Host faecal miRNA regulates gut microbiota

Mouse and human faeces contains functional microRNAs (miRNAs), according to a new study published in Cell Host & Microbe. The researchers also showed that host faecal miRNA directly regulates microbial gene expression and growth. “It is known that the commensal bacteria in the gut are important in health and disease. However, little is known about how they are naturally regulated, or strategies to manipulate them,” explains first author Shirong Liu. Previous studies have shown that extracellular miRNAs are present in human faeces, leading Liu et al. to investigate whether faecal extracellular miRNAs are functional, and if they can regulate the gut microbiota by altering bacterial gene expression in the gut. The researchers isolated RNA from human and mouse faeces, finding that samples from both species contained specific miRNAs, such as miR-155 and miR-1224.

Bioinformatic analysis predicted that a number of these miRNAs could bind multiple genomic sites in selected bacterial species. The researchers cultured two bacterial species in the presence of synthetic mimetics of identified miRNAs and found that bacterial growth was markedly affected. After showing that fluorescently labelled miRNA was able to enter bacteria, the authors also demonstrated that bacterial gene expression is directly altered when bacteria were cultured with human or mouse faecal miRNAs. Mice lacking the miRNAgenerating protein Dicer only in intestinal epithelial cells had reduced levels of faecal miRNA, suggesting that intestinal epithelial cells are a major source of miRNA in faeces. Faecal miRNA levels were also reduced in mice in which Dicer was knocked out in intestinal goblet cells and Paneth cells.

Further experiments showed that mice with Dicer knocked out specifically in intestinal epithelial cells had dysbiosis, and were more susceptible to induced colitis than wild-type mice. When these knockout mice received faecal miRNA from wild-type mice via gavage before colitis induction, colonic damage was lessened. “Our findings show that the host can actively affect the microbes through miRNAs, and this provides a unique way to manipulate them,” concludes corresponding author Howard Weiner. “We will investigate whether faecal miRNAs are abnormal in disease, and we plan to explore ways to use exogenously administered miRNAs as therapeutic compounds.

ORIGINAL ARTICLE Liu, S. et al. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe 19, 32–43 (2016)

Chronic sleep disruption, or social jet lag, impairs normal liver function and may contribute to liver cancer

Science Translation

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC was traditionally considered a rare cancer but its incidence has been steadily on the rise since the 1980’s and is now the fastest rising cause of cancer death. Major risk factors for HCC include: hepatitis infection, fungal toxin exposure (Aflatoxins), and obesity. In developed countries, nearly 50% of all HCC cases are due to fatty liver disease caused by obesity. Fatty liver disease causes accumulation of fats droplets in the liver resulting in inflammation, scaring, and liver dysfunction. It can be caused by excessive alcohol consumption (called Alcoholic Fatty liver disease) or by insulin resistance, type-2 diabetes, and obesity (called Non-alcoholic Fatty liver disease). In the developed world, Non-alcoholic Fatty liver disease is found in 95% of people who are morbidly obese. In these patients the disease can predispose them to liver cancer, specifically HCC. Another risk…

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Working the night shift could limit your body’s ability to repair damaged DNA

Science Translation

Shift work, or work that occurs outside the normal 9-5 hours, has been associated with chronic disease and illness including an increased risk of certain cancers, heart disease, obesity, and depression. These negative effects are likely due to a loss of a normal sleep schedule which disrupts the body’s production of melatonin. Melatonin is a hormone produced by the pineal gland (specialized gland in your brain) that helps to regulate your sleep cycles. Melatonin also has an important role as an antioxidant and as a protector of DNA in your cells. Previous studies have linked shift work with elevated levels of oxidative stress which is known to damage DNA and potentially lead to an increase risk for chronic disease. To understand if shift work and sleep disruptions are associated with a loss in the melatonin anti-oxidant mechanism, a team of researchers from Seattle recruited night shift workers and monitored the…

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Psychobiotics, gut biomarkers, and the future of mental health

The past five years have been an especially rapid time of discovery, thanks to scientists studying the gut microbiota and how it influences the gut-brain axis—the two-way communication channel between the digestive tract and the brain. Not only are links being made between gut microbiota composition and conditions like depression and anxiety, but the gut also shows potential for revealing new approaches to diagnosis and treatment of brain-related disorders.

Jane A. Foster, associate professor at the Department of Psychiatry & Behavioural Neurosciences of McMaster University (Canada), has zeroed in on the gut microbiota and its metabolites in her study of the relationship between body and brain. She and other scientists are on a quest to find parameters in the gut that could tell them something about the brain—especially when it comes to addressing mental health.

Foster says, “What we’re looking at is the signalling systems that might go between the bacteria in the gut and the brain, because in the long run we want to know if biomarkers that we can look at outside the brain might give us indications of what’s happening in the central nervous system.”

“We have studies going on both in mice and in people,” she explains. “In the people we’re interested in getting a blood test, or a urine marker that we can use as a marker to help determine: how can we clean up some of the heterogeneity in mental illness by sub-typing people into better groups so that we can apply the correct treatment?”

This would mean, for instance, from the large and diverse group of people currently categorized as having depression, it might be possible to identify smaller groups with something biologically in common. This ‘precision medicine’ approach could involve directing people toward more effective treatments. Foster gives an example of how it could play out: “Somebody comes into their doctor’s office and the doctor can do a blood test or [brain imaging] that would identify the best approach for that individual—whether it be [a drug], neural stimulation, cognitive behavioural therapy—among all the choices for depressed patients.”

At the same time, Foster and other scientists are looking to realize the development of new mental health treatments that leverage the gut microbiome, called “psychobiotics”.

The term psychobiotic was introduced by Irish scientists in 2013 and originally referred to a subset of probiotics that could produce a health benefit in those with psychiatric illness. Foster says, “People like the term—it makes them think about it, and that’s a good thing.” She supports a recent proposal by the same Irish scientists to expand the definition of psychobiotics beyond probiotics, to include prebiotics and other means of influencing the microbiome for the benefit of mental health.

Certain probiotics are leading contenders in the category of psychobiotics, according to Foster. For example, probiotics were associated with a reduction in depressive symptoms, especially for those aged 60 or younger, in a review of multiple studies on probiotics for depression; moreover, some species of probiotics appeared to reduce both depression and anxiety in another review of multiple studies.

Psychobiotic treatments need more study in humans, especially when it comes to understanding how the biology works—but they could be a reality sooner than some people think, says Foster. “Some products are readily available and they’re being applied to clinical trials,” she notes. “They’re easy to apply to clinical populations. Even if it’s an adjunctive treatment.”

Understandings of mental health may change rapidly in the years ahead as we come to grasp new therapeutic approaches enabled by this gut-brain work. “It’s one of the fastest moving areas I’ve ever seen,” Foster says. “The ideas that we’ve generated in the mouse, the fact that clinical people are talking about them immediately has never been seen before.”

The association between gut bacteria and food sensitivity in young children.

Science Translation

Sensitization to food allergens often occurs early in the preschool years. While not all kids who develop food sensitivities end up with full-blown allergies, it is often considered the precursor to the development of allergies and asthma. These conditions are typically grouped together under the term atopic disease because of their tendency to be caused by over active IgE, an antibody in your blood. This IgE latches onto allergens in everyday objects you come in contact with and initiates the allergic response. Atopic diseases include asthma, anaphylaxis and eczema and it is not uncommon for someone with atopic disease to develop all forms of the disease at some point in their life. This is called the atopic march.

Courtesy of LEAP Study, Evelina Children's Hospital, London Courtesy of LEAP Study, Evelina Children’s Hospital, London

One of the leading theories behind the development of atopic diseases, or an over active IgE response, is called the hygiene hypothesis

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Exposure to pets in early life alters the gut microbiome of babies potentially protecting from allergies

Science Translation

It wasn’t that long ago that having a family history of allergies meant that the family dog or cat must go. The thought was that their presence would aggravate allergies and that  a clean house free of dust and allergens could prevent children from developing allergies. How the times have changed, there is now plenty of research to support the notion that children who grow up with pets have lower rates of asthma and allergies. This research has resulted in the hypothesis that living in a home that is too clean (ie. free of germs and allergens) can actually increase someone’s susceptibility to developing allergic diseases like asthma, eczema, and rhinitis. This hypothesis is called the hygiene hypothesis and has been a hot topic of research for years. The idea is that our immune system needs certain types of microbes present in our body to educate them and help…

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Wearable Glucose Device Includes Drug-Delivery Module

Researchers have developed a convenient accurate sweat-based glucose monitoring and maintenance device that provides rapid glucose measurement and allows doctors to prescribe a multistep precisely controlled dosage of drugs.

The research group, from the Center for Nanoparticle Research of the Institute for Basic Science, has furthered its previous study (2016) by enhancing the efficiency of the sweat collection, sensing, therapy processes. The glucose measurement system also comes in a convenient disposable strip-sensor format.

Image: A diagram of the wearable sweat-monitoring patch. A porous sweat-uptake layer is placed on a Nafion layer and sensors (Photo courtesy of the Institute for Basic Science).

A diagram of the wearable sweat-monitoring patch. A porous sweat-uptake layer is placed on a Nafion layer and sensors (Photo courtesy of the Institute for Basic Science).

The conventional protocol causes high stress to diabetes patients as it requires painful, repetitive blood-withdrawal and insulin shots. Many patients become reluctant to take the required periodic tests and treatments, resulting in worsened symptoms. The recent alternative approach of sweat-based monitoring offers a painless blood glucose monitoring method. However, many challenges for clinical application include: tedious blood collection procedure, error-prone enzyme-based glucose sensing that may lead to overtreatment of drugs, etc.

To address such issues, the research group developed an easy-to-use multistage module. To speed up the sweat collection, they revised the system to work under a low volume of sweat. In the glucose and pH sensors, the reference and counter electrodes are closely packed to minimize the required amount of sweat. The device features more sensors of a smaller size than the previous study, resulting in a miniaturized sensor that allows for reliable analysis even with 1 µl of sweat.

“It was quite a challenge to find the optimal size of the sensors. If the size is too small, the signal becomes too small or the surface functionalization becomes difficult to handle,” said study first-author Dr. Hyunjae Lee.

They used electrochemically active, porous metal electrodes (replacing the graphene materials of the previous study) to enhance sensitivity. Also, the porous structure allows it to form strong linkage among enzymes, resulting in increased reliability of sensors under mechanical friction and deformation.

For more accurate reading and feedback therapy, the patch system incorporates an additional sweat uptake layer (water-soluble and porous carbohydrate network to efficiently absorb the sweat exuding from skin) and a waterproof band behind the silicone patch facilitates sweat collection and keeps the patch intact even under physical deformation of the skin.

The system also enables reliable drug delivery to prevent overtreatment. Drugs for the feedback therapy are loaded on two different temperature-responsive phase change nanoparticles (PCNs) embedded in microneedles, which are additionally coated with phase change materials (PCMs).

Dr. Lee underscores the role of the additional PCM spray coating: “The previous systems cannot prevent natural diffusion of the drugs from drug reservoir, and rely heavily upon elevation of temperature to enhance the rate of drug diffusion. Our system uses PCMs to prevent drug release by using the melting properties of phase change materials above critical temperature, enabling stepwise drug delivery. Furthermore, different drugs can also be loaded in PCNs for stepwise and multiple drug delivery.”

The thermo-responsive microneedles controlled by three multichannel heaters can deliver a drug up to 6 steps of dosages in response to the measured glucose level. In experiments with diabetic mice, the researchers confirmed that as more drug is delivered, the blood glucose level is further suppressed.

“This convenient and accurate system is also compatible for mass-production as it uses the metal electrode that can be easily fabricated via a conventional semiconductor fabrication process,” said Dr. Lee, though “there is still room for improvement before […] clinical application.” Co-corresponding author KIM Dae-Hyeong noted, “The fundamental mechanism underlying this system can be applied in the diagnosis and clinical treatments of various diseases.”

The study, by Lee H et al, was published March 8, 2017, in the journal Science Advances.

Neonatal mouse brain differentially activates maternal and paternal gene copies during development

One of the fundamental rules of genetics is under assault: the idea that our body treats each copy of DNA instructions, one from each parent, equally. Scientists have discovered that the main culprits challenging this convention are the cells analyzed in the brain, specifically the ones associated with the dorsal raphe nucleus in newborn mice. Researchers have found that it is actually not uncommon for a developing mouse brain to differentially activate one copy over the other in certain instances.

How often does differential activation occur and what does it mean?

The scientists in the study screened thousands of genes to quantify levels of activation for each copy to see if there was a discrepancy. Scientists at the University of Utah School of Medicine have found that in the dorsal raphe nucleus of neonatal mouse brains, 85% of genes differentially activate their gene copies. This region is primarily known for secreting serotonin, which is responsible for the feelings associated with well-being and happiness. In juvenile brains, the phenomenon still occurs, but at a smaller percentage, with the percentage falling to 10% of genes that are differentially activated. This genetic imbalance may help us understand brain disorders and irregularities in the future. It could not only explain susceptibility to certain disease, but also explain why certain individuals are not prone to them as well.

peptide news book Huang et al. Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain. Neuron, 2017.
DOI: http://dx.doi.org/10.1016/j.neuron.2017.01.033