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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Mosquitoes and an evolved taste for humans

In a recent study published in BMC Biology, Dr. Frank Jiggins and his team at the university of Cambridge uncovered the evolutionary history of mosquito migrations and domestication events.

The group found that human-feeding Ae. aegypti mosquitos from an urban population in Senegal, West Africa, were more closely related to populations in Mexico and Sri Lanka than they were to a nearby forest population that fed on animals.

Dr. Jiggins and his team believe that an ancestral population of Ae. aegypti evolved into a human specialist, thus, giving rise to a subspecies known as aegypti aegypti. It is thought that this population migrated out of Africa, therefore explaining why there are such similarities between distant Asian and American populations.

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BMC Biology201715:16; DOI: 10.1186/s12915-017-0351-0

Transplanted Microbes Alter Gut Function and Behavior

Transplantation of fecal microbiota from patients with irritable bowel syndrome (IBS) resulted in IBS-like changes in gut function as well as behavior in recipient mice. Such findings could facilitate development of improved diagnostics as well as effective treatments to replace current symptom-targeting treatments.

The underlying causes of IBS are unknown, which has hindered development of improved diagnostics and therapeutics. The research team, led by Prof. Premysl Bercik and Dr. Stephen Collins of McMaster University (Ontario, Canada) in collaboration with researchers from University of Waterloo (Ontario, Canada), explored effects of fecal microbiota from human IBS patients with diarrhea, with or without anxiety, on gut and brain function in recipient mice. Using fecal transplants, they transferred microbiota from these IBS patients into germ-free mice. The mice developed changes both in intestinal function and behavior reminiscent of the donor IBS patients, compared to mice that were transplanted with microbiota from healthy individuals.

The researchers found that aspects of the illness that were impacted through fecal transplants included gastrointestinal transit (the time it takes for food to leave the stomach and travel through the intestine); intestinal barrier dysfunction; low-grade inflammation; and anxiety-like behavior.

This study “moves the field beyond a simple association, and towards evidence that changes in the microbiota impact both intestinal and behavioral responses in IBS,” said study first author Giada De Palma, research associate at McMaster U.

They authors noted that the study “adds to evidence suggesting that the intestinal microbiota may play some role in the spectrum of brain disorders ranging from mood or anxiety to other problems that may include autism, Parkinson’s disease, and multiple sclerosis.” Further studies are needed to better define the relationship in these conditions. The authors suggested “microbiota-directed therapies, including pre- or probiotic treatment, may be beneficial in treating not only intestinal symptoms but also components of the behavioral manifestations of IBS.”

“Our findings provide the basis for developing therapies aimed at the intestinal microbiota, and for finding biomarkers for the diagnosis of IBS,” said Prof. Bercik.

The study, by De Palma G et al, was published March 1, 2017, in the journal Science Translational Medicine.

Aquamin and Gut Health

Aquamin is a unique Marine multimineral complex, providing bioactive calcium, magnesium and 72 other trace marine minerals, for the fortification of food, beverage and supplement products.

Unlike other mineral sources used in food, beverage and supplement preparation, Aquamin is derived from 100% seaweed, which absorbs trace minerals from the surrounding seawater. This form of absorption, coupled with Aquamins’s unique structure, results in a mineral rich product that is neutral tasting, free of chalky texure and easily absorbed by the human body. Aquamin contains a unique trace mineral profile gained from its marine source. The elements contained are at trace quantities and are insignificant alone, but within a multimineral matrix they work synergistically and give a powerful boost to the action of the calcium and magnesium.

Aquamin is a unique natural ingredient for the enhancement of gut health. It contains significant amounts of calcium and magnesium as well as trace amounts of 72 additional minerals complexed together in a structure engineered by the cell wall of the seaweed lithothamnion sp.

Aquamin has been the subject of 33 peer reviewed publications over the last 10 years, which support its unique health promoting properties.

Aquamin has been shown to enhance gut health by restoring a balanced immune response, promoting the differentiation of colonic cells and providing a balanced gut microflora.

Synthetic bacteria reduce tumor volume in mice

Bacterial cancer therapy (BCT) is an immunotherapy strategy that uses attenuated bacterial strains to suppress tumor growth. While the strains are attenuated, there is still a safety risk associated with their use, and this has prompted investigation into alternative BCT methods. In a recent Science Translational Medicine publication, researchers have actually engineered a bacterium to fight tumors by overexpressing and unlikely protein. In this paper, flagellin protein (FlaB) was overexpressed in Salmonella typhimurium strains. The rationale behind this was that flagellin is known to activate immune responses via Toll-like receptors, specifically TLR5, which would make it a good cancer immunotherapy candidate. These modified bacteria were delivered into tumors in mice, and the impact on tumor volume and TLR signaling was analyzed. The authors discovered that following delivery of the engineered Salmonella, there was a localized increase in immune cells, such as monocytes and macrophages, as a result of TLR4 signaling. Subsequently, the increased immune response inhibited metastasis and tumor growth, further promoting recovery in mice without any deleterious effects from the microbes. Together, these results provide renewed support behind the use of modified bacteria for cancer therapy.

viral communication

Zheng et al. Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Science Translational Medicine. 2017. DOI: 10.1126/scitranslmed.aak953