Life Support System Alternative (MELiSSA) project is tackling this challenge by developing water recycling and looking for ways to cook nutritious meals from less common ingredients.

While they might not sound appetising, bacteria are promising ingredients for space food. They grow exponentially and can provide many nutrients in an astronaut’s diet on a long mission to the Moon or Mars.

As part of its search for the perfect mix of ingredients, the MELiSSA project tested a bacterium, codenamed Red, for safety at the Dutch TNO research institute. 

A bioreactor is basically a vat kept at ideal temperatures and under the right amount of light. By controlling the light, pressure, ingredients and general conditions inside the vat, a bioreactor can ’cook’ many kinds of biomaterials. They can also be used to recycle and treat the waste into edible biomass and for waste water treatment systems, recycling of biological waste and controlled crop growth.

The bacterium was shown to be safe and nutritious but also, remarkably, to cut levels of LDL cholesterol – the ‘bad’ cholesterol.

High levels of cholesterol in the blood increase the risk of heart disease and stroke and 39% of the world’s population have raised levels according to the World Health Organisation. Finding more ways to keep cholesterol in check has obvious benefits.

With ESA’s support, spin-off company EzCOL BV was set up by IPStar BV, MELiSSA’s technology transfer partner, to continue research and market the cholesterol-diminishing bacterium.

Based in the Netherlands, EzCOl has taken over the development under ESA’s Business Incubation Centre in Noordwijk, where they were supported to start their business.

“Our tests demonstrated a reduction in LDL cholesterol levels of up to 50%,” says director Rob Suters of EzCOL.

“We are now scaling up production and doing more tests. All signs show that our product is more effective at lower concentrations than existing cholesterol drugs.” 

The Red bacterium, formally Rhodospirillum rubrum, is a purple Proteobacterium, with a size of 800–1000 nanometres.  It offers several potential uses in biotechnology.

The bacteria are grown in Belgium at MELiSSA’s partner SCK·CEN research centre in vats that need to be kept at ideal temperatures and under the right amount of light.

They could be marketed as a medicine or potentially as a food supplement to existing products.

“Within 18–24 months we will complete our research and be ready to market the technology,” says Rob. “We are already talking to major food producers and pharmaceutical companies.”

Red will not be used by MELiSSA as a cooking ingredient for astronauts because an alga was found to be more suitable for the job. But the nifty bacterium does has another trick up its sleeve: it has proven its worth as a major part of the MELiSSA loop for organic waste and water recycling.

As well as colonising space, Red might soon be conquering supermarkets near you in the fight against cholesterol.

Source : ESA
By Science and universe