Age prediction using Microbiota


Bacteroides are the most common bacteria species found in the human intestinal tract. Dennis Kunkel Microscopy/Science Source

The idea that you can predict someone’s age based on their gut microbiome is “very plausible” and of “tremendous interest” to scientists.

Dr. Zhavoronkov, longevity researcher at InSilico Medicine, Maryland and computer scientist and microbiome researcher, Robin Knight, director of the Center for Microbiome Innovation at the University of California, San Diego, and colleagues found out how the microbiome changes over time by examining more than 13,000 samples of gut bacteria from healthy individuals living across the globe.

Please see below Dr. Alex Zhavoronkov and colleagues’s abstract:

The human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Zhavoronkov says this “microbiome aging clock” could be used as a baseline to test how fast or slow a person’s gut is aging

Previous analyses of gut microflora revealed associations between specific microbes and host health and disease status, genotype and diet.

Here, we developed a method of predicting biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals (3,663 microbiome samples).

Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation.

The performance of the deep microbiome clock was also evaluated on several additional populations.

We further introduce a platform for biological interpretation of individual microbial features used in age models, which relies on permutation feature importance and accumulated local effects.

This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their host’s aging.

Overall, we show that (a) micro biological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.

These topics will be discussed during the conference, in the session Microbiota and recent scientific advances.

Sources: Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

https://www.biorxiv.org/content/early/2018/12/28/507780

Microbiome characterization by high-throughput transfer RNA sequencing and modification analysis

A research team from the University of Chicago has created a new computational high-throughput RNA sequencing strategy that will provide insights into the activity of gut microbiome like never before.
 
“Advances in high-throughput sequencing have facilitated remarkable insights into the diversity and functioning of naturally occurring microbes; however, current sequencing strategies are insufficient to reveal physiological states of microbial communities associated with protein translation dynamics. Transfer RNAs (tRNAs) are core components of protein synthesis machinery, present in all living cells, and are phylogenetically tractable, which make them ideal targets to gain physiological insights into environmental microbes. Here we report a direct sequencing approach, tRNA-seq, and a software suite, tRNA-seq-tools, to recover sequences, abundance profiles, and post-transcriptional modifications of microbial tRNA transcripts. Our analysis of cecal samples using tRNA-seq distinguishes high-fat- and low-fat-fed mice in a comparable fashion to 16S ribosomal RNA gene amplicons, and reveals taxon- and diet-dependent variations in tRNA modifications. Our results provide taxon-specific in situ insights into the dynamics of tRNA gene expression and post-transcriptional modifications within complex environmental microbiomes.”
 
News source: www.nature.com

Comprehensive skin microbiome analysis reveals the uniqueness of human skin and evidence for phylosymbiosis within the class Mammalia

Skin forms a critical protective barrier between a mammal and its external environment. Baseline data on the mammalian skin microbiome elucidates which microorganisms are found on healthy skin and provides insight into mammalian evolutionary history. To our knowledge, this study represents the largest existing mammalian skin microbiome survey. Our findings demonstrate that human skin is distinct, not only from other Primates, but from all 10 mammalian orders sampled. Identifying significant similarities between branching of mammalian phylogenetic trees and relatedness trees for their corresponding microbial communities raises the possibility that mammals have experienced coevolution between skin microbiota and their corresponding host species.

Skin is the largest organ of the body and represents the primary physical barrier between mammals and their external environment, yet the factors that govern skin microbial community composition among mammals are poorly understood. The objective of this research was to generate a skin microbiota baseline for members of the class Mammalia, testing the effects of host species, geographic location, body region, and biological sex. Skin from the back, torso, and inner thighs of 177 nonhuman mammals was sampled, representing individuals from 38 species and 10 mammalian orders. Animals were sampled from farms, zoos, households, and the wild. The DNA extracts from all skin swabs were amplified by PCR and sequenced, targeting the V3-V4 regions of bacterial and archaeal 16S rRNA genes. Previously published skin microbiome data from 20 human participants, sampled and sequenced using an identical protocol to the nonhuman mammals, were included to make this a comprehensive analysis. Human skin microbial communities were distinct and significantly less diverse than all other sampled mammalian orders. The factor most strongly associated with microbial community data for all samples was whether the host was a human. Within nonhuman samples, host taxonomic order was the most significant factor influencing skin microbiota, followed by the geographic location of the habitat. By comparing the congruence between host phylogeny and microbial community dendrograms, we observed that Artiodactyla (even-toed ungulates) and Perissodactyla (odd-toed ungulates) had significant congruence, providing evidence of phylosymbiosis between skin microbial communities and their hosts.

News source: www.pnas.org

Scientists make cells that enable the sense of touch

Human embryonic stem cell-derived neurons (green) showing nuclei in blue. Left: with retinoic acid added. Right: with retinoic acid and BMP4 added, creating proprioceptive sensory interneurons (pink). Credit: UCLA Broad Stem Cell Research Center/Stem Cell Reports

Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have, for the first time, coaxed human stem cells to become sensory interneurons—the cells that give us our sense of touch. The new protocol could be a step toward stem cell-based therapies to restore sensation in paralyzed people who have lost feeling in parts of their body.

The study, which was led by Samantha Butler, a UCLA associate professor of neurobiology and member of the Broad Stem Cell Research Center, was published today in the journal Stem Cell Reports.

Sensory interneurons, a class of neurons in the spinal cord, are responsible for relaying information from throughout the body to the central nervous system, which enables the of touch. The lack of a sense of touch greatly affects people who are paralyzed. For example, they often cannot feel the touch of another person, and the inability to feel pain leaves them susceptible to burns from inadvertent contact with a hot surface.

“The field has for a long time focused on making people walk again,” said Butler, the study’s senior author. “‘Making people feel again doesn’t have quite the same ring. But to walk, you need to be able to feel and to sense your body in space; the two processes really go hand in glove.”

In a separate study, published in September by the journal eLife, Butler and her colleagues discovered how signals from a family of proteins called bone morphogenetic proteins, or BMPs, influence the development of sensory interneurons in chicken embryos. The Stem Cell Reports research applies those findings to human in the lab.

When the researchers added a specific called BMP4, as well as another signaling molecule called retinoic acid, to human , they got a mixture of two types of sensory interneurons. DI1 sensory interneurons give people proprioception—a sense of where their body is in space—and dI3 sensory interneurons enable them to feel a sense of pressure.

The researchers found the identical mixture of sensory interneurons developed when they added the same signaling molecules to induced , which are produced by reprogramming a patient’s own mature such as skin cells. This reprogramming method creates stem cells that can create any cell type while also maintaining the genetic code of the person they originated from. The ability to create sensory interneurons with a patient’s own reprogrammed cells holds significant potential for the creation of a cell-based treatment that restores the sense of touch without immune suppression.

Butler hopes to be able to create one type of interneuron at a time, which would make it easier to define the separate roles of each cell type and allow scientists to start the process of using these cells in clinical applications for who are paralyzed. However, her research group has not yet identified how to make stem cells yield entirely dI1 or entirely dI3 cells—perhaps because another signaling pathway is involved, she said.

The researchers also have yet to determine the specific recipe of growth factors that would coax stem cells to create other types of sensory interneurons.

The group is currently implanting the new dI1 and dI3 sensory interneurons into the spinal cords of mice to understand whether the cells integrate into the nervous system and become fully functional. This is a critical step toward defining the clinical potential of the cells.

“This is a long path,” Butler said. “We haven’t solved how to restore but we’ve made a major first step by working out some of these protocols to create sensory interneurons.”

News source: www.phys.org

More information: Sandeep Gupta et al. Deriving Dorsal Spinal Sensory Interneurons from Human Pluripotent Stem Cells, Stem Cell Reports (2018). DOI: 10.1016/j.stemcr.2017.12.012

Researchers find factor that delays wound healing

New research carried out at The University of Manchester has identified a bacterium—normally present on the skin that causes poor wound healing in certain conditions.

Pseudomonas aeruginosa and its variants are associated with delays in .

Damage to a receptor that allows the body to recognise the is associated with a change in the balance of the community of bacteria present normally on the skin. And according to Dr Sheena Cruickshank, the shift in balance has an enormous impact on the ability of the wound to heal.

The study was carried out at Manchester and co-led by Dr Cruickshank and Dr Matthew Hardman, who is now at now at The University of Hull. The bacterium has previously been associated with wound infections, and such infection is a major complication of that fail to heal. At least one in 10 people will develop a wound that heals poorly.

The research, published in the Journal of Investigative Dermatology and funded by the Medical Research Council, casts new light on why one in 10 people will develop a which does not heal well.

The research was carried out using mice that were previously shown to heal poorly. The mice lack the receptor Nod2 that recognises bacterial components and has been shown to help regulate the host response to bacteria. The team found that mice lacking Nod2 had more Pseudomonas aeruginosa than , which is associated with delayed wound healing.

The bacteria also caused normal mice to heal poorly. The team says the findings are also applicable to humans as Pseudomonas aeruginosa is associated with that heal poorly in people. Dr Cruickshank said, “There is an urgent need to understand the bacterial communities in our skin and why so many of us will develop wounds that do not heal.

“Wounds can be caused by a multitude of factors from trauma to bed sores, but infection is a complication that can, on occasion, lead to life-threatening illness. Many people are struggling with wounds that heal poorly, but this new study suggests that the types of bacteria present may be responsible for our failure to heal, which is important for considering how we manage wound treatment.”

Explore further: Bacteria on the skin: New insights on our invisible companions

More information: Helen Williams et al. Cutaneous Nod2 Expression Regulates the Skin Microbiome and Wound Healing in a Murine Model, Journal of Investigative Dermatology (2017). DOI: 10.1016/j.jid.2017.05.029

Topical gel made from oral blood pressure drugs shown effective in healing chronic wounds

An international team of researchers led by Johns Hopkins has shown that a topical gel made from a class of common blood pressure pills that block inflammation pathways speeds the healing of chronic skin wounds in mice and pigs.

A report of the findings, published Oct. 16 in the Journal of Investigative Dermatology, marks efforts to seek approval from the U.S. Food and Drug Administration (FDA) to use the gel application in treatment-resistant skin among diabetics and others, particularly older adults.

“The FDA has not issued any new drug approval for in the past 10 years,” says Peter Abadir, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and the paper’s first author. “Using medicines that have been available for more than two decades, we think we have shown that this class of medicines holds great promise in effectively healing that are prevalent in diabetic and aged patients.”

Chronic wounds, defined as skin injuries that fail to heal in a timely manner and increase the risk of infection and tissue breakdown, accounted for more than 100 million hospital visits in United States hospitals in 2008, according to Abadir.

In recent years, attention has turned to the skin’s renin-angiotensin system (RAS), which is involved in the skin’s inflammatory response, collagen deposition and signaling necessary for wound healing. Studies show that the RAS system is abnormally regulated in diabetic and older adults.

Abadir and colleagues experimented with gel formulations of angiotensin II receptor antagonists, or blockers, a long-standing class of drugs that includes losartan and valsartan, prescribed to treat hypertension. The drugs block RAS and increase wound blood flow, and the goal was to apply the gels directly to wounds, increasing wound tissue level of the drugs that promote faster healing.

Abadir and colleagues first tested 5 percent topical losartan on mice in three different phases of wound healing: group 1 treatment, for up to three days post-wound infliction to target the inflammatory phase; group 2 treatment, starting on day seven after wound infliction to target the proliferative/remodeling (later) phase of tissue healing; and group 3 treatment, starting the first day of wound infliction until closure to treat all wound healing phases. A fourth group was kept back as a control and given standard care and a placebo. Mice in group 2 experienced the most accelerated wound healing rate.

Next, Abadir and colleagues compared the effects of different concentrations of losartan and valsartan on young diabetic and aged mice during the proliferation/remodeling phase of wound healing, which involves the regrowth of normal tissue.

The results showed that valsartan was more effective in accelerating wound healing than losartan, without any significant difference in healing time between valsartan doses. Overall, 1 percent valsartan had the greatest impact on total closure compared with the other agents, and 10 percent losartan led to the worst wound healing, which Abadir says may be attributed to toxicity.

Wound. Credit: Johns Hopkins Medicine

Final results showed that half of all mice that received 1 percent valsartan achieved complete wound healing, while only 10 percent of the mice given the placebo did.

Driven by 1 percent valsartan’s promising results in mice, the researchers tested its effects on wounds among aged, diabetic pigs, as pig skin has more similar properties to human skin.

Compared with pigs in the placebo group, wounds that received 1 percent valsartan healed much more quickly, and all 12 wounds were closed by day 50, compared with none of the placebo-treated wounds, the researchers say.

Of note, Abadir says, a low concentration (1 to 50 nanomoles) of valsartan was detected in the pigs’ blood near the beginning of treatment, and none was detected later in the treatment course, suggesting that the drug acts locally on the tissues where it’s absorbed, rather than affecting the entire body.

For comparison, oral ingestion of valsartan generally yields 4,000 to 5,000 nanomoles in the blood level for a human. This suggests that topical application of valsartan will not be absorbed into the bloodstream and could have unintended physiological effects, such as those that affected blood pressure, body weight or kidney function.

Finally, to determine the quality of 1 percent valsartan’s biological effects on wound repair—not just rate of repair—Abadir and colleagues examined collagen content and tensile strength in the pigs’ skin. Pigs treated with valsartan had a thicker epidermal layer (the outermost layer of the skin) and dermal collagen layer, as well as a more organized collagen fiber arrangement, all of which indicate 1 percent valsartan application leads to stronger healing skin, Abadir says.

“Our strategy for specifically targeting the biology that underlies chronic wounds in diabetics and older adults differs greatly from other approaches to wound care thus far. The topical gel likely enables a cascade of positive biological effects that facilitates and accelerates chronic wound ,” says Jeremy Walston, M.D., professor of medicine and the paper’s senior author.

“Now that we’ve proven efficacy in animals, we’re moving on to the next stage of FDA-required testing in humans. Hopefully, this medication will be available for public use in a few years, if further research bears out our results,” adds Walston. Walston and colleagues envision that the medication could one day also be used to treat scars, wrinkles and other skin problems.

Twenty-nine million Americans have diabetes and 1.7 million are newly diagnosed each year. Of this group, approximately 900,000 will develop annually. With an aging population and incidence of diabetes increasing rapidly across the globe. Abadir estimates the total number of diabetic foot ulcers to be more than 20 million per year, with an estimated total cost of $25 billion annually in the U.S. alone.

More information: Peter Abadir et al, Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds, Journal of Investigative Dermatology (2017). DOI: 10.1016/j.jid.2017.09.030

News source: www.medicalxpress.com