Combating the deadly gastrointestinal infection C. diff

Researchers from the University of California, Irvine and Harvard University have discovered how the Clostridium difficile toxin B (TcdB) recognizes the human Frizzled protein, the receptor it uses to invade intestinal cells and lead to deadly gastrointestinal infections. The findings, published today in Science, could pave the way for new C. diff antitoxins and also show potential for the development of novel anti-cancer drugs.

In a C. diff infection (CDI), TcdB targets colonic epithelia and binds to what are called Frizzled (FZD) receptors. Researchers in the labs of Rongsheng Jin, PhD, professor of physiology & biophysics from the UCI School of Medicine, and Min Dong, PhD, from Boston Children's Hospital -- Harvard Medical School, found that during this binding process, the toxin locks certain lipid molecules in FZD, which block critical Wnt signaling that regulates renewal of colonic stem cells and differentiation of the colonic epithelium.

"This toxin is indeed very smart. It takes advantage of an important lipid that FZD uses for its own function, to improve its binding affinity and specificity to FZD," said Jin, "However, the need for this lipid also exposes a vulnerability of TcdB that could be exploited to develop antitoxins that block toxin-receptor recognition."

Jin and Dong believe that the novel FZD-antagonizing mechanism exploited by toxin B could be used to turn this deadly toxin into a potential pharmacological tool for research and therapeutic applications, including anti-cancer drugs.

The team's preliminary data show that a non-toxic fragment of TcdB that they identified could significantly inhibit the growth of some cancer cells with dysregulation in Wnt signaling. A patent application has been filed.

Clostridium difficile, also called "C. diff," causes severe gastrointestinal tract infections and tops the Center for Disease Control and Prevention's list of urgent drug-resistant threats. Clostridium difficile infection has become the most common cause of antibiotic-associated diarrhea and gastroenteritis-associated death in developed countries, accounting for half-million cases and 29,000 deaths annually in the United States. It is classified as one of the top three "urgent threats" by the CDC.

The research was funded with National Institute of Health grants R01AI091823, R01AI125704, and R21AI123920 to Jin, and R01 NS080833 and R01 AI132387 to Dong.

---

Story Source:

Materials provided by University of California - Irvine. Note: Content may be edited for style and length.

---

Journal Reference:

1. Peng Chen, Liang Tao, Tianyu Wang, Jie Zhang, Aina He, Kwok-ho Lam, Zheng Liu, Xi He, Kay Perry, Min Dong, Rongsheng Jin. Structural basis for recognition of frizzled proteins byClostridium difficiletoxin B. Science, 2018; 360 (6389): 664 DOI: 10.1126/science.aar1999

Divide and conquer: Creating better medicines with fewer side effects

Today, a new study published in Science by Professors Yossi Paltiel of the Hebrew University of Jerusalem and Ron Naaman from the Weizmann Institute of Science describes a breakthrough technology with the power to create drugs with fewer unwanted side effects.

Chemical compounds are made up of molecules. The most important molecules in biology are chiral molecules. "Chiral," the Greek word for "hand," describes molecules that look almost exactly alike and contain the same number of atoms but are mirror images of one another -- meaning some are "left-handed" and others are "right-handed." This different "handedness" is crucial and yields different biological effects.

Understanding chiral differences was made painfully clear by the drug thalidomide. Marketed to pregnant women in the 1950's and 1960's to ease morning sickness, thalidomide worked well under a microscope. However, thalidomide is a chiral drug -its "right" chiral molecule provides nausea relief while the "left" molecule causes horrible deformities in babies. Since the drug company producing Thalidomide did not separate out the right and left molecules, Thalidomide had disastrous results for the children of women who took this medication.

Though a crucial step for drug safety, the separation of chiral molecules into their right- and left- handed components is an expensive process and demands a tailor-made approach for each type of molecule. Now, however, following a decade of collaborative research, Paltiel and Naaman have discovered a uniform, generic method that will enable pharmaceutical and chemical manufactures to easily and cheaply separate right from left chiral molecules.

Their method relies on magnets. Chiral molecules interact with a magnetic substrate and line up according to the direction of their handedness -- "left" molecules interact better with one pole of the magnet, and "right" molecules with the other one. This technology will allow chemical manufacturers to keep the "good" molecules and to discard the "bad" ones that cause harmful or unwanted side effects.

"Our finding has great practical importance," shared Prof. Naaman. "It will usher in an era of better, safer drugs, and more environmentally-friendly pesticides."

While popular drugs, such as Ritalin and Cipramil, are sold in their chirally-pure (i.e., separated) forms, many generic medications are not. Currently only 13% of chiral drugs are separated even though the FDA recommends that all chiral drugs be separated. Further, in the field of agrochemicals, chirally-pure pesticides and fertilizers require smaller doses and cause less environmental contamination than their unseparated counterparts.

With these statistics in mind, Paltiel and Naaman's simple and cost effective chiral separation technique has the ability to produce better medical and agricultural products, including medicines, food ingredients, dietary supplements and pesticides.

"We are now transforming our science into practice, with the help of Weizmann's and the Hebrew University's technology transfer companies. Placing better medical and environmental products on the market is a win-win for industry and for patients," concluded Paltiel.

---

Story Source:

Materials provided by The Hebrew University of Jerusalem. Note: Content may be edited for style and length.

---

Journal Reference:

1. Koyel Banerjee-Ghosh, Oren Ben Dor, Francesco Tassinari, Eyal Capua, Shira Yochelis, Amir Capua, See-Hun Yang, Stuart S. P. Parkin, Soumyajit Sarkar, Leeor Kronik, Lech Tomasz Baczewski, Ron Naaman, Yossi Paltiel. Separation of enantiomers by their enantiospecific interaction with achiral magnetic substrates. Science, 2018; eaar4265 DOI: 10.1126/science.aar4265

Alcohol and tobacco are by far the biggest threat to human welfare of all addictive drugs

A new review published online today in the journal Addiction has compiled the best, most up-to-date source of information on alcohol, tobacco, and illicit drug use and the burden of death and disease. It shows that in 2015 alcohol and tobacco use between them cost the human population more than a quarter of a billion disability-adjusted life years, with illicit drugs costing a further tens of millions.

The largest health burden from substance use was attributable to tobacco smoking and the smallest was attributable to illicit drugs. Global estimates suggest that nearly one in seven adults (15.2%) smoke tobacco and one in five adults report at least one occasion of heavy alcohol use in the past month.

Compared with the rest of the world, Central, Eastern, and Western Europe recorded consistently higher alcohol consumption per capita (11.61, 11.98 and 11.09 litres, respectively) and a higher percentage of heavy consumption amongst drinkers (50.5%, 48.2%, and 40.2%, respectively). The same European regions also recorded the highest prevalence of tobacco smoking (Eastern Europe 24.2%, Central Europe 23.7%, and Western Europe 20.9%).

In contrast, use of illicit drugs was far less common. Fewer than one in twenty people were estimated to use cannabis in the past year, and much lower estimates were observed for amphetamines, opioids and cocaine. Hotspots included the US, Canada, and Australasia. The US and Canada had one of the highest rates of cannabis, opioid, and cocaine dependence (748.7 [694.8, 812.3], 650.0 [574.5, 727.3], and 301.2 [269.3, 333.7] per 100,000 people, respectively). Australasia (Australia and New Zealand) had the highest prevalence of amphetamine dependence (491.5 per 100,000 people [441.4, 545.5]), as well as high rates of cannabis, opioid and cocaine use dependence (693.7 [648.1, 744.4], 509.9 [453.7, 577.8], and 160.5 [136.4, 187.1] per 100,000 people, respectively).

Some countries and regions (e.g., Africa, Caribbean and Latin America, Asia regions) have little or no data on substance use and associated health burden. These are typically low or middle income countries that frequently have punitive drug policies, and may experience serious political and social unrest. These countries need enhanced monitoring because they are at risk of rapid escalation in substance use and related health burden.

The report, 'Global Statistics on Alcohol, Tobacco, and Illicit Drug Use: 2017 Status Report', uses data mainly obtained from the World Health Organization, United Nations Office on Drugs and Crime, and Institute for Health Metrics and Evaluation. The authors note that there are important limitations to the data, especially for illicit drugs, but believe that putting all this information in one place will make it easier for governments and international agencies to develop policies to combat substance use.

---

Story Source:

Materials provided by Society for the Study of Addiction. Note: Content may be edited for style and length.

---

Journal Reference:

1. Amy Peacock, Janni Leung, Sarah Larney, Samantha Colledge, Matthew Hickman, Jürgen Rehm, Gary A. Giovino, Robert West, Wayne Hall, Paul Griffiths, Robert Ali, Linda Gowing, John Marsden, Alize J. Ferrari, Jason Grebely, Michael Farrell, Louisa Degenhardt. Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction, 2018; DOI: 10.1111/add.14234

Dietary seaweed used to manipulate gut bacteria

Gut bacteria thrive on the food we eat. In turn, they provide essential nutrients that keep us healthy, repel pathogens and even help guide our immune responses.

Understanding how and why some bacterial strains we ingest can successfully take up residence in the large intestine, while others are quickly evicted, could help scientists learn how to manipulate the makeup of thousands of bacterial species there in ways that enhance our health or help fend off disease. But the sheer complexity of gut ecology has hampered this task.

Now, researchers at the Stanford University School of Medicine working with laboratory mice have shown that it's possible to favor the engraftment of one bacterial strain over others by manipulating the mice's diet. The researchers also have shown it's possible to control how much a bacterium grows in the intestine by calibrating the amount of a specific carbohydrate in each mouse's water or food.

"We're all endowed with a microbial community in our guts that assembled in a chaotic manner during our first few years of life," said Justin Sonnenburg, PhD, associate professor of microbiology and immunology. "Although we continue to acquire new strains throughout life, this acquisition is a poorly orchestrated and not-well-understood process. This study suggests it could be possible to reshape our microbiome in a deliberate manner to enhance health and fight disease."

A paper describing the research will be published online May 9 in Nature. Sonnenburg is the senior author. Former graduate student Elizabeth Shepherd, PhD, is the lead author.

Giving bacterium a leg up

The burgeoning field of probiotics -- live, presumably healthful bacterial cultures naturally found in food such as yogurt or included in over-the-counter oral supplements -- is an example of a growing public awareness of the importance of gut bacteria. Even if you don't take probiotics or eat yogurt, however, each of us unknowingly consumes low levels of gut-adapted microbes throughout our life. But, regardless of the source, it's not known what causes one strain to be successful over another. Many pass quickly through our digestive tract without gaining a foothold in our teeming intestinal carpet.

Sonnenburg and his colleagues wondered whether a dietary boost would give specific bacterial strains a leg up in the wild west of the gut microbiome. To investigate, they trekked to the San Jose Wastewater Treatment Facility to find members of the Bacteroides -- the most prominent genus in the human gut microbiota -- specifically looking for strains that are able to digest an ingredient relatively rare in American diets: the seaweed called nori used in sushi rolls and other Japanese foods. They screened the bacteria collected in the primary effluent for an ability to use a carbohydrate found in nori called porphyran.

"The genes that allow a bacterium to digest porphyran are exceedingly rare among humans that don't have seaweed as a common part of their diet," Sonnenburg said. "This allowed us to test whether we could circumvent the rules of complex ecosystems by creating a privileged niche that could favor a single microbe by allowing it to exist in the absence of competition from the 30 trillion other microbes in the gut."

Once they'd found a nori-gobbling strain of Bacteroides, the researchers attempted to introduce it into each of three groups of laboratory mice. Two groups of the mice had their own gut bacteria eliminated and replaced with the naturally occurring gut bacteria from two healthy human donors, each of whom donated exclusively to one group or the other. The third group of mice harbored a conventional mouse-specific community of gut microbiota.

A direct effect

The researchers found that when the mice were fed a typical diet of mouse chow, the porphyran-digesting strain was able to engraft in two groups of mice to varying and limited degrees; one of the groups of mice with human gut bacteria rejected the new strain completely. However, when the mice were fed a porphyran-rich diet, the results were dramatically different: The bacteria engrafted robustly at similar levels in all the mice. Furthermore, Shepherd found that she could precisely calibrate the population size of the engrafted bacteria by increasing or decreasing the amount of nori the animals ingested.

"The results of this dilution experiment blew us away," Sonnenburg said. "The direct effect of diet on the bacterial population was very clear."

In addition to showing that they could favor the engraftment and growth of the nori-gobbling bacterial strain, the researchers went one step further by showing that the genes necessary to enable the digestion of porphyran exist as a unit that can be engineered into other Bacteroides strains, giving them the same engraftment advantage. Now they're working to identify other genes that confer similar dietary abilities.

"We can use these gene modules to develop a vast toolkit to make therapeutic microbial treatments a reality," Sonnenburg said. "Porphyran-digesting genes and a diet rich in seaweed is the first pair, but there could potentially be hundreds more. We'd like to expand this simple paradigm into an array of dietary components and microbes."

The researchers also envision developing bacteria that harbor kill switches and logic gates that will permit clinicians to toggle bacterial activity on and off at will, or when a specific set of circumstances occur.

"It's become very clear over the last 10 years that gut microbes are not only wired to many aspects of our biology, but that they are also very malleable," Sonnenburg said. "Our growing ability to manipulate them is going to change how precision health is practiced. A physician whose patient is about to begin immunotherapy for cancer may choose to also administer a bacterial strain known to activate the immune system, for example. Conversely, a patient with an autoimmune disease may benefit from a different set of microbiota that can dial down an overactive immune response. They are just a very powerful lever to modulate our biology in health and disease."

---

Story Source:

Materials provided by Stanford Medicine. Original written by Krista Conger. Note: Content may be edited for style and length.

---

Journal Reference:

1. Elizabeth Stanley Shepherd, William C. DeLoache, Kali M. Pruss, Weston R. Whitaker, Justin L. Sonnenburg. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature, 2018; DOI: 10.1038/s41586-018-0092-4

Newly-discovered anti-inflammatory substances may potentially treat variety of diseases

Inflammation, and in particular chronic inflammation, are major contributors to a large number of diseases, such as cancer, acute pancreatic inflammation, fatty liver disease, diabetes, ulcerative colitis, Crohn's disease, rheumatoid arthritis, chronic liver disease, atherosclerosis, multiple sclerosis, and many others. These pathological conditions are associated with the release of substances, known as pro-inflammatory cytokines, by the immune system. These substances participate in the neutralization of invading pathogens, repair injured tissues, and promote wound healing. However, during chronic or excessive activation of the immune system, when these cytokines are released in an uncontrolled manner, they can lead to unnecessary inflammation that frequently causes tissue damage.

In addition, a family of substances, designated as reactive oxygen species (ROS) is also among the major contributors to many chronic diseases. ROS are involved in oxidation processes. Although oxidative reactions catalyzed by ROS are of great importance in metabolic processes and removal of toxic substances from the body, they are also involved in major damage to cells and tissues leading to cell death, possible DNA mutations and aging. Though the presence of oxygen is necessary for maintaining life, oxygen and its derived products (ROS) are involved in a variety of toxic effects. It has been said that "without oxygen we die but oxygen kills us."

Prof. Abraham Nudelman and his graduate student Shani Zeeli, from the Department of Chemistry at Bar-Ilan University, in collaboration with Prof. Marta Weinstock and her students and assistants from the School of Pharmacy at the Hebrew University, have discovered a new family of substances which has been found to display highly potent activity against the release of pro-inflammatory cytokines and the toxicity induced by ROS. Their findings were recently published in the Journal of Medicinal Chemistry, and in other early papers.

The novel compounds synthesized and evaluated belong to a family of low molecular weight substances named indolines. In early experiments, these compounds have shown promising activity in the treatment of acute pancreatic inflammation, acute fatty liver damage, and diabetes.

"It is expected that further studies in humans will reveal the potential usefulness of these substances in the treatment of a variety of diseases where inflammation is a major contributor to the disease," says Prof. Nudelman, a lead author of the paper. Further studies on the influence of these compounds on these diseases, and other pathological conditions, are being conducted.

This research program has been supported by the Israel Ministry of Science and Technology, and by the Marcus Center for Medicinal Chemistry at Bar-Ilan University.

---

Story Source:

Materials provided by Bar-Ilan University. Note: Content may be edited for style and length.

---

Journal Reference:

1. Shani Zeeli, Tehilla Weill, Efrat Finkin-Groner, Corina Bejar, Michal Melamed, Svetlana Furman, Michael Zhenin, Abraham Nudelman, Marta Weinstock. Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents. Journal of Medicinal Chemistry, 2018; DOI: 10.1021/acs.jmedchem.8b00001

AUTISM :EEG signals accurately predict autism as early as 3 months of age

Autism is challenging to diagnose, especially early in life. A new study in the journal Scientific Reports shows that inexpensive EEGs, which measure brain electrical activity, accurately predict or rule out autism spectrum disorder (ASD) in infants, even in some as young as 3 months.

"EEGs are low-cost, non-invasive and relatively easy to incorporate into well-baby checkups," says Charles Nelson, PhD, director of the Laboratories of Cognitive Neuroscience at Boston Children's Hospital and co-author of the study. "Their reliability in predicting whether a child will develop autism raises the possibility of intervening very early, well before clear behavioral symptoms emerge. This could lead to better outcomes and perhaps even prevent some of the behaviors associated with ASD."

The study analyzed data from the Infant Sibling Project (now called the Infant Screening Project), a collaboration between Boston Children's Hospital and Boston University that seeks to map early development and identify infants at risk for developing ASD and/or language and communication difficulties.

William Bosl, PhD, associate professor of Health Informatics and Clinical Psychology at the University of San Francisco, also affiliated with the Computational Health Informatics Program (CHIP) at Boston Children's Hospital, has been working for close to a decade on algorithms to interpret EEG signals, the familiar squiggly lines generated by electrical activity in the brain. Bosl's research suggests that even an EEG that appears normal contains "deep" data that reflect brain function, connectivity patterns and structure that can be found only with computer algorithms.

The Infant Screening Project provided Bosl with EEG data from 99 infants considered at high risk for ASD (having an older sibling with the diagnosis) and 89 low-risk controls (without an affected sibling). The EEGs were taken at 3, 6, 9, 12, 18, 24 and 36 months of age by fitting a net over the babies' scalps with 128 sensors as the babies sat in their mothers' laps. (An experimenter blew bubbles to distract them.) All babies also underwent extensive behavioral evaluations with the Autism Diagnostic Observation Schedule (ADOS), an established clinical diagnostic tool.

Bosl's computational algorithms analyzed six different components (frequencies) of the EEG (high gamma, gamma, beta, alpha, theta, delta), using a variety of measures of signal complexity. These measures can reflect differences in how the brain is wired and how it processes and integrates information, says Bosl.

The algorithms predicted a clinical diagnosis of ASD with high specificity, sensitivity and positive predictive value, exceeding 95 percent at some ages.

"The results were stunning," Bosl says. "Our predictive accuracy by 9 months of age was nearly 100 percent. We were also able to predict ASD severity, as indicated by the ADOS Calibrated Severity Score, with quite high reliability, also by 9 months of age."

Bosl believes that the early differences in signal complexity, drawing upon multiple aspects of brain activity, fit with the view that autism is a disorder that begins during the brain's early development but can take different trajectories. In other words, an early predisposition to autism may be influenced by other factors along the way.

"We believe that infants who have an older sibling with autism may carry a genetic liability for developing autism," says Nelson. "This increased risk, perhaps interacting with another genetic or environmental factor, leads some infants to develop autism -- although clearly not all, since we know that four of five "infant sibs" do not develop autism."

---

Story Source:

Materials provided by Boston Children's Hospital. Note: Content may be edited for style and length.

---

Journal Reference:

1. William J. Bosl, Helen Tager-Flusberg, Charles A. Nelson. EEG Analytics for Early Detection of Autism Spectrum Disorder: A data-driven approach. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-24318-x

Hormone from fat boosts metabolism in both exercise and cold

Sad but true, we don't all respond equally to exercise. Researchers at Joslin Diabetes Center have uncovered a new kind of clue to this variable response -- a hormone whose levels in the bloodstream rise sharply in exercise as well as in cold.

The finding came from the first comprehensive study of fat-controlling hormones (known as lipokines) in exercise. "This is a whole new area in research on exercise metabolism, and we seem to have found another mechanism by which exercise can have beneficial effects," says Laurie Goodyear, Ph.D., Head of Joslin's Section on Integrative Physiology and Metabolism and senior author on a report on the work published in Cell Metabolism.

Experiments in both humans and mice have shown that levels of one lipokine, with the unwieldy name of 12,13-diHOME, climb significantly in exercise, unlike the levels of other lipokines analyzed.

The study followed up on research published last year in joint work with the lab of Joslin's Yu-Hua Tseng, Ph.D. This collaboration explored the release of lipokines from brown fat, which can burn energy in people or other mammals exposed to cold. In both humans and mice, the researchers demonstrated that the 12,13-diHome molecule was released from brown fat during cold exposure and offered beneficial metabolic effects.

"We found it very striking that when we then analyzed lipokines in exercise, the same lipokine that increased with cold also increased with exercise," says Goodyear, an Associate Professor in Medicine at Harvard Medical School.

The Joslin researchers began by measuring levels of lipokines before exercise, immediately after exercise and three hours after exercise in the blood of 27 healthy male volunteers of various ages. When measured immediately after exercise, "12,13-diHOME really stood out quite dramatically," says Goodyear. The scientists followed up by studying another set of volunteers, 12 healthy young people (split evenly between women and men) without regular exercise routines. Again, levels of the lipokine generally climbed substantially during exercise. Additionally, the scientists found that, in general, the more fit people were, the greater their resting levels of 12,13-diHOME.

The team next studied lipokines in exercising mice and saw similar results. "When mice do a single bout of exercise, we see an increase in 12,13-diHOME," Goodyear says. "We also saw an increase after exercise training."

Next, the investigators looked at molecular clues to the source of the lipokine and discovered that brown fat was a likely suspect. This was confirmed when the scientists removed most brown fat from mice and found that 12,13-diHOME levels in exercise dropped sharply. "It seems to be the first example of a hormone released from brown fat that might regulate some of the metabolic effects of exercise," Goodyear notes.

Researchers around the world look for ways to increase energy expenditure, and thus reduce obesity, by boosting brown fact activity. "Most of our data suggests that exercise doesn't ramp up the energy expenditure of brown fat, but here, exercise is clearly having an effect on brown fat," she says.

Further work in both mice and mice muscle cells that were given 12,13-diHOME revealed that the lipokine acts as a signal to boost the use of fatty acids as fuels, Goodyear adds.

She and her colleagues are broadening and deepening their research on the role of the lipokine, and other lipokines that decrease during exercise, in larger human cohorts as well as in further animal studies. "The more knowledge we have about exercise and how it works, the better we can understand how to combat metabolic disease," she says.

---

Story Source:

Materials provided by Joslin Diabetes Center. Note: Content may be edited for style and length.

---

Journal Reference:

1. Kristin I. Stanford, Matthew D. Lynes, Hirokazu Takahashi, Lisa A. Baer, Peter J. Arts, Francis J. May, Adam C. Lehnig, Roeland J.W. Middelbeek, Jeffrey J. Richard, Kawai So, Emily Y. Chen, Fei Gao, Niven R. Narain, Giovanna Distefano, Vikram K. Shettigar, Michael F. Hirshman, Mark T. Ziolo, Michael A. Kiebish, Yu-Hua Tseng, Paul M. Coen, Laurie J. Goodyear. 12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake. Cell Metabolism, 2018; 27 (5): 1111 DOI: 10.1016/j.cmet.2018.03.020

Fasting boosts stem cells' regenerative capacity

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.

This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study from MIT biologists. The researchers found that fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.

In fasting mice, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative. The researchers found that they could also boost regeneration with a molecule that activates the same metabolic switch. Such an intervention could potentially help older people recovering from GI infections or cancer patients undergoing chemotherapy, the researchers say.

"Fasting has many effects in the intestine, which include boosting regeneration as well as potential uses in any type of ailment that impinges on the intestine, such as infections or cancers," says Omer Yilmaz, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. "Understanding how fasting improves overall health, including the role of adult stem cells in intestinal regeneration, in repair, and in aging, is a fundamental interest of my laboratory."

David Sabatini, an MIT professor of biology and member of the Whitehead Institute for Biomedical Research, is also a senior author of the paper, which appears in the May 3 issue of Cell Stem Cell.

"This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat," Sabatini says. "Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies."

The paper's lead authors are Whitehead Institute postdoc Maria Mihaylova and Koch Institute postdoc Chia-Wei Cheng.

Boosting regeneration

For many decades, scientists have known that low caloric intake is linked with enhanced longevity in humans and other organisms. Yilmaz and his colleagues were interested in exploring how fasting exerts its effects at the molecular level, specifically in the intestine.

Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover.

"Intestinal stem cells are the workhorses of the intestine that give rise to more stem cells and to all of the various differentiated cell types of the intestine. Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage," Yilmaz says. "In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells."

After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to "mini-intestines" known as organoids.

The researchers found that stem cells from the fasting mice doubled their regenerative capacity.

"It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven," Mihaylova says. "This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this."

Metabolic switch

Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids.

The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.

They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs. "That was also very surprising," Cheng says. "Just activating one metabolic pathway is sufficient to reverse certain age phenotypes."

The findings suggest that drug treatment could stimulate regeneration without requiring patients to fast, which is difficult for most people. One group that could benefit from such treatment is cancer patients who are receiving chemotherapy, which often harms intestinal cells. It could also benefit older people who experience intestinal infections or other gastrointestinal disorders that can damage the lining of the intestine.

The researchers plan to explore the potential effectiveness of such treatments, and they also hope to study whether fasting affects regenerative abilities in stem cells in other types of tissue.

---

Story Source:

Materials provided by Massachusetts Institute of Technology. Note: Content may be edited for style and length.

---

Journal Reference:

1. Maria M. Mihaylova, Chia-Wei Cheng, Amanda Q. Cao, Surya Tripathi, Miyeko D. Mana, Khristian E. Bauer-Rowe, Monther Abu-Remaileh, Laura Clavain, Aysegul Erdemir, Caroline A. Lewis, Elizaveta Freinkman, Audrey S. Dickey, Albert R. La Spada, Yanmei Huang, George W. Bell, Vikram Deshpande, Peter Carmeliet, Pekka Katajisto, David M. Sabatini, Ömer H. Yilmaz. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell, 2018; 22 (5): 769 DOI: 10.1016/j.stem.2018.04.001

How low is too low? Experts debate blood pressure targets in post-SPRINT era

Following the landmark SPRINT trial, there is a growing body of evidence for reducing systolic blood pressure targets, resulting in the development of new US guidelines. However, this has led to many questions about the impact of such fundamental changes in blood pressure management, and whether they should be implemented in other constituencies. Two new studies published in the Canadian Journal of Cardiology assess the benefits and costs of incorporating these more aggressive goals into clinical practice.

The Systolic Blood Pressure Intervention Trial (SPRINT) published in 2015 was a randomized, controlled, open-label trial conducted at 102 clinical sites in the US. It compared an intensive systolic blood pressure target of 120 mmHg to the current standard target of 140 mmHg in individuals at high cardiovascular risk and without diabetes. It was halted early after interim analyses showed patients in the intensive arm showed a significant decrease in fatal and nonfatal cardiovascular events and death from any cause.

Based on these statistically-significant findings, as well as the growing global body of evidence showing a strong association between lower systolic blood pressure targets and a reduction in cardiovascular events, an intensive systolic treatment target of <120 2016.="" adopted="" canada="" clinical="" for="" guidelines="" high-risk="" hypertension="" in="" into="" mmhg="" p="" patients="" practice="" selected="" the="" was="">

In Fall 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) issued new guidelines for high blood pressure that redefined hypertension as a blood pressure equal or above 130/80 mmHg, as well as lowered the blood pressure treatment goal for the general American population. However, there has been fierce discussion on both sides of the 49th parallel where to go from here.

In the first of the new studies, Alexander Leung, MD, MPH, from the University of Calgary, Calgary, Alberta, Canada, explained that, "The generalizability of the SPRINT intensive blood pressure treatment strategy to the Canadian population remains unknown. Uptake of these recommendations into clinical practice is expected to have broad implications on healthcare policy, resource utilization, and clinical outcomes and may pose certain challenges such as more frequent clinic visits, increased drug costs, increased rates of adverse events, and other heightened healthcare expenditures."

Dr. Leung and colleagues report on a cross-sectional study, using population-based, nationally representative data, to estimate the prevalence and characteristics of blood pressure in Canadian adults between the ages of 20 and 79 meeting SPRINT eligibility criteria. They found that 1.3 million (5.2 percent) Canadian adults met the criteria. If fully implemented, lowering the systolic blood pressure target to <120 100="" 180="" 50="" 750="" above="" addition="" adults="" age="" annually="" antihypertensive="" around="" be="" blood="" but="" canadian="" considered="" currently="" deaths="" five="" for="" further.="" have="" high-risk="" high="" hypertension="" in="" included.="" increase="" individuals="" initiation="" intensification="" medication="" mmhg="" more="" need="" not="" of="" older="" one="" or="" over="" p="" people="" pressure.="" pressure="" prevent="" previously="" proportion="" receiving="" reduce="" require="" sprint-eligible="" substantially="" the="" their="" therapy="" to="" treated="" treatment="" were="" who="" would="">

"Adopting intensive systolic blood pressure targets would result in a large number of individuals with treated hypertension being relabeled as inadequately controlled, as well as a significant proportion of the general population not previously considered to have elevated blood pressure being reclassified as requiring blood pressure lowering therapy," noted Dr. Leung. "Such a change would have far-reaching implications on healthcare resource utilization, public policy, and healthcare delivery."

In the second study, Remi Goupil, MD, MSc, from the Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada, and colleagues examined the differences between the 2017 Hypertension Canada and 2017 American College of Cardiology and American Heart Association (ACC/AHA) blood pressure guidelines.

"The 2017 ACC/AHA guidelines present a paradigm shift in the definition of high blood pressure, while updating treatment initiation thresholds and blood pressure targets," said Dr. Goupil. "This has led to many questions about the impact of such fundamental changes in blood pressure management, and whether it should be implemented in Canada."

The investigators assessed the number of individuals with a diagnosis of hypertension, blood pressure above thresholds for treatment initiation, and blood pressure below targets using the CARTaGENE population-based cohort. CARTaGENE is a population-based cohort designed to study demographic, clinical, and genetic determinants of chronic diseases. Individuals from the province of Quebec were randomly selected, based on provincial health registries, to be broadly representative of the general population. In total, 20,004 individuals 40-69 years old were selected in four distinct urban areas.

Analysis showed that adopting recommendations from the 2017 ACC/AHA guidelines in Canada would result in a substantial increase in diagnoses of hypertension and of individuals requiring drug treatment in Canadians aged between 40 and 69. It would also result in a change in blood pressure targets in a high proportion of hypertensive patients already receiving treatment. This would represent approximately 1.25 million more individuals with hypertension, and 500,000 more individuals requiring antihypertensive treatment.

"Switching to these new guidelines would result in a higher prevalence of hypertensive individuals in Canada and an increase in the number of people that would need to be treated," remarked Dr. Goupil. "Almost one in five individuals needing treatment would have a different blood pressure target from one guideline to the other. These changes would greatly impact the lives of millions of Canadians and result in a significant increase in the economic burden of this condition, with uncertain effects on cardiovascular complications."

In an accompanying editorial, Ross Feldman, MD, Medical Director of the WRHA Cardiac Sciences Program, Winnipeg, Manitoba, Canada, points out that undertaking these more aggressive goals should be based on frank discussions with patients outlining both benefits and risk, and that management should be based on automatic office blood pressure (AOBP) readings, as used in the SPRINT trial, which may well correspond with higher ambulatory blood pressure (ABP) readings. Dr. Feldman is past President of the Canadian Hypertension Society and Hypertension Canada and has been involved in the Canadian hypertension guidelines since 1991.

"Regardless of the guidelines we use, in the post-SPRINT era there are more patients than ever who can expect clear benefit from applying lower targets for their blood pressure control -- but with increased risk of adverse effects. These studies remind us that on a public health basis, getting the guidelines right does matter. For every adjustment in blood pressure targets, there are benefits and there are costs -- both for patients and in our publicly-funded healthcare system, for all Canadians," remarked Dr. Feldman.

However, Dr. Feldman also points out that more important than any of the fine details of a guidelines process is the effectiveness in their dissemination and implementation. "It is better to have suboptimal guidelines that are followed than it is to have 'perfectly' crafted and up-to-date guidelines that are ignored."

---

Story Source:

Materials provided by Elsevier. Note: Content may be edited for style and length.

---

Journal Reference:

1. Alexander A. Leung, Hsiu-Ju Chang, Finlay A. McAlister, Nadia A. Khan, Doreen M. Rabi, Hude Quan, Raj S. Padwal. Applicability of the S ystolic Blood Pr essure In tervention T rial (SPRINT) to the Canadian Population. Canadian Journal of Cardiology, 2018; 34 (5): 670 DOI: 10.1016/j.cjca.2018.01.008

Increased nerve activity may raise blood pressure in anxiety

Sympathetic nerve activity to skeletal muscle blood vessels -- a function of the nervous system that helps regulate blood pressure -- increases during physiological and mental stress in people with chronic anxiety, a new study finds. Over time, this response may increase the risk of high blood pressure and heart disease, although the study did not test this specifically. The study, published ahead of print in the Journal of Neurophysiology, was chosen as an APSselect article for May.

Researchers from the University of Iowa studied the responses of two groups of volunteers after they experienced physiological and mental stressors. One group of people had chronic anxiety as determined by standardized scales used to measure anxiety and depression. The control group did not have anxiety. The research team placed the volunteers' hands in an ice-water bath for two minutes to assess their responses to physiological stress. After a brief recovery period, the participants verbally solved simple math problems as fast as they could for four minutes to induce mental stress. Before the start of each test, the researchers gave the participants a two-minute "warning" countdown.

The research team inserted a tiny microelectrode into a nerve near the back of the participants' knee to measure sympathetic nerve activity throughout testing. They monitored the volunteers' rate of blood flow and blood pressure in the upper arm and heart rate via a finger cuff during both activities. Blood samples showed that the anxiety group had higher levels of norepinephrine, a hormone that sympathetic nerve fibers release in response to stress, before testing began. Norepinephrine causes the blood vessels to contract, which raises blood pressure.

The researchers observed increased nerve responses in both groups before and during the ice bath and math activities. However, the increase "was significantly greater among [the anxiety group] compared with [the control group], suggesting an enhanced sympathetic anticipatory response," the research team wrote.

Heart rate increased during the two-minute countdown, another sign that the anticipation of impending stress or discomfort caused physiological changes in the body. However, there was no significant difference between the anxiety and control groups. "Future studies are warranted to determine whether augmented [sympathetic nerve activity] is associated with deleterious end-organ consequences in persons with anxiety and cardiovascular disease or cardiovascular disease risk factors," the researchers wrote.

---

Story Source:

Materials provided by American Physiological Society. Note: Content may be edited for style and length.

---

Journal Reference:

1. Seth W. Holwerda, Rachel E. Luehrs, Allene L. Gremaud, Nealy A. Wooldridge, Amy K. Stroud, Jess G Fiedorowicz, Francois M. Abboud, Gary L. Pierce. Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety. Journal of Neurophysiology, 2018; DOI: 10.1152/jn.00064.2018