Gut bacteria help regulate contraction and relaxation of colon muscles

Micro-organisms in the gut support healthy digestion by helping nerve cells within the intestine to regulate the contraction and relaxation of the muscle wall of the colon, according to new research from the Crick and Bern University.

The study, published in Nature, identified how the contraction and relaxation of muscles in the colon, which is regulated by nerve cells and is needed to push food along, is influenced by the bacteria resident in our gut. When such microbes are present, a specific gene called Ahr is activated in intestinal nerves, resulting in healthy contraction and relaxation of the colon (peristalsis). This relationship can be disrupted in cases of intestinal disorders, like irritable bowel syndrome (IBS).

There is a clear link between the presence of microbes in the colon and the speed at which food moves through the system. If this relationship goes off-kilter it could cause considerable harm."    Yuuki Obata, lead author and postdoc in the Development and Homeostasis of the Nervous System Laboratory at the Crick

A healthy gut contains trillions of microorganisms which help the digestion of food and promote the fitness of gut tissues, such as the epithelial lining of the lumen and the vast collection of immune and nerve cells within the gut wall. The levels and types of microorganisms in the gut vary from person to person and are affected by diet and commonly used drugs, such as antibiotics, which often result in abnormal gut contractions. The work described in this paper helps us understand how nerve cells sense the microbes in the gut and how they could coordinate their function with other gut tissues.

"Disturbances of intestinal motility are extremely common and cause a lot of suffering in patients after surgical operations or in conditions such as irritable bowel syndrome. This work provides a foundation to unravel why patients that are colonised with different groups of microbes are susceptible to these intestinal problems", explains Andrew Macpherson, Professor of Medicine and Director of Gastroenterology at the University Hospital of Bern.

"By drawing on different teams at the Crick and internationally with Bern University, we've combined expertise on the gut and how environmental signals from microbiota and diet are passed to cells, to gain understanding of how gut physiology and digestion are affected by these signals," says Brigitta Stockinger, co-lead author and group leader in the AhRimmunity Laboratory at the Crick.

"While it's been well-documented that the micro-organisms in our gut influence the function of many organs in our body, including the brain, there's less understanding about the role they play in maintaining the healthy functioning of the millions of nerve cells within digestive system itself. The work we describe here shows that AhR, a molecule which is very important for the function of immune and epithelial cells in the gut, is also used by intestinal nerve cells to sense the presence of microbes and regulate peristalsis, and in doing so, promote healthy digestion," says Vassilis Pachnis, co-lead author and group leader in the Development and Homeostasis of the Nervous System Laboratory at the Crick.

"In the future, the use of microbial products that change the activity of AhR in nerve cells could help us alleviate the consequences of abnormal gut peristalsis that is often associated with gastrointestinal diseases," continues Vassilis.

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Scientists Just Found a Super-Powerful New Class of Antibiotics in Dirt

The modern medical era began when an absent-minded British scientist named Alexander Fleming returned from vacation to find that one of the petri dishes he forgot to put away was covered in a bacteria-killing mould. He had discovered penicillin, the world's first antibiotic.

Ninety years later, the world faces an antibiotic crisis.

Superbugs have evolved resistance to dozens of drugs in doctors' arsenals, leading to infections that are increasingly difficult to treat. Global deaths from antibiotic-resistant infections are predicted to hit 10 million a year by 2050.

So in labs around the world, scientists are racing against time to cultivate new microbe-destroying molecules – but most of the low-hanging fruit has already been picked.

With due respect to Fleming, a microbiologist thinks it's time to shift tactics. Instead of growing antibiotics in a petri dish, he hopes to find them in the ground.

"Every place you step, there's 10,000 bacteria, most of which we've never seen," said the researcher, an associate professor.

Many of these bacteria behave in ways that aren't yet understood and produce molecules that we haven't been seen before.

"Our idea is, there's this reservoir of antibiotics out in the environment we haven't accessed yet," the researcher said.

That idea is beginning to pay off: in a study published recently,the researchers report the discovery of a new class of antibiotic extracted from unknown microorganisms living in the soil.

This class, which they call malacidins, kills several superbugs – including the dreaded methicillin-resistant Staphylococcus aureus (MRSA) – without engendering resistance.

You won't find this antibiotic at your pharmacy next week, the researcher cautioned. It takes years for a novel molecule to be developed, tested and approved for distribution.

But its discovery is proof of a powerful principle, he said: a world of potentially useful untapped biodiversity is still waiting to be discovered.

Though antibiotics are prized for their ability to combat the microbes that make humans sick, most of the drugs come from bacteria.

For example, streptomycin, which has been used to treat tuberculosis and plague, is produced by the bacterium Streptomyces griseus. (This microbe was originally found in the dirt of a New Jersey farm field, though the antibiotic research was conducted using cell cultures.)

Bacteria have been fighting one another for billions of years – far, far longer than humans have been around – so it's hardly surprising that they have evolved all the best weapons.

Yet the vast majority of these microbes don't grow well under controlled laboratory conditions, making them difficult to study.

"Maybe, using that simple culture-based approach, we've missed most of the chemistry that are produced by bacteria," the researcher said.

It would be better to derive interesting molecules directly from the environment. And with the advent of metagenomics, techniques that allow all the genetic material in a sample to be sequenced en masse, researchers can do just that.

For this study, the team cloned vast quantities of DNA from hundreds of soil samples contributed by citizen scientists across the country and then sorted through the material in search of interesting sequences.

"Most of what's there is completely unknown, and that's the future," the researcher said.

He and his colleagues were looking specifically for a known gene associated with the production of calcium-dependent antibiotics – molecules that attack bacterial cells, but only when calcium is around.

It's thought that the existence of such an "on-off" switch may make it harder for microbes to evolve resistance.

Because of this, the gene for calcium dependence might serve as a flag for a much longer sequence controlling the production of antibiotics – much the same way that coming across instructions for making crust might flag cookbook readers that they've found a recipe for pie.

Having identified a sequence containing the calcium-dependence gene, the researchers cloned it and injected it into a microbe that can be cultured. Soon enough, those microbes were making malacidins.

When applied to cuts in the skin of MRSA-infected rats, the previously unknown molecule successfully sterilised the wounds. The bacterium didn't show signs of resistance, even after three weeks of exposure.

According to the researcher, malacidins work by interfering with the process that bacteria use to build their cell walls. Human cells rely on a different process, so the antibiotic isn't toxic to people.

He and his colleagues don't know what species the molecules come from, but they don't need to – they already have the genetic blueprint for building it.

"The effort now is to scale it," he said.

Two years ago, the scientist launched a company, which aims to accelerate the discovery process and ultimately produce new medications that can be used to treat disease.

He is not the only scientist with this idea. Researchers elsewhere are using metagenomics to seek out new antibiotics in ocean water and insect guts.

Meanwhile, the same technique has been applied to urban sewage and polluted lakes to reveal the vast extent of antibiotic resistance.

Speaking to the media, the microbiologist noted that searching for the calcium-dependence gene allowed Brady's team to sort through massive amounts of DNA.

"They've used a clever approach to mine for antibiotics," he said.

But a scientist, who was not involved in the research, pointed out that the researchers will need to continue identifying new DNA signatures associated with antibiotics for their technique to keep working: "Now we need to say, 'You guys can do even better.' "

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