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GASTROINTESTINAL

Studies Show Calorie Restriction Decreased Systemic Oxidative Stress

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One of the first studies to explore the effects of calorie restriction on humans showed that cutting caloric intake by 15% for 2 years slowed aging and metabolism and protected against age-related disease. The study, which will appear March 22 in the journal Cell Metabolism, found that calorie restriction decreased systemic oxidative stress, which has been tied to age-related neurological conditions such as Alzheimer’s and Parkinson’s diseases, as well as cancer, diabetes, and others.

“Restricting calories can slow your basal metabolism, and if by-products of metabolism accelerate aging processes, calorie restriction sustained over several years may help to decrease risk for chronic disease and prolong life,” says lead author Leanne M. Redman, associate professor of Clinical Sciences at Pennington Biomedical Research in Baton Rouge, LA.

CALERIE (Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy) was the first randomized controlled trial to test the metabolic effects of calorie restriction in non-obese humans. The second phase of the study reports results from 53 healthy, non-obese men and women between ages 21 and 50 who cut calories by 15% over 2 years and underwent additional measurements for metabolism and oxidative stress. The calorie reductions were calculated individually through the ratio of isotopes absorbed by the participants’ molecules and tissues over 2 weeks, a technique that accurately pinpoints a weight-maintenance calorie level.

Those in the calorie restriction group lost an average of almost 9 kg, although they did not follow a particular diet and weight loss was not the study’s goal. No adverse effects, such as anemia, excessive bone loss, or menstrual disorders were noted; in fact, both trials led to improvements in mood and health-related quality of life. “We found that even people who are already healthy and lean may benefit from a calorie restriction regimen,” Redman says.

In lab animals, calorie restriction lowers core body temperature and resting metabolic rate. Redman emphasized that CALERIE looked at the effects of calorie restriction on aging, not weight loss, where discussions of “fast” or “slow” metabolism most often arise. “We know from mammalian studies that the smaller the mammal, the faster their metabolism and the shorter their longevity,” she says.

Many factors, such as antioxidant mechanisms and dietary and biological factors, influence metabolism, Redman says, but current theories hold that a slower metabolism is most beneficial for healthy aging and that organisms that burn energy most efficiently should experience the greatest longevity.

“The CALERIE trial rejuvenates support for two of the longest-standing theories of human aging: the slow metabolism ‘rate of living’ theory and the oxidative damage theory,” she says.

The latter ties overproduction of free radicals to oxidative damage to lipids, proteins, and DNA, leading to chronic diseases such as atherosclerosis, cancer, diabetes, and rheumatoid arthritis.

While the number of participants was relatively small and the duration short in the context of a human lifespan, biomarkers of aging were improved in study participants. Next steps include establishing robust biomarkers of human aging and examining the effects of calorie restriction in conjunction with antioxidant foods or substances like resveratrol, which mimic calorie restriction.

GASTROINTESTINAL

Viruses In Blood Lead To Digestive Problems

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While studying viruses best known for infecting the brain, researchers at Washington University School of Medicine in St. Louis stumbled upon clues to a conundrum involving a completely different part of the anatomy: the bowel, and why some people possibly develop digestive problems seemingly out of the blue.

The researchers found that viruses such as West Nile and Zika that target the nervous system in the brain and spinal cord also can kill neurons in the guts of mice, disrupting bowel movement and causing intestinal blockages. Other viruses that infect neurons also may cause the same symptoms, the researchers said.

The findings, published Oct. 4 in the journal Cell, potentially could explain why some people experience recurrent, unpredictable bouts of abdominal pain and constipation — and perhaps point to a new strategy for preventing such conditions.

“There are a number of people who are otherwise healthy who suddenly develop bowel motility problems, and we don’t understand why,” said Thaddeus S. Stappenbeck, MD, PhD, the Conan Professor of Laboratory and Genomic Medicine and the study’s co-senior author.

“But now we believe that one explanation could be that you can get a viral infection that results in your immune cells killing infected neurons in your gut. That might be why all of a sudden you can’t move things along any more.”

Postdoctoral researcher and first author James White, PhD, was studying mice infected with West Nile virus, a mosquito-borne virus that causes inflammation in the brain, when he noticed something peculiar. The intestines of some of the infected mice were packed with waste higher up and empty farther down, as if they had a blockage.

“We actually noticed this long ago, but we ignored it because it wasn’t the focus of our research at the time,” said West Nile expert Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the paper’s co-senior author.

“But Jim White dug in. He wanted to figure out why this was happening.”

White, Diamond, Stappenbeck and colleagues including Robert Hueckeroth, MD, PhD, of the University of Pennsylvania, found that not only West Nile virus but its cousins Zika, Powassan and Kunjin viruses — all of which target the nervous system like West Nile — caused the intestines to expand and slowed down transit through the gut. In contrast, chikungunya virus, an unrelated virus that does not target neurons, failed to cause bowel dysfunction.

Further investigation showed that West Nile virus, when injected into a mouse’s foot, travels through the bloodstream and infects neurons in the intestinal wall. These neurons coordinate muscle contractions to move waste smoothly through the gut. Once infected, the neurons attract the attention of immune cells, which attack the viruses — and kill the neurons in the process.

“Any virus that has a propensity to target neurons could cause this kind of damage,” said Diamond, who is also a professor of molecular microbiology and of pathology and immunology.

“West Nile and related viruses are not very common in the U.S. But there are many other viruses that are more widespread, such as enteroviruses and herpesviruses, that also may be able to target specific neurons in the wall of the intestine and injure them.”

If that’s the case, such widespread viruses may provide a new target in the prevention or treatment of painful digestive issues. Having chronic gut motility problems is a miserable experience, and while the condition can be managed, it can’t be cured or prevented.

“Many of the viruses that might target the gut nervous system cause mild, self-limiting infections, and there’s never been reason to develop a vaccine for them,” Diamond said.

“But if you knew that some particular viruses were causing this serious and common problem, you might be more apt to try to develop a vaccine.”

The infected mice’s digestive tracts gradually recovered over an eight-week time span. But when the researchers challenged the mice with an unrelated virus or an immune stimulant, the bowel problems promptly returned. This pattern echoed the one seen in people, who cycle through bouts of gastrointestinal distress and recovery. The flare-ups often are triggered by stress or illness, but they also can occur for no apparent reason.

“It’s amazing that the nervous system of the gut is able to recover and re-establish near normal motility, even after taking a pretty big hit and losing a lot of cells,” said Stappenbeck, who is also a professor of developmental biology.

“But then, it’s really just barely functioning normally, and when you add any stress, it malfunctions again.”

Previous studies have linked bowel motility to changes in the microbiome – the community of bacteria, viruses and fungi that live in the gut.

“What we need to explore now is how this story connects to everything else we know about gut motility,” Stappenbeck said.

“What effect does damage to the gut nervous system have on the microbiome? We would love to connect those dots.”

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GASTROINTESTINAL

Could The Microbiome Of Our Gut, Hold The Secret To Living Longer?

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You are what you eat. Or so the saying goes. Science now tells us that we are what the bacteria living in our intestinal tract eat and this could have an influence on how well we age. Building on this, McGill University scientists fed fruit flies with a combination of probiotics and an herbal supplement called Triphala that was able to prolong the flies’ longevity by 60 % and protect them against chronic diseases associated with aging.

The study, published in Scientific Reports, adds to a growing body of evidence of the influence that gut bacteria can have on health. The researchers incorporated a symbiotic — made of probiotics with a polyphenol-rich supplement — into the diet of fruit flies.

The flies fed with the synbiotic lived up to 66 days old — 26 days more than the ones without the supplement. They also showed reduced traits of aging, such as mounting insulin resistance, inflammation and oxidative stress.

“Probiotics dramatically change the architecture of the gut microbiota, not only in its composition but also in respect to how the foods that we eat are metabolized,” says Satya Prakash, professor of biomedical engineering in McGill’s Faculty of Medicine and senior author of the study.

“This allows a single probiotic formulation to simultaneously act on several biochemical signaling pathways to elicit broad beneficial physiological effects, and explains why the single formulation we present in this paper has such a dramatic effect on so many different markers.”

The fruit fly is remarkably similar to mammals with about 70 % similarity in terms of their biochemical pathways, making it a good indicator of what would happen in humans, adds Prakash.

“The effects in humans would likely not be as dramatic, but our results definitely suggest that a diet specifically incorporating Triphala along with these probiotics will promote a long and healthy life.”

The authors also say that the findings can be explained by the “gut-brain axis,” a bidirectional communication system between microorganisms residing in the gastrointestinal tract — the microbiota — and the brain. In the past few years, studies have shown the gut-brain axis to be involved in neuropathological changes and a variety of conditions such as irritable bowel syndrome, neurodegeneration and even depression. Few studies, however, have successfully designed gut microbiota-modulating therapeutics having effects as potent or broad as the formulation presented in the new study.

Learning from traditional medicine

The herbal supplement used in the study, Triphala, is a formulation made from amalaki, bibhitaki and haritaki, fruits used as medicinal plants in Ayurveda, a form of traditional Indian medicine.

Susan Westfall, a former PhD student at McGill and lead author of the study, says the idea of combining Triphala and probiotics comes from her long-standing interest in studying natural products derived from traditional Indian medicine and their impact on neurodegenerative diseases.

“At the onset of this study, we were hopeful that combining Triphala with probiotics would be at least a little better than their individual components in terms of physiological benefit, but we did not imagine how successful this formulation would be,” says Westfall, who is now a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai in New York, USA.

The new study, which includes data filed in a US provisional patent through a company cofounded by the authors, has the potential to impact the field of the microbiome, probiotics and human health.

Considering the broad physiological effects of this formulation shown in the fruit fly, Prakash hopes their formulation could have interesting applications in a number of human disorders such as diabetes, obesity, neurodegeneration, chronic inflammation, depression, irritable bowel syndrome and even cancer.

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GASTROINTESTINAL

Ingestible ‘Bacteria On A Chip’ Could Help Diagnose Disease

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MIT researchers have built an ingestible sensor equipped with genetically engineered bacteria that can diagnose bleeding in the stomach or other gastrointestinal problems.

This “bacteria-on-a-chip” approach combines sensors made from living cells with ultra-low-power electronics that convert the bacterial response into a wireless signal that can be read by a smartphone.

“By combining engineered biological sensors together with low-power wireless electronics, we can detect biological signals in the body and in near real-time, enabling new diagnostic capabilities for human health applications,” says Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering.

In the new study, appearing in the May 24 online edition of Science, the researchers created sensors that respond to heme, a component of blood, and showed that they work in pigs. They also designed sensors that can respond to a molecule that is a marker of inflammation.

Lu and Anantha Chandrakasan, dean of MIT’s School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science, are the senior authors of the study. The lead authors are graduate student Mark Mimee and former MIT postdoc Phillip Nadeau.

Wireless communication

In the past decade, synthetic biologists have made great strides in engineering bacteria to respond to stimuli such as environmental pollutants or markers of disease. These bacteria can be designed to produce outputs such as light when they detect the target stimulus, but specialized lab equipment is usually required to measure this response.

To make these bacteria more useful for real-world applications, the MIT team decided to combine them with an electronic chip that could translate the bacterial response into a wireless signal.

“Our idea was to package bacterial cells inside a device,” Nadeau says. “The cells would be trapped and go along for the ride as the device passes through the stomach.”

For their initial demonstration, the researchers focused on bleeding in the GI tract. They engineered a probiotic strain of E. coli to express a genetic circuit that causes the bacteria to emit light when they encounter heme.

They placed the bacteria into four wells on their custom-designed sensor, covered by a semipermeable membrane that allows small molecules from the surrounding environment to diffuse through. Underneath each well is a phototransistor that can measure the amount of light produced by the bacterial cells and relay the information to a microprocessor that sends a wireless signal to a nearby computer or smartphone. The researchers also built an Android app that can be used to analyze the data.

The sensor, which is a cylinder about 1.5 inches long, requires about 13 microwatts of power. The researchers equipped the sensor with a 2.7-volt battery, which they estimate could power the device for about 1.5 months of continuous use. They say it could also be powered by a voltaic cell sustained by acidic fluids in the stomach, using technology that Nadeau and Chandrakasan have previously developed.

“The focus of this work is on system design and integration to combine the power of bacterial sensing with ultra-low-power circuits to realize important health sensing applications,” Chandrakasan says.

Diagnosing disease

The researchers tested the ingestible sensor in pigs and showed that it could correctly determine whether any blood was present in the stomach. They anticipate that this type of sensor could be either deployed for one-time use or designed to remain the digestive tract for several days or weeks, sending continuous signals.

Currently, if patients are suspected to be bleeding from a gastric ulcer, they have to undergo an endoscopy to diagnose the problem, which often requires the patient to be sedated.

“The goal with this sensor is that you would be able to circumvent an unnecessary procedure by just ingesting the capsule, and within a relatively short period of time you would know whether or not there was a bleeding event,” Mimee says.

To help move the technology toward patient use, the researchers plan to reduce the size of the sensor and to study how long the bacteria cells can survive in the digestive tract. They also hope to develop sensors for gastrointestinal conditions other than bleeding.

In the Science paper, the researchers adapted previously described sensors for two other molecules, which they have not yet tested in animals. One of the sensors detects a sulfur-containing ion called thiosulfate, which is linked to inflammation and could be used to monitor patients with Crohn’s disease or other inflammatory conditions. The other detects a bacterial signaling molecule called AHL, which can serve as a marker for gastrointestinal infections because different types of bacteria produce slightly different versions of the molecule.

“Most of the work we did in the paper was related to blood, but conceivably you could engineer bacteria to sense anything and produce light in response to that,” Mimee says. “Anyone who is trying to engineer bacteria to sense a molecule related to disease could slot it into one of those wells, and it would be ready to go.”

The researchers say the sensors could also be designed to carry multiple strains of bacteria, allowing them to diagnose a variety of conditions.

“Right now, we have four detection sites, but if you could extend it to 16 or 256, then you could have multiple different types of cells and be able to read them all out in parallel, enabling more high-throughput screening,” Nadeau says.

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