Huge discovery: microbes in human blood/tissue vastly more diverse than previously known

September 20th, 2017 by Amy Proal

Last post I described fascinating research on the immune response by the Mark Davis Lab at Stanford. But another Stanford research team, led by Steven Quake, has published the results an equally exciting study. In fact, the team’s discovery marks one of the most important findings in modern science.

Quake and team used new methods to search for the DNA of microbes in human blood and tissue. They found that 99% of microbes identified were previously unknown to science. As this article in Stanford News describes, the discovery clarifies that “the microbes living within us are vastly more diverse than previously known.” 

DNA reads corresponding to known, divergent, and novel microbes detected by Quake and team.

DNA reads corresponding to known, divergent, and novel microbes detected by Quake and team.

To be specific, Quake and team examined microbe DNA fragments in the blood of patients with a range of conditions characterized by immunosuppression (liver transplant recipients, pregnant women etc). They collected over 1,000 blood samples, and found that they contained hundreds of never before discovered bacteria and viruses. In fact, ~3,761 of the organisms detected represent microbes not known to exist before the study was performed. 

These species include thousands of new bacteria, but also new viruses and phages (viruses that infect bacteria). The research team was forced to add new branches to the “tree of life” in order to classify many of these new microbes. Indeed, their findings literally double the total number of anelloviruses found in humans.

Quake and team conclude their paper by stating that these novel microbes “have potential consequences for human health. They may prove to be the cause of acute or chronic diseases that, to date,  have unknown etiology…”

I AGREE

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More thoughts: I experienced several “eureka moments” while reading the Quake study.  First, I have long predicted that new microbes would be identified in human tissue and blood.  I began my microbiology career by studying the work of microbiologists/pathologists in the 1960s. The papers/textbooks published by these scientists are seldom discussed in 2017. However, their work repeatedly identified numerous microbes/pathogens in blood/tissue samples taken from human subjects.

Why are these 1960s studies seldom referenced? In the 1970s, the “theory of autoimmunity” gained hold and research on chronic microbes was largely shelved. When the 1960s microbiologists contested this mindset, their work was often dismissed on the basis of contamination (they were told that external microbes in their laboratories had “contaminated” their human samples). I’ve never believed these claims to be accurate, but most of the general scientific community has accepted them.

In fact, the possible contamination of blood/tissue samples by laboratory microbes is an ongoing concern: Quake and team were careful to include a full section in their paper called “Novel Contigs (DNA reads) are Not Artifacts or Contaminants.” There, they discuss the results of several extra experiments aimed at proving exactly that (see the study’s Methods section).

Stanford researcher Dave Relman

Stanford researcher Dave Relman

Furthermore, over the past two decades, several research teams using molecular tools have already identified numerous microbes in the blood. For example, this 2001 study by Stanford researcher Dave Relman found many bacterial species in the blood of healthy subjects. Relman is one of my greatest role models, so I’ve taken his findings and related studies very seriously.

The Quake study also hammers home a point I’ve made in every speech/paper/book chapter since 2005. Imbalances of the gut microbiome, and external body microbiomes (skin, mouth etc) can contribute to chronic disease. However, microbes in the blood reach internal human tissue, and thus may play the greatest role in driving infectious disease processes. This is especially true since many of these blood/tissue microbes persist inside the cells of the immune system. Quake and team echo this sentiment in their paper stating, “Blood circulates throughout the human body and contains molecules drawn from virtually every body tissue.” Quake also told Stanford News the following about his team’s discovery:

“I’d say it’s not that baffling in some respects because the lens that people examined the microbial universe was one that was very biased…For one thing, researchers tend to go deep in the microbiome in only one part of the body, such as the gut or skin, at a time. Blood samples, in contrast, “go deeply everywhere at the same time.”

Last but not least, the Quake team derived their results by correctly separating the microbe DNA in their samples from the human DNA in their samples. This distinction can prove difficult because microbe and human DNA are often very similar in structure. 

Many other research teams studying the microbiome ARE NOT DOING THIS (CORRECTLY SEPARATING MICROBE/HUMAN DNA).  In conjunction with my colleague Trevor Marshall I have warned about this problem in several peer reviewed papers. For example, Marshall and I state the following about correctly identifying microbe DNA in this Current Opinions in Rheumatology paper:

“What are we actually measuring? Genetic science has not yet noticed the elephant in the room – the microbial DNA and RNA that the human microbiome exudes from infected cells. This contaminates the samples of “human DNA” being analyzed.”

Well…Quake  and team noticed the elephant in the room. And doing so made a dramatic difference in the results they obtained! I am extremely excited to see how their new findings impact microbiome research in the years to come.

New Stanford University data clarifies immune dysfunction/infection in cancer, ME/CFS, MS

September 15th, 2017 by Amy Proal

Mark Davis and his lab at Stanford University are on fire! They recently released fascinating data (some unpublished) on patients with cancer, Lyme disease, MS and ME/CFS. Davis discussed this data at a recent Open Medicine Foundation meeting. The talk was recorded and I HIGHLY encourage you to watch it!

New Davis Lab Findings:

Davis starts by confirming that ME/CFS is characterized by high levels of systemic inflammation. In fact, in concert with Dr. Jose Montoya at Stanford, Davis detected elevated cytokines (inflammatory molecules) in the blood of patients with ME/CFS. First, this cytokine activation distinguished the ME/CFS patients from healthy controls: does anyone still want to argue that the ME/CFS is psychosomatic!? (please tell me no). Second, patients with more severe cases of ME/CFS demonstrated greater cytokine activation; indicating that ME/CFS disease progression is characterized by increased immune dysfunction over time. 

In another series of experiments, Davis looked at T cells responses in ME/CFS and related inflammatory conditions. T cells are part of the adaptive immune response: the branch of the immune system that creates antibodies in response to specific microbes or pathogens. Davis used a novel assay developed at Stanford to obtain T cell sequences from the tissues/blood of patients with colon cancer, MS, Lyme disease, and ME/CFS.

In all four diseases, T cells were activated in a manner not observed in healthy control subjects. To be specific, the team observed massive clonal expansion of the T cells – both in tumor tissue and in the blood of patients with MS, ME/CFS, and Lyme disease.

T cell expansion in healthy subjects as compared to patients with Lyme disease, MS, and ME/CFS

T cell expansion in healthy subjects as compared to patients with Lyme disease, ME/CFS and MS. Unpublished data by Mark Davis Lab, Stanford University.

What does this mean? In simple terms, T cell clonal expansion indicates that the T cells became increasingly activated against a “target.” This activation caused the cells to divide and proliferate. As Davis explains, this “target” could be a pathogen or dysregulated human tissue.

Davis leans towards the “target” being a pathogen, stating that antibodies driving T cell proliferation are likely formed “originally against some pathogen peptide.” In some cases, these “pathogen peptides” may cross react with similarly structured human peptides – causing the immune system to accidentally target human tissue. This is exactly in line with the new model of autoimmune/inflammatory disease I’ve described on this site.

Indeed, Davis’ next goal is to further study the activated T cells in his samples. He hopes to correlate the T cell activity with the presence of specific pathogens (and the antibodies created in response to their presence). This could lead to a better understanding of exact microbes involved in driving cancer, MS, ME/CFS etc.

CONSIDERATIONS: Davis’ data strongly suggests that in cancer, MS, Lyme disease, and ME/CFS the immune system is activated against an infectious threat. This threat could be one pathogen, or it could be many pathogens acting together (in a community).

I support the latter possibility: I suspect that T cells are activated in these conditions as part of a generalized response to microbiome dysbiosis or imbalance. However it is very possible that certain microbes in these communities play a larger role than others in driving disease processes (these microbes are often referred to as “keystone” pathogens.”)

Also, the same general pattern of T cell clonal expansion was observed in cancer, autoimmune disease, and infectious disease. This strongly supports what I have long advocated: different inflammatory conditions, commonly studied in isolation, may actually result from the same root causes. This overlap certainly explains the high levels of co-morbidity observed between patients with different diagnoses! If this is true we should be studying these illnesses TOGETHER, with an increased focus on multidisciplinary research.

Finally, the T cell activation Davis observed in patients with ME/CFS could serve as an excellent biomarker for the disease. In my opinion, we do not need to know the exact microbial species involved for the data to be useful. Nor does it matter that other related diseases demonstrate a similar pattern. For the sake of treatment, all we need to know is that patients with ME/CFS show different T cell activity than that of healthy subjects.

T cell expansion in colon carcinomas (tumors)

T cell expansion in colon carcinomas (tumors). Figure: Mark Davis Lab, Stanford University.

 

My new peer-reviewed paper: Microbes INTERACT to cause chronic inflammatory disease

September 10th, 2017 by Amy Proal

Hello readers!

The image above shows different species of microbes communicating inside communities called biofilms. In many instances this kind of signaling is able to drive inflammatory disease processes. For much more on this topic, please check out my latest peer-reviewed paper published in Discovery Medicine “Microbe-Microbe and Host-Microbe Interactions Drive Microbiome Dysbiosis and Inflammatory Processes.” Then come back here and ask me questions! Or give me feedback/constructive criticism! Thanks.

http://www.discoverymedicine.com/Amy-D-Proal/2017/01/microbe-microbe-and-host-microbe-interactions-drive-microbiome-dysbiosis-and-inflammatory-processes/

Abstract: An extensive microbiome comprised of bacteria, viruses, bacteriophages, and fungi is now understood to persist in nearly every human body site, including tissue and blood. The genomes of these microbes continually interact with the human genome in order to regulate host metabolism. Many components of this microbiome are capable of both commensal and pathogenic activity. They are additionally able to persist in both “acute” and chronic forms. Inflammatory conditions historically studied separately (autoimmune, neurological and malignant) are now repeatedly tied to a common trend: imbalance or dysbiosis of these microbial ecosystems. Population-based studies of the microbiome can shed light on this dysbiosis. However, it is the collective activity of the microbiome that drives inflammatory processes via complex microbe-microbe and host-microbe interactions. Many microbes survive as polymicrobial entities in order to evade the immune response. Pathogens in these communities alter their gene expression in ways that promote community-wide virulence. Other microbes persist inside the cells of the immune system, where they directly interfere with host transcription, translation, and DNA repair mechanisms. The numerous proteins and metabolites expressed by these pathogens further dysregulate human gene expression in a manner that promotes imbalance and immunosuppression. Molecular mimicry, or homology between host and microbial proteins, complicates the nature of this interference. When taken together, these microbe-microbe and host-microbe interactions are capable of driving the large-scale failure of human metabolism characteristic of many different inflammatory conditions.

Probably the most important sentence in the paper:

  1. In effect, under conditions of increasing imbalance and inflammation, the whole community appeared to act together as a pathogen.

TOP IMAGE: Property of the Center For Biofilm Engineering. They are an awesome organization, check them out:

http://www.biofilm.montana.edu/

The power of patient reported feedback: Part 1

January 29th, 2016 by Amy Proal

Last year I was invited to give a speech at a scientific conference that examined the role of the microbiome in autoimmune disease – concepts I describe in this Current Opinion in Rheumatology journal article. Our research team had also developed an immunostimulatory treatment for autoimmune disease based off concepts in the paper. Doctors in at least a dozen countries were using the treatment with their patients, often with success.

I didn’t discuss this treatment in my speech, but made the following statement during the last twenty seconds of the talk: “We have developed an immunostimulatory treatment that patients are using in conjunction with their doctors. If you’re interested in any of our case histories find me later.” Continue reading

Of mice and not men: can complex human inflammatory disease be studied in mice?

January 13th, 2016 by Amy Proal

Much of my junior year at Georgetown University was spent in an animal research facility. Along with my undergraduate thesis mentor and several fellow students, I studied the impact of a high-fat (ketogenic) diet in Sprague-Dawley rats. We had read reports in which human children with epilepsy who were fed this ketogenic diet experienced fewer seizures. Now we were attempting to ascertain whether rats eating a ketogenic chow would experience seizures at a different rate than those eating a chow rich in carbohydrates.

I graduated before the research project was complete, but later learned that some differences in seizure incidence between the two groups of rats were identified. Yet the team was never able to figure out the root cause underlying these differences.

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Mothers and microbes, Part 2: The placental, breast milk, and breast tissue microbiomes

December 27th, 2015 by Amy Proal

While the vaginal microbiome has received a great deal of attention from the research community, recent research also indicates that microbes persist in the womb, where they come in contact with a fetus before it is born. Studies demonstrating the presence of microbes in the amniotic fluid have now been bolstered by the discovery of a placental microbiome. Dysregulation of this placental microbiome by pathogens has also been associated with preterm birth and low infant birth weight.

Consistent with the presence of a placental microbiome, naturally-born infants often harbor microbes not commonly found in the vagina. For example, while vaginal communities are often composed of up to 80 percent Lactobacillus, the microbiomes of newborn infants contain high levels of other taxa, such as Actinobacteria, Proteobacteria, and Bacteroides. Infants appear to have acquired these microbes in the womb, and not during the birthing process. Continue reading

Mothers and microbes, Part 1: The vaginal microbiome in health and disease

December 20th, 2015 by Amy Proal

“Like mother, like daughter.” The phrase is often invoked to describe how children resemble their parents. While we know that human genes are passed from generation to generation, an expanding body of research now shows that many microbiome populations are also inherited. The microbes a child inherits are acquired from both parents and even siblings. However, microbial populations inherited from the mother have a particularly strong impact on a child’s development and health.

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Stanford researchers: The immune response is shaped by microbes rather than human genes

December 11th, 2015 by Amy Proal

Two different people are riding the subway. A third person coughs on these individuals over the course of their trip. One person gets the flu, but the other doesn’t. Somewhere nearby, two more people accidentally eat a piece of meat that wasn’t correctly refrigerated. One develops food poisoning, but the other remains healthy. What factors contribute to these different outcomes?

The key factor is the immune response. Immune cells such as macrophages and granulocytes kill invading microbes. Other immune proteins called cytokines and chemokines aid cellular communication and stimulate the movement of cells towards sites of inflammation. Immune growth factors also form part of the immune response by stimulating the proliferation of specific tissues. If profiles of these immune parameters differ between individuals, then their ability to respond to pathogens will also vary. Continue reading

Industry ties deeply influence guidelines for calcium/vitamin D intake

December 3rd, 2015 by Amy Proal

Are you taking vitamin D and calcium for bone health? If so, a new analysis makes it clear that the supplement guidelines you follow are often shaped by money rather than science. In July, Andrew Grey and Mark Bolland (University of Auckland, New Zealand) published an article in the British Medical Journal. Their article, “Web of industry-advocacy, and academia in the management of osteoporosis,” powerfully illustrates how industry ties and financial gain have tarnished the legitimacy of worldwide vitamin D and calcium supplementation guidelines.

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Disease-induced solitary confinement and the gut microbiome

November 25th, 2015 by Amy Proal

What happens when a person dies alone, with no relatives or friends to provide information or help? Why do people die alone in some of the most populated areas of the world? A recent article in the New York Times delves into the topic by examining the life of George Bell, a man found dead in his Jackson Heights apartment in Queens, New York. I live just ten minutes away. His body was found after it had rotted to the point where neighbors noticed a smell. He knew only one person during the last decade of his life, a man he sometimes met at a bar. Yet with no family or friends in his life, it took over three months to identify his corpse.

I think that many readers may have started reading the article assuming that George Bell would, at the very least, have done some bad things to others. After all, before his death at 72, he spent nearly a decade living completely alone, with negligible social contact. How could that happen to an average, generally nice individual?

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