It's All in Your Gut

A study out of Cornell University made the news recently when Maureen Hanson's team found distinct alterations in the gut flora of patients with ME/CFS. The headlines trumpeted the "first" biological marker for the disease in the microbiome.

Those of us who have kept track of the research know that this is not a "first." De Meirleir, Maes, Lemle, as well as Dunstan, and Butt in Australia have all published papers documenting alterations in gut flora in patients with ME/CFS (not to mention Lipkin and Hornig's huge Microbe Discovery Project). Those alterations laid the groundwork for Butt's successful treatment of ME with fecal transplants in the late 90s.

The question that needs to be asked is whether these alterations are the cause or the result of the disease. Every disease produces alterations in gut flora - diabetes, Crohn's, heart disease, HIV, and cancer are among them, as well as all infections. (For a good paper on this topic go HERE.) The gut, which is the seat of your immune system, responds instantly to pathogens. It even changes in accord with what you are eating withing a few hours.

But rather than chicken or egg, these gut changes could be chicken and egg. For example, the pathogen that causes ME results in changes to the microbiome, then subsequent chronicity due to an altered immune system results in a perpetuation of microbiome changes. These, in turn, lead to more chronicity as commensal bacteria enter the bloodstream.

It's a good model, even if it doesn't identify the original culprit that started this chain of events.

You can read the full study HERE.

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Key to chronic fatigue syndrome is in your gut, not head

By Melissa Osgood, Cornell University

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn't alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

"Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn't normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease," said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper's senior author. "Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin."

"In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease," said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn's disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

Journal Reference: Ludovic Giloteaux, Julia K. Goodrich, William A. Walters, Susan M. Levine, Ruth E. Ley, Maureen R. Hanson. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome, 2016; 4 (1) DOI: 10.1186/s40168-016-0171-4

Guts, Bugs and "Slow Sepsis" in ME/CFS

Last fall, Invest in ME announced an update in its research into the microbiome of ME/CFS patients. The study is based on the hypothesis that exposure to gut microbes through increased intestinal permeability (aka "leaky gut") initiates microbe-driven inflammatory reactions in ME/CFS. The researchers hope to detect increases in serum antibodies towards specific intestinal bacteria.

The goal of the study is "to determine if alterations in intestinal barrier function and/or microbiota firstly, exists in ME/CFS patients and secondly, whether there is an interaction between microbe-driven inflammatory responses and neuronal proteins."

As a hypothesis, this study has a firm foundation. 

Antibodies produced by the infiltration of gut bacteria into the bloodstream can initiate, among other things, a cascade of potentially lethal inflammatory responses. In 2014, researchers at the University of Chicago found that patients in the Intensive Care Unit had only limited kinds of gut flora left in their intestines after multiple rounds of antibiotics. Not surprisingly, these were flora that were pathogenic (Candida, a yeast, and antibiotic-resistant Staph). What was more, once the normal flora had been killed off, these pathogens became deadly. Three of the ICU patients died - not from injuries or from infections - but from pathogenic gut flora.

Slow Sepsis

Dr. David Bell proposed that patients with ME/CFS have what he called "slow sepsis." In his monograph, Cellular Hypoxia and Neuro-Immune Fatigue, he suggests that ME/CFS is a slow, chronic form of septic shock. The sequence of events in septic shock is: 1) a serious infection, 2) production of cytokines, 3) increased nitric oxide, and 4) interference with the production of cellular energy. In severe cases of septic shock, the loss of cellular energy is so profound that it can be fatal.

Dr. Bell suggests that a similar sequence takes place in ME/CFS, but more gradually. In ME/CFS there is: 1) an initiating infection or toxic exposure, which 2) leads to immune activation, increasing the production of cytokines, 3) the increase in cytokines leads to the production of increased nitric oxide (NO), 4) NO increases peroxynitrite and superoxide, which leads oxidative stress, and interferes with mitochondrial function, 5) the cell becomes hypoxic (oxygen-starved), and 6) vasculopathies, neuropathies, and autoimmune processes develop.

While Dr. Bell does not propose that this sequence of events can be initiated by leaky gut, there is absolutely no reason to assume that it can't. The destruction of the tight juncture between the cells of the intestinal lining has a host of causes. Any infection in the intestines (e.g. enteroviruses, parasites), drugs (e.g. NSAIDs. steroids), viral infections, radiation therapy for cancer, nutrient deficiencies (e.g. zinc), inflammatory conditions, toxins, and antibiotics can lead to the production of excess NO (oxidative stress), compromising the integrity of the gut lining (Wu et al, 2002). Given the high level of oxidative stress found in people ME/CFS it is likely that the majority of patients will develop leaky gut.

Evidence of gut dysbiosis in ME/CFS

The involvement of intestinal flora in the perpetuation of ME/CFS is one that is backed by solid research.

Dr. Kenny De Meirleir found that gut dysbiosis correlates with cognitive dysfunction in people with ME/CFS. He discovered that in people with ME/CFS there are high levels of bacteria not normally found in gut flora, notably gram positive lactic acid bacteria. In addition, Dr. De Meirleir's team found active parvovirus B19 infections in the GI tracts of 40% of CFS/ME patients, as well as EBV and herpesvirus 6 in lesser amounts. Dr. John Chia has found a chronic form of enteroviral infection in the stomachs of ME/CFS patients, which he believes could lead to a variety of symptoms without causing direct organ damage.

In 2012, Michael Maes et al. published research indicating that translocation of bacteria due to increased intestinal permeability correlated with systemic inflammatory responses in ME/CFS patients. The researchers concluded that "translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients."

With the mounting evidence for GI infection, comprised gut lining, and translocation of gram-negative bacteria in patients with ME/CFS, it is imperative that research leading to treatment - such as the research conducted by Invest in ME - be supported.

Remedies for leaky gut

While research that helps explain the mechanisms of ME/CFS is important, people who have leaky gut and "slow sepsis" need to find ways of fixing the problem without delay. Poisoning, however slow, has immediate immune system consequences that cannot be ignored.

Although there is no drug to cure leaky gut, there are supplements that have been proven to help heal the mucosa of the gut lining;

Zinc carnosine: A 2007 study by A Mahmood et al, found that zinc carnosine stimulates gut repair processes. (You can read the full study here.)

Fiber: There is considerable debate about whether insoluble fiber (cellulose) is better for restoring the gut lining than soluble fiber. Research supports the idea that insoluble fiber is better for intestinal health, and that large amounts of soluble fiber may actually impair gut health (Shiao and Chang, 1986). In any case, diets that do not contain fiber increase intestinal permeability (G Spaeth, 1990).

Essential fatty acids (EFAs): Essential fatty acids, such as fish oil, flaxseed oil and borage oil, can help repair injury to the lining of the gut and restore gut mucosa. EFAs also limit the harmful effects created by the translocation of endotoxins (gram-negative bacteria found in the large intestine) (Vanderhoof et al. 1991).

Antioxidants: In 2008, M. Maes and J.C. Leunis found that leaky gut in patients with ME/CFS could be corrected with natural anti-inflammatories and antioxidants. Some of the antioxidants that have been reported as helpful for leaky gut are: NAC, Glutathione, and Gamma oryzanol.

Butyrates: Butyrates (also called butyric acid) are short-chain fatty acids produced in the colon by the fermentation of carbohydates through the action of intestinal flora. Butyrates enable your gut to function. Without them, the cells that line your intestines die by autophagy (they eat themselves). Butryrates are found naturally in butter. They can also be taken as a supplement (ButyrEn).

 

Further Reading:

Leaky Gut Syndromes: Breaking The Vicious Cycle by Leo Galland.

Also see:

What Is Hiding in Your Gut? ME/CFS, Leaky Gut, Enteroviruses, and the Potential for Treatment

Do Gut Bacteria Rule Our Minds? Cravings, Weight Gain, and Bugs in ME/CFS

Feed me, Seymour. Feed me!

Every once in a while, I come across an article that inspires an "Aha!" moment. The article below is one of them.

Researchers from UC San Francisco have discovered that not only do those trillions of bacteria that live in our guts influence our mood, they can choose what we eat.

Food cravings, especially for sugar, are common in ME/CFS. Formerly, this was chalked up to an overgrowth of Candida, a yeast that thrives on sugar. Dr. Carol Jessop found that after putting her CFS patients on anti-yeast medication, as well as an anti-Candida diet, they made considerable improvement. John Rutter, a well-known composer and ME patient, reported that an anti-Candida regimen was the turning point in his illness.

But, what if the picture is more complicated? What if gut bacteria also play a role in the symptomology of ME/CFS?

Nearly 20 years ago, Lauren Gellman (co-author of Chronic Fatigue Syndrome: A Treatment Guide), and I conducted a survey. Among the questions we asked ME/CFS patients was whether they had recently been treated for infections. Every single one of the respondents answered that they had taken long-term antibiotics prior to contracting ME/CFS.

Antibiotics have saved millions of lives, but, as Oakland, CA gastroentrologist and fecal transplant proponent Dr. Neil Stollman points out, "antibiotics are a scourge." By altering the microbiome with antibiotics, the body's immune system is compromised. And with the proliferation of unhealthy bacteria in our guts, we are prone to inflammation, which can lead to autoimmune disease and colitis. We are also prone to an overgrowth of bacteria in the small intestines known as SIBO, or small intestine bacterial overgrowth. 

Dr. Cheney has proposed that the majority of patients with ME/CFS suffer from SIBO. The symptoms of SIBO include every GI symptom you can think of -  including IBS - as well as exhaustion, insomnia, night sweats, brain fog, muscle weakness, flu-like symptoms, muscle aches, and a horrible night-time malaise. Among gastroenterologists, the cause of SIBO is recognized as antibiotics, which, like the hair of the dog that bit you, are also used to treat SIBO (Xifaxan is preferred).

The test for SIBO is the lactulose breath test. After refraining from eating sugar and milk products, both of which feed the overgrowth, a small amount of lactulose (a synthetic sugar which acts as a mild laxative) is administered. The gases that are produced - methane and hydrogen - are then measured. In simple terms, the more gas produced, the more severe the infection. (You can order this test without a prescription, and administer it yourself.)

So, the question is, what do you crave? Do you crave ice cream, sweets? And, is it you craving those foods, or is it the overgrowth in your small intestine? Nearly all physicians who treat ME/CFS recommend the elimination of sweets. Perhaps the bugs in your gut provide an explanation for why sweets make patients feel worse - and why we crave them.

Even if the elimination of sweets and milk products from your diet doesn't cure you of ME/CFS, there are definitely a few trillion good reasons to refrain from eating them.

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Do gut bacteria rule our minds? In an ecosystem within us, microbes evolved to sway food choices

By Jeffrey Norris 

Press Release: UCSF, August 15, 2014. It sounds like science fiction, but it seems that bacteria within us -- which outnumber our own cells about 100-fold -- may very well be affecting both our cravings and moods to get us to eat what they want, and often are driving us toward obesity.

In an article published this week in the journal BioEssays, researchers from UC San Francisco, Arizona State University and University of New Mexico concluded from a review of the recent scientific literature that microbes influence human eating behavior and dietary choices to favor consumption of the particular nutrients they grow best on, rather than simply passively living off whatever nutrients we choose to send their way.

Bacterial species vary in the nutrients they need. Some prefer fat, and others sugar, for instance. But they not only vie with each other for food and to retain a niche within their ecosystem -- our digestive tracts -- they also often have different aims than we do when it comes to our own actions, according to senior author Athena Aktipis, PhD, co-founder of the Center for Evolution and Cancer with the Helen Diller Family Comprehensive Cancer Center at UCSF.

While it is unclear exactly how this occurs, the authors believe this diverse community of microbes, collectively known as the gut microbiome, may influence our decisions by releasing signaling molecules into our gut. Because the gut is linked to the immune system, the endocrine system and the nervous system, those signals could influence our physiologic and behavioral responses.

"Bacteria within the gut are manipulative," said Carlo Maley, PhD, director of the UCSF Center for Evolution and Cancer and corresponding author on the paper." "There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals, and others not."

Fortunately, it's a two-way street. We can influence the compatibility of these microscopic, single-celled houseguests by deliberating altering what we ingest, Maley said, with measurable changes in the microbiome within 24 hours of diet change.

"Our diets have a huge impact on microbial populations in the gut," Maley said. "It's a whole ecosystem, and it's evolving on the time scale of minutes."

There are even specialized bacteria that digest seaweed, found in humans in Japan, where seaweed is popular in the diet.

Research suggests that gut bacteria may be affecting our eating decisions in part by acting through the vagus nerve, which connects 100 million nerve cells from the digestive tract to the base of the brain.

"Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad, and releasing chemical rewards to make us feel good," said Aktipis, who is currently in the Arizona State University Department of Psychology.

In mice, certain strains of bacteria increase anxious behavior. In humans, one clinical trial found that drinking a probiotic containing Lactobacillus casei improved mood in those who were feeling the lowest.

Maley, Aktipis and first author Joe Alcock, MD, from the Department of Emergency Medicine at the University of New Mexico, proposed further research to test the sway microbes hold over us. For example, would transplantation into the gut of the bacteria requiring a nutrient from seaweed lead the human host to eat more seaweed?

The speed with which the microbiome can change may be encouraging to those who seek to improve health by altering microbial populations. This may be accomplished through food and supplement choices, by ingesting specific bacterial species in the form of probiotics, or by killing targeted species with antibiotics. Optimizing the balance of power among bacterial species in our gut might allow us to lead less obese and healthier lives, according to the authors.

"Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating," the authors wrote.

The authors met and first discussed the ideas in the BioEssays paper at a summer school conference on evolutionary medicine two years ago. Aktipis, who is an evolutionary biologist and a psychologist, was drawn to the opportunity to investigate the complex interaction of the different fitness interests of microbes and their hosts and how those play out in our daily lives. Maley, a computer scientist and evolutionary biologist, had established a career studying how tumor cells arise from normal cells and evolve over time through natural selection within the body as cancer progresses.

In fact, the evolution of tumors and of bacterial communities are linked, points out Aktipis, who said some of the bacteria that normally live within us cause stomach cancer and perhaps other cancers.

"Targeting the microbiome could open up possibilities for preventing a variety of disease from obesity and diabetes to cancers of the gastro-intestinal tract. We are only beginning to scratch the surface of the importance of the microbiome for human health," she said.

The co-authors' BioEssays study was funded by the National Institutes of Health, the American Cancer Society, the Bonnie D. Addario Lung Cancer Foundation and the Institute for Advanced Study, in Berlin.

Journal Reference: Joe Alcock, Carlo C. Maley, C. Athena Aktipis. Is eating behavior manipulated by the gastrointestinalmicrobiota? Evolutionary pressures and potential mechanisms. BioEssays, 2014; DOI: 10.1002/bies.201400071

Microbe Discovery Project Launches Crowdfunding for ME/CFS Microbiome Study

 (The following message comes from the Microbe Discovery Project. To find out more, go HERE.)
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"I think that the microbiome is going to be where the action is [in ME/CFS] ... I am really eager to pursue that work." ~Dr. W. Ian Lipkin

WE CAN DO IT!

In the past year our ME/CFS community has shown that it can rapidly raise hundreds of thousands of dollars for specific projects. After patients and supporters in Norway – with a population sixty times smaller than that of the US – raised $430,000 in 90 days for a clinical trial of Rituximab, a slew of US campaigns began crowdfunding and reached or exceeded their targets at astonishing speeds: $213,000 in 31 days for the documentary film Canary in a Coal Mine; $18,000 in 35 days for the documentary The Blue Ribbon; and $150,000 in 75 days for an Open Medicine Foundation study of Vitamin B12.

So, we can do this and we can do it quickly. Please donate now, from any country, so we can all benefit from the results of the study; Dr. Lipkin’s prestige is such that his findings will have international impact and help all of us. Tell your friends, your family and your local community to donate and spread the word.

Together, we can do this!

[Watch Dr. Lipkin describe this project here: https://www.youtube.com/watch?v=z_v3bfbBupA]

ME/CFS: a devastating neuro-immune disease as disabling as multiple sclerosis, affecting one million Americans and 17 million people worldwide.

The study: a cutting-edge hunt for the causes of ME/CFS in the gut “microbiome” – the bacteria, viruses and fungi in the digestive system – led by “the world’s most celebrated virus hunter”, Dr W. Ian Lipkin at the world’s largest and most advanced center for microbe discovery and diagnosis at Columbia University in New York.

The payoff: a world-class study with the potential to swiftly lead to treatments using drugs, probiotics or exclusion diets.

Our challenge: to raise $1.27 million (£760,000; €910,000) to fund the project and do it fast! The scientists are ready to go and can complete and publish the study within 12 months. The sooner we fund it, the sooner it starts.

Donate HERE.