High-Fiber Diet Keeps Gut Microbes From Eating the Colon's Lining, Protecting Against Infection

It sounds like the plot of a 1950s science fiction movie: normal, helpful bacteria that begin to eat their host from within, because they don’t get what they want.

But new research shows that’s exactly what happens when microbes inside the digestive system don’t get the natural fiber that they rely on for food.

Starved, they begin to munch on the natural layer of mucus that lines the gut, eroding it to the point where dangerous invading bacteria can infect the colon wall.

In a new paper in Cell, an international team of researchers show the impact of fiber deprivation on the guts of specially raised mice. The mice were born and raised with no gut microbes of their own, then received a transplant of 14 bacteria that normally grow in the human gut. Scientists know the full genetic signature of each one, making it possible to track their activity over time.

The findings have implications for understanding not only the role of fiber in a normal diet, but also the potential of using fiber to counter the effects of digestive tract disorders.

“The lesson we’re learning from studying the interaction of fiber, gut microbes and the intestinal barrier system is that if you don’t feed them, they can eat you,” says Eric Martens, Ph.D., an associate professor of microbiology at the University of Michigan Medical School, who led the research along with his former postdoctoral fellow Mahesh Desai, Ph.D., now a principle investigator at the Luxembourg Institute of Health.

Using U-M’s special gnotobiotic, or germ-free, mouse facility, and advanced genetic techniques that allowed them to determine which bacteria were present and active under different conditions, they studied the impact of diets with different fiber content – and those with no fiber. They also infected some of the mice with a bacterial strain that does to mice what certain strains of Escherichia coli can do to humans – cause gut infections that lead to irritation, inflammation, diarrhea and more. 

The result: the mucus layer stayed thick, and the infection didn’t take full hold, in mice that received a diet that was about 15 percent fiber from minimally processed grains and plants. But when the researchers substituted a diet with no fiber in it, even for a few days, some of the microbes in their guts began to munch on the mucus.

They also tried a diet that was rich in prebiotic fiber – purified forms of soluble fiber similar to what some processed foods and supplements currently contain. This diet resulted in a similar erosion of the mucus layer as observed in the lack of fiber.

The researchers also saw that the mix of bacteria changed depending on what the mice were being fed, even day by day. Some species of bacteria in the transplanted microbiome were more common – meaning they had reproduced more – in low-fiber conditions, others in high-fiber conditions.

And the four bacteria strains that flourished most in low-fiber and no-fiber conditions were the only ones that make enzymes that are capable of breaking down the long molecules called glycoproteins that make up the mucus layer.

In addition to looking at the of bacteria based on genetic information, the researchers could see which fiber-digesting enzymes the bacteria were making. They detected more than 1,600 different enzymes capable of degrading carbohydrates – similar to the complexity in the normal human gut.

Just like the mix of bacteria, the mix of enzymes changed depending on what the mice were being fed, with even occasional fiber deprivation leading to more production of mucus-degrading enzymes.

Images of the mucus layer, and the “goblet” cells of the colon wall that produce the mucus constantly, showed the layer was thinner the less fiber the mice received. While mucus is constantly being produced and degraded in a normal gut, the change in bacteria activity under the lowest-fiber conditions meant that the pace of eating was faster than the pace of production – almost like an overzealous harvesting of trees outpacing the planting of new ones.

When the researchers infected the mice with Citrobacter rodentium – the E. coli-like bacteria – they observed that these dangerous bacteria flourished more in the guts of mice fed a fiber-free diet. Many of those mice began to show severea signs of illness and lost weight.

When the scientists looked at samples of their gut tissue, they saw not only a much thinner or even patchy mucus later – they also saw inflammation across a wide area. Mice that had received a fiber-rich diet before being infected also had some inflammation but across a much smaller area.

“To make it simple, the “holes” created by our microbiota while eroding the mucus serve as wide open doors for pathogenic micro-organisms to invade,” explains Desai, who is Group Leader at LIH’s Department of Infection and Immunity.

Martens notes that in addition to the gnotobiotic facility, the research was possible because of the microbe DNA and RNA sequencing capability built up through the Medical School’s Host Microbiome Initiative, as well as the computing capability to plow through all the sequence data.

“Having all the resources here was the key to making this work, and the fact that it was all across the street from our lab allowed us to pin it all together,” he says. He also notes the role of U-M colleagues led by Gabriel Nunez and Nobuhiko Kamada in providing the C. rodentium pathogen model, and of French collaborators from the Aix-Marseille Université in studying the enzymes in the mouse gut. 

Going forward, Martens and Desai intend to look at the impact of different prebiotic fiber mixes, and of diets with more intermitted natural fiber content over a longer period. They also want to look for biomarkers that could tell them about the status of the mucus layer in human guts – such as the abundance of mucus-digesting bacteria strains, and the effect of low fiber on chronic disease such as inflammatory bowel disease.

“While this work was in mice, the take-home message from this work for humans amplifies everything that doctors and nutritionists have been telling us for decades: Eat a lot of fiber from diverse natural sources,” says Martens. “Your diet directly influences your microbiota, and from there it may influence the status of your gut’s mucus layer and tendency toward disease. But it’s an open question of whether we can cure our cultural lack of fiber with something more purified and easy to ingest than a lot of broccoli.”

In addition to Martens, Desai, Nunez and Kamada and the French collaborators, the paper’s authors are U-M’s Anna Seekatz, Nicole Koropatkin, Nicholas Pudlo, Sho Kitamoto and Vincent Young, and colleagues from the Washington University School of Medicine and the Luxembourg Centre for Systems Biomedicine and the Luxembourg Institute of Health. The research was funded by the Luxembourg National Research Fund and Luxembourg Ministry of Higher Education and Research; the National Institutes of Health (GM099513) and the U-M Host Microbiome Initiative and Center for Gastrointestinal Research (DK034933).

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Laboratory

Helpful Forms of E. Coli May Protect Babies from Infections

Some of the first living things to greet a newborn baby do a lot more than coo or cuddle: They help the little one’s digestive system prepare for a lifetime of fighting off dangerous germs.

These things? Not parents, grandparents or siblings, but helpful bacteria.

New research suggests such bacteria may help the lining of the newborn gut prepare for the surge of other bacteria that will soon enter the body, and eventually make up the thriving and diverse population of microbes that lives within each of us.

In a new paper published in the journal eLife, a team from the University of Michigan Medical School reports its findings about the impact of a helpful strain of E. coli on the cells that line the gut.

The team concludes that nonpathogenic E. coli serves a crucial function of preparing the gut for the development of the microbiome to come, and the onslaught of pathogenic, or harmful, microbes.

The new results may help explain what past research has shown about the connection between the gut microbiome and the development of the newborn immune system. They may also lead to better understanding of what can protect or rescue premature newborns from the rare but devastating gut infection condition necrotizing enterocolitis, in which bacteria invade the gut wall and cause potentially fatal infection and inflammation.

Mini guts stand in for little guts

To do the research, the team studied a strain of E. coli related to ones commonly found in newborn babies’ stool. The researchers couldn’t do their research in actual newborns’ intestines, of course. Instead, they used stem cells to grow miniature versions of the gut lining, called human intestinal organoids.

Each HIO, as they’re called, is made up of thousands of cells that the scientists coax to grow, divide and organize into structures that resemble the actual gut. At each HIO’s center is a hollow area called a lumen, which mimics the hollow inner portion of the tube-like human intestine.

“We have previously shown that HIOs closely resemble the immature human intestine,” says lead author David Hill, Ph.D., a postdoctoral fellow in gastroenterology at Michigan Medicine, U-M’s academic medical center. “In this study, we wanted to discover the effects of colonization on the intestine with a nonharmful strain of E. coli, a type of bacteria that is commonly found in the guts of newborn babies.”

During growth, they kept these HIOs germ-free, just like the gut of a fetus in the womb. Then, they introduced the helpful E. coli into the hollow center of the organoids. They tracked what happened inside the cells whose surfaces face the center and in the spaces between the cells. They looked at how the cells were altering gene activity over time in response to the introduction of E. coli.

The results were clear. After the scientists introduced the E. coli, the cells facing the lumen began to mature, form tighter connections with one another and produce mucus to coat their surface.

Genes involved in cell-to-cell communication, and the physical structures cells use to link with their neighbors, activated. So did genes involved in making antimicrobial substances and mucus and transporting them to the cell surface, and in adaptation to low oxygen, which is caused by bacterial metabolism and is a hallmark of the mature adult intestine.

This activity led the HIOs to develop better resistance to inflammation-causing stimuli, which meant less damage to the cells lining the lumen.

“Our results show that colonization of the immature intestinal tract with E. coli results in intestinal tissue that is more robust to challenge by potentially damaging pathogens or inflammatory substances,” says senior author Jason Spence, Ph.D., an associate professor of internal medicine and of cell and developmental biology at U-M.

“We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease,” adds co-senior author Vincent Young, M.D., Ph.D.

Young is a professor of internal medicine who specializes in infectious diseases and is also a professor of microbiology and immunology at Michigan Medicine and a leader of U-M’s Host Microbiome Initiative.

What’s next

The research grew out of cooperation between the Spence lab, which focuses on HIOs, and the Young lab, which focuses on the gut microbiome. The work was made possible by funding from the National Institutes of Health, and by investments the Medical School has made in tools that help with organoid, microbiome and DNA sequencing research.

The team is now studying additional strains of nonharmful E. coli and other bacteria that take up long-term residence in the newborn gut, as well as pathogens.

“We hope to examine whether different bacteria produce different types of responses in the gut,” says Hill. “This type of work might help to explain why different types of gut bacteria seem to be associated with positive or negative health outcomes.”

The Spence team is preparing to launch a “core” service to provide HIOs for other researchers to study.

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Laboratory

New early signals to quantify the magnitude of strong earthquakes

After an earthquake, there is an instantaneous gravitational disturbance that could be recorded before the seismic waves that seismologists can detect. In a study published in Science on December 1, 2017, a team comprising researchers from CNRS, IPGP, the Université Paris Diderot and Caltech has managed to observe these weak signals related to gravity and to understand where they come from. Because they are sensitive to the magnitude of earthquakes, these signals may play an important role in the early identification of the occurrence of a major earthquake.

This work came out of the interaction between seismologists who wanted to better understand earthquakes and physicists who were developing fine gravity measurements with a view to detecting gravitational waves. Earthquakes brutally change the equilibrium of forces on Earth and emit seismic waves whose consequences can be devastating. But these same waves also disturb the Earth's field of gravity, which produces a different signal. This is particularly interesting with a view to fast quantification of tremors, because it moves at the speed of light, unlike tremor waves, which propagate at speeds between three and 10 km/s. So seismometers at a station located 1000 km from the epicenter may potentially detect this signal more than two minutes before the seismic waves arrive.

The work presented here follows on a 2016 (J.-P. Montagner et al., Nat. Commun. 7, 13349 (2016)) study that demonstrated this signal for the first time. First, the scientists observed these signals on the data from about 10 seismometers located between 500 and 3000 km from the epicenter of the 2011 Japanese earthquake (magnitude 9.1). From their observations, the researchers then demonstrated that these signals were due to two effects. The first is the gravity change that occurs at the location of the seismometer, which changes the equilibrium position of the instrument's mass. The second effect, which is indirect, is due to the gravity change everywhere on Earth, which disturbs the equilibrium of the forces and produces new seismic waves that will reach the seismometer.

Taking account of these two effects, the researchers have shown that this gravity-related signal is very sensitive to the earthquake's magnitude, which makes it a good candidate for rapidly quantifying the magnitude of strong earthquakes. The future challenge is to exploit this signal for magnitudes below about eight to 8.5, because below this threshold, the signal is too weak relative to the seismic noise emitted naturally by Earth, and dissociating it from this noise is complicated. So Researchers plan to test several technologies, including some inspired from instruments developed to detect gravitational waves.

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PHYS.ORG

Married people are much less likely to get dementia

An analysis of more than 800,000 people has concluded that people who remain single for life are 42 per cent more likely to get dementia than married couples.

The study also found that people who have been widowed are 20 per cent more likely to develop the condition, but that divorcees don’t have an elevated risk.

Previous research has suggested that married people may have healthier lifestyles, which may help explain the findings. Another hypothesis is that married people are more socially engaged, and that this may protect against developing the condition. The stress of bereavement might be behind the increased risk in those who have been widowed.

But marriage isn’t always good for the health. While men are more likely to survive a heart attack if they are married, single women recover better than those who are married.

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New Scientist