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)

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

Gut infectious bacteria can modify their genes according to their environment

gene expression, maternal genes, paternal genes, differential expression, dorsal raphe nucleus, brain disorders, neurodegenerative disease

Enterobacteria, a group of gram-negative bacteria that can thrive in the digestive tract of animals, includes both harmless and pathogenic types of bacteria. Some of the more familiar pathogens within this group of bacteria include Salmonella and E. coli. While it has been clear that these enteropathogenic bacteria prefer the optimal conditions within our gut, the manner in which they establish themselves and proliferate is not well understood. Scientists, in a new article publish in Science, have now discovered that pathogens not only sense their host, but further tailor their gene expression profiles to better infect and colonize their host.

Through what mechanisms do pathogens sense their host and tailor their gene expression profiles?

The pathogens themselves are able to initiate the type III secretion system and related proteins through contact induced expression of NleA. Scientists discovered, through GFP-tagged NleA, that only cells attached to the intestinal wall were able to express the contact-induced version of NleA. Furthermore, it was found that the T3SS mechanism (type III secretion system) was able to inject a group of effector proteins that made the host cell and environment more susceptible to infection. It is through these two key mechanisms caused by the T3SS mechanism that allows enterobacteria to better infect their hosts and cause possible pathogenic effect on their hosts.

peptide news book Katsowich et al. Host cell attachment elicits posttranscriptional regulation in infecting enteropathogenic bacteria. Science, 2017; 355 (6326): 735. Neuron, 2017.
DOI: http://dx.doi.org/10.1126/science.aah4886

Researchers discover that the lung is a major producer of platelets and blood stem cells

Your blood is composed of a number of different types of cells. There are the red blood cells whose primary job is to carry oxygen throughout the body. You also have the white blood cells which are important in your immune system. Finally, your blood has small cell fragments known as platelets which play an important role in clotting to prevent blood loss. Platelets contain no nucleus but instead are small pieces of a cell released from a larger cell known as a megakaryocyte. Blood, including megakaryocytes, is normally made in the bone marrow. The platelets are shed from the megakaryocytes into the circulation where they perform their job. This is the traditional thinking but recently a team of researchers from California have turned this notion and our understanding of platelets and lung biology on its head.

The team had previously witnessed data suggesting that megakaryocytes may circulate throughout the body and set up shop in the lungs. To test this idea further, the researchers used a type of microscopy that can be done on living animals to look at the small blood vessels within the lungs of mice. Looking at mice who had been engineered to have their platelets fluoresce green, the researchers noticed a striking number of large green glowing megakaryocytes in the lung vasculature of mice. Monitoring the activity of these megakaryocytes the researchers witnessed them making around 10 million platelets per hour, that’s nearly half the mouse’s platelets being made in the lungs. The researchers also noticed a large number of blood stem cells within the lung vasculature indicating that not only does the lung produce platelets, but it also houses stem cells that may repopulate the bone marrow if it is damaged. To test this theory, the researchers took the lung of a mouse whose cells were made to glow green and transplanted it into a mouse who had its bone marrow destroyed. They noticed that the bone marrow in this mouse began to regrow, only this time with cells that glowed green from the donor lung. Additionally, they noted in mice who had the transplanted green lung there was a large increase in the number of platelets in the blood that glowed green indicating that the transplanted megakaryocytes were making platelets for the new mouse.

This research is fascinating and provides a number of new and very interesting avenues of exploration for human health. First, do these megakaryocytes contribute to lung diseases like COPD or asthma? What happens to these megakaryocytes in people who get lung transplants? Can these lung blood stem cells be used to help someone with bone marrow defects? Lots of interesting research is sure to come from this paper.

Reference: Lefrançais et al., 2017. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. NATURE | LETTER doi:10.1038/nature21706.

Biomarker Predicts Death In Sepsis

Almost all type of pathogens – bacteria, fungi, parasites, and viruses – can aggravate the life-threatening condition, which leads to the body’s immune system overreacting and attacking its own tissues and organs. Sepsis is difficult to diagnose and even more difficult to treat. Duke scientists have discovered a biomarker of the runaway immune response to sepsis that could improve early diagnosis, prognosis, and treatment to save lives.

Facts and Figures:
The 20th century witnessed a remarkable decrease in infectious disease deaths. Although a great deal of the decline was due to improved sanitation, early antibiotics, resuscitation, and supportive hospital care have also played major roles, particularly in improving outcomes in bacteremia and sepsis.

  • With sepsis mortality, still up to 5.3 million people each year, there has long been hoping that this therapeutic arsenal could be complemented by host-directed sepsis therapies.
  • However, failures in more than 100 clinical trials aimed at modulating the immune response in sepsis have demonstrated that a better understanding of host biology and differences in clinical factors is necessary.

According to a 2012 study, sepsis affects one in four in intensive care units (ICUs) across the country every year. Very few people know the key warning signs.

The study – Indian Intensive Care Case Mix and Practice Patterns (INDICAPS) – based on a sample size of 4,209 patients, including 171 children, admitted to 124 ICUs across 17 states, showed that 26% patients in ICUs contracted sepsis. The mortality rate in patients with sepsis is 42.2%.

Conventional approaches
People with sepsis are typically treated with a combination of antibiotics and supportive care, treatments that target the pathogens but do nothing to address the runaway immune response that, ironically, proves more deadly than the infection itself.

  • Metabolite markers are particularly attractive for this goal because they serve to integrate multiple inputs (transcriptional, translational, and environmental) into an active biomolecule that can have large effects on physiology.
  • On the other hand, genetic markers of susceptibility have the advantage of not changing during the course of the disease, making the direction of causation for true genetic associations unambiguous.
  • Therefore, an improved understanding of human genetic differences that contribute to regulation of metabolite levels could powerfully couple the larger effect sizes of metabolites to the causality of genetic variants for prioritizing and designing interventions.

Discovery of methylthioadenosine (MTA)
One component of the host response that has received significant interest in characterizing and possibly treating sepsis is the activation of inflammatory caspases.

  • Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite, and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients.
  • Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway.
  • Measurement of the pathway’s substrate, MTA, in two cohorts of sepsis patients demonstrated increased plasma MTA in non-survivors.
  • Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation.
  • A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death.
  • The results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of the disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

MTA thus can predict which patients are most likely to die from the illness.

This could help determine whether patients could benefit from therapies that either enhance or suppress the immune system, paving the way for new treatments.

Reference:

  • Todi, S., Chatterjee, S., Sahu, S., & Bhattacharyya, M. (2010). Epidemiology of severe sepsis in India: an update.Critical Care, 14(S1), P382.
  • Wang, L., Ko, E. R., Gilchrist, J. J., Pittman, K. J., Rautanen, A., Pirinen, M., & Salinas, R. E. (2017). Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Science Advances, 3(3), e1602096.

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