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)

Enemy turned ally: Poliovirus is used to fight brain tumors

One of the world’s most dreaded viruses has been turned into a treatment to fight deadly brain tumors. Survival was better than expected for patients in a small study who were given genetically modified poliovirus, which helped their bodies attack the cancer, doctors report.

It was the first human test of this and it didn’t help most patients or improve median survival. But many who did respond seemed to have long-lasting benefit: About 21 percent were alive at three years versus 4 percent in a comparison group of previous brain tumor patients.

Similar survival trends have been seen with some other therapies that enlist the immune system against different types of cancer. None are sold yet for brain tumors.

“This is really a first step,” and doctors were excited to see any survival benefit in a study testing safety, said one researcher, Duke University’s Dr. Annick Desjardins.

Preliminary results were to be discussed Tuesday at a conference in Norway and published online by the New England Journal of Medicine.


Brain tumors called glioblastomas often recur after initial treatment. Sen. John McCain is being treated for one now. Immunotherapy drugs like Keytruda help fight some cancers that spread to the brain but have not worked well for ones that start there.

Polio ravaged generations until a vaccine came out in the 1950s. The virus invades the nervous system and can cause paralysis. Doctors at Duke wanted to take advantage of the strong immune system response it spurs to try to fight cancer. With the help of the National Cancer Institute, they genetically modified poliovirus so it would not harm nerves but still infect tumor cells.

The treatment is dripped directly into the brain through a thin tube. Inside the tumor, the immune system recognizes the virus as foreign and mounts an attack.

When doctors explained the idea to Michael Niewinski, it seemed a feat “like putting a man on the moon,” he said. The 33-year-old from Boca Raton, Florida, was treated last August, and said a recent scan seemed to show some tumor shrinkage.

“I’m pain-free, symptom-free,” he said.


The study tested the modified poliovirus on 61 patients whose tumors had recurred after initial treatments. Median survival was about a year, roughly the same as for a small group of similar patients given other brain tumor treatments at Duke. After two years, the poliovirus group started faring better.

Follow-up is continuing, but survival is estimated at 21 percent at two years versus 14 percent for the comparison group. At three years, survival was still 21 percent for the virus group versus 4 percent for the others.

Eight of the 35 patients who were treated more than two years ago were alive as of March, as were five out of 22 patients treated more than three years ago.

Stephanie Hopper, 27, of Greenville, South Carolina, was the first patient treated in the study in May 2012 and it allowed her to finish college and become a nurse. Scans as recent as early June show no signs that the tumor is growing, she said.

“I believe wholeheartedly that it was the cure for me,” she said. Her only lasting symptom has been seizures, which medicines help control. “Most people wouldn’t guess that I had brain cancer.”


The treatment causes a lot of brain inflammation, and two thirds of patients had side effects. The most common ones were headaches, muscle weakness, seizure, trouble swallowing and altered thinking skills. Doctors stressed that these were due to the immune response in the brain and that no one got polio as a result of treatment.

One patient had serious brain bleeding right after the procedure. Two patients died relatively soon after treatment — one from worsening of the tumor and the other from complications of a drug given to manage a side effect. The planned doses had to be reduced because there were too many seizures and other problems at the higher doses initially chosen.

One independent expert, Dr. Howard Fine, brain tumor chief at New York-Presbyterian and Weill Cornell Medicine, said it was disappointing to see no improvement on median survival, but encouraging to see “extraordinary responders, a small group of patients who have done markedly better than one would expect.”

The numbers in the study are small, but it’s unusual to see many alive after several years, and suggests the approach merits more and bigger studies, he said.


The National Cancer Institute manufactured the modified virus. Federal grants and several charities funded the work. Some study leaders have formed a company that licenses patents on the treatment from Duke.

Duke has started a second study in adults, combining the poliovirus with chemotherapy, to try to improve response rates. A study in children with brain tumors also is underway, and studies for breast cancer and the skin cancer melanoma also are planned.


The Associated Press Health & Science Department receives support from the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content.

Mini Digestive Tract Found inside Cancerous Cells

Duke University researchers have now discovered a miniature gastrointestinal tract embedded in a lung cancer tumour. The observed gut cells were found to be rudimentary but functional stomachs, small intestines, and duodenums growing inside cancerous lungs—illustrating how varied and plastic these metastatic cells can be.

They discovered that these cells had lost a gene called NKX2-1 that acts as a master switch, flipping a network of genes to set the course for a lung cell. Without it, the cells follow the path of their nearest developmental neighbour- the gut -much like a train jumping tracks when a railroad switch fails.

Cancer cells will do whatever it takes to survive,” said Purushothama Rao Tata, Ph.D., lead study author and assistant professor of cell biology at Duke University School of Medicine and a member of the Duke Cancer Institute. “Upon treatment with chemotherapy, lung cells shut down some of the key cell regulators and pick up the characteristics of other cells in order to gain resistance.

Scan of a lung cancer tumor invading the left inferior lobe. Credit: Cavallini James Getty Images

Since both lungs and gut cells come from the same progenitor cells, Tata hypothesized, that in absence of NKX2-1, lung tumor cells would lose their lung identity and take on the characteristics of other cells. Because during development lung cells and gut cells are derived from the same parent, or progenitor, cells, it made sense that once the lung cells lost their way they would follow the path of their nearest developmental sibling.

The team tested this out on animal models using mice which had NKX2-1 gene removed from their lung tissue. Under the microscope, they noticed features that normally only appear in the gut, such as crypt-like structures and gastric tissues. Amazingly, these structures produced digestive enzymes, as if they resided in the stomach and not the lung.

The researchers next activated the oncogenes SOX2 or KRAS in addition to knocking out the NKX2-1. They found that mice with the superimposed SOX2 mutations developed tumors that looked as if they belonged in the foregut; those with KRAS mutations developed tumors that resembled parts of the mid- and hindgut.

New research from Duke has found that some lung cancer cells with errors in transcription factors begin to resemble their nearest relatives – the cells of the stomach and gut. (Credit – Tata Lab, Duke University)

Cancer biologists have long suspected that cancer cells could shape shift in order to evade chemotherapy and acquire resistance, but they didn’t know the mechanisms behind such plasticity,” said Tata. “Now that we know what we are dealing with in these tumors – we can think ahead to the possible paths these cells might take and design therapies to block them.”

Genes associated with extreme morning sickness identified

Science Translation

Extreme morning sickness, also known as Hyperemesis gravidarum (HG), is a complication of pregnancy affecting between 0.3-2% of pregnancies. It is characterized by severe nausea, vomiting, weight loss, and dehydration. HG is more than just feeling sick, it can cause serious health problems for mother and child and in extreme cases can lead to maternal or fetal death. There are a number of risk factors associated with HG which include: first pregnancy, multiple pregnancy (twins, triplets, etc), obesity, and a family history of HG. The most common treatment plan is management of the symptoms through medication, bland diet, plenty of fluids, and sometimes hospitalization. If we could understand the underlying factors that contribute to the disorder, then we could provide more targeted treatments and perhaps prevention from the beginning. This is the aim of a team of scientists from California, who screened the genetics of over 15,000 participants who…

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Drug-Delivery System Can Help Heal Even Without Drugs

Drug-Delivery System Can Help Heal Even Without Drugs

Tests showed that subcutaneous implants, left, of a hydrogel developed at Rice University encouraged blood vessel and cell growth as new tissue replaced the degrading gel.

Stress Cancer Cells to Death: Turning Off Autophagy Helps Chemotherapy

A process called autophagy (from the Greek term for “self-eating”) helps cells survive stress – very basically, autophagy acts as a kind of cellular recycling system in which unwanted or old parts of the cell are degraded and reused to promote cell health. Unfortunately, cancer cells can hijack autophagy to avoid the stress of anti-cancer drugs that are designed to kill them. This makes autophagy an attractive target for anti-cancer therapies; blocking autophagy may make cancer cells unable to overcome the stress of treatments, leading to their death. In fact, dozens of clinical trials are testing the ability of autophagy-inhibitors along with chemotherapy drugs, radiation or targeted treatments to push cancer cells over the edge into a specific kind of cell death known as apoptosis.

However, while researchers have known of the relationship between autophagy and apoptosis, what creates this link hasn’t been clear – in other words, we have known that turning off autophagy can help drugs push cancer cells into apoptosis, but we haven’t known how.

Until now. A University of Colorado Cancer Center study published today in the journalDevelopmental Cell pinpoints a molecule that links autophagy and apoptosis, namely a transcription factor called FOXO3a.

“The problem is this: many anti-cancer treatments push cancer cells to the brink of death. But the cells use autophagy to go into a kind of suspended animation, pausing but not dying. We don’t want cancer cells to pause; we want them to die. We show that FOXO3a may make the difference between these two outcomes,” says Andrew Thorburn, DPhil, CU Cancer Center investigator, professor and chairman of the CU School of Medicine Department of Pharmacology.

The Thorburn lab has spent decades picking apart the inner workings of the complex and sometimes seemingly contradictory process of autophagy. For example, the lab has shown that turning off autophagy sensitizes some cancers but not others to chemotherapy/radiotherapy and some cancers even thrive in the absence of autophagy (which in turn upregulates researcher face-palming).

Taken alone, these contradictions make little sense. There must me more going on. And it turns out that “what’s going on” is FOXO3a.

Imagine this: the colder your body gets, the more you shiver to warm up. Thus, shivering helps to maintain equilibrium – despite variations in air temperature, your body stays at 98.6 degrees. Autophagy has a similar mechanism of equilibrium: FOXO3a regulates and is regulated by autophagy. This means that when autophagy goes up, FOXO3a goes down, which in turn acts to dial back autophagy. And when autophagy goes down, FOXO3a goes up, which reinvigorates autophagy. By this mechanism, autophagy stays relatively constant…even, sometimes, in the face of oncologists’ attempts to dampen it with drugs.

However, FOXO3a not only maintains autophagy equilibrium but also controls the gene that makes a protein called PUMA – and PUMA drives the cell death known as apoptosis.

Putting it all together, inhibiting autophagy boosts FOXO3a, which has two important results: first, it increases autophagy in an attempt to keep it in a Goldilocks range; and second, it increases the production of PUMA, which pushes cells toward apoptosis.

Thorburn and colleagues including first author Brent E. Fitzwalter tested autophagy inhibition along with a drug called Nutlin. Previously, the drug has been shown to inhibit the growth of cancer cells, but hasn’t necessarily resulted in cancer cell death – the “pause but not die” outcome described above. Here is an important point: Nutlin and autophagy-inhibition both increase PUMA, but do so in completely independent ways (autophagy inhibition through FOXO3a and Nutlin through another transcription factor called p53).

“What we wanted to see is whether these two things together – Nutlin along with autophagy inhibition – would increase PUMA past the point of growth inhibition and into actual cell death,” Fitzwalter says.

The answer was yes. The combination was much more effective against cancer cells than either strategy alone. This was true in cell studies and also in test tumors grown in mice.

“The punchline was that we turned a drug that could slow down tumor growth but couldn’t kill cancer cells into one that now kills the cells,” Thorburn says.

The results provide a rationale for which types of drugs that could combined with autophagy inhibition in future clinical trials.

This article has been republished from materials provided by University of Colorado Cancer Center. Note: material may have been edited for length and content. For further information, please contact the cited source.