Could the Microbiome be the Key to Ending Chemotherapy-Induced Pain?

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Most of us have experienced the odd sensation of “pins and needles” in our hands or feet. While annoying and painful, the sensation usually goes away quickly.

But for many people with peripheral neuropathy, a disorder involving increased sensitivity of nerves outside of the brain and spinal cord, this experience may linger for months to years.

“It’s a horrible condition,” said Shiqian Shen, MD, clinical investigator in the Massachusetts General Hospital Center for Translational Pain Research and director of the Mass General TelePain Program. “You literally want to shake off your leg, but you can’t.”

Unfortunately, a third of cancer patients who receive chemotherapy encounter this as a side effect, a condition known as chemotherapy-induced peripheral neuropathy (CIPN). This neuropathy is a result of nerve damage or impairment of the nervous system and often is chronic. If the pain is severe enough, chemotherapy dosages must be lowered, which causes the treatment to be less effective.

With the survival rates for many cancers increasing due to the improved understanding of genetic mutations, targeted therapies and immunotherapy, CIPN has become a major challenge and can hurt a survivor’s quality of life.

Dr. Shen and Jianren Mao, MD, PhD, chief of the Mass General Pain Management Center and vice chair for research in the Department of Anesthesia, Critical Care and Pain Medicine, are leading a research team in exploring why patients undergoing chemotherapy develop CIPN.

There is strong evidence that the gut, which carries about 10 trillion bacteria, has a major impact on the central nervous system. Previous research in the field has also shown that gut microbiota plays a critical role in the tumor-killing effect of many chemotherapeutics drugs. In a recent study published in Nature Neuroscience, the researchers questioned whether an immune response that results from interactions between chemotherapy drugs and the bacteria in the microbiome also plays a role in developing CIPN.

The researchers exposed two sets of mice, one with a normal microbiome and one that had their microbiome essentially eliminated through antibiotic treatments or genetic engineering, to oxaliplatin—a chemotherapy drug used to treat colon or rectal cancer and that is known to cause CIPN. The normal mice manifested symptoms of CIPN while those without a microbiome did not. Therefore, a microbiome is necessary for CIPN symptoms to manifest.

Next, the team dug into why the microbiome influences the onset of CIPN.

The researchers determined that the mice who experienced CIPN had higher levels of two proteins involved in inflammation (IL-6 and TNFalpha) in the dorsal root ganglia (DRG). This inflammatory response in the DRG leads to an increase in neuron sensitivity, which is what causes the neuropathy pain and tingling in a person’s extremities.

The team found further evidence that suggests a reaction between the chemotherapy agent and bacteria in the microbiome, releases lipopolysaccharides (LPS), a molecule found in bacteria on the gut lining, into the bloodstream. LPS then appears to cause a chain reaction that increases the levels of the two inflammatory proteins in the DRG.

“We found there’s a concurrent response—one initiated by the chemotherapy agent, and one by the inflammatory response,” said Shen. “They work hand in hand to promote the pain.”

However, there is a dilemma to sort out. Previous research has found that chemotherapy treatments such as oxaliplatin and cyclophosphamide are dependent on the gut microbiome. Meaning chemotherapy does not work well without help from a normal microbiome, but having it runs the risk of developing CIPN.

“Our research has revealed that you cannot get rid of the gut microbiome entirely to prevent side-effects because your therapeutic effect is also linked to the same presence,” says Shen.

The researchers are conducting follow-up studies to see if the same results are found in humans, and to see whether the same phenomenon exists in other type of neuropathic pain.

Potential in the Clinic

Since eliminating a cancer patient’s microbiome will essentially render chemotherapy treatment ineffective, more research will need to be done to see if investigators can determine if and how an individual’s microbiome composition affects their likelihood of developing CIPN. If they can identify favorable bacteria profiles, clinicians may be able to reduce the risk of developing CIPN by prescribing probiotics or fecal transplants in advance of starting chemotherapy. On the flipside, knowing the optimal microbiome profile that reduces risk of CIPN for every chemotherapy agent may help oncologists select the ideal chemotherapy drug for each patient.

Faherty Hopes to Stop Shigella from Wreaking Havoc in the Digestive System

A research team at Massachusetts General Hospital is hoping to create new treatments for shigellosis, a potentially fatal digestive disorder, by factoring in genetic changes that occur in Shigella bacteria during the journey through the human digestive system.

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From a human perspective, there is a lot to dislike about Shigella.

The more you learn about these infection-causing microbes, the easier it is to picture them as the dastardly, mustache-twirling villains of the microbial world.

Let’s take a quick look at Shigella’s rap sheet.

Shigella is a group of pathogenic bacteria that has evolved over millions of years specifically to infect humans. It is primarily transmitted through contaminated food or water, but it can also be transmitted through surface contact.

A shigellosis infection can cause a bad case of diarrhea, fever and stomach cramps that lasts from five to seven days. Shigella causes about 500,000 cases of diarrhea in the United States annually. Fortunately, most cases resolve without causing lasting damage.

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Christina Faherty, PhD

Worldwide, Shigella is a much bigger problem. It is estimated to cause up to 165 million cases of disease and 600,000 deaths each year, primarily in children under the age of five in developing nations. To add to the challenge, there are new, antibiotic-resistant strains of Shigella emerging that are much more difficult to treat.

Christina Faherty, PhD, a researcher at the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital for Children, is developing two new strategies for treating Shigellathat could finally overcome 50 years of failed treatment efforts. Continue reading “Faherty Hopes to Stop Shigella from Wreaking Havoc in the Digestive System”

Guess what? You’re Only 10% Human

From the University of California research blog:

Is space really the final frontier or are the greatest mysteries closer to home? Researchers estimate that there are more undiscovered microbes on Earth than stars in the sky.
The microbiome is fast becoming an exciting new frontier in human health. That’s because our bodies are made up of a staggering amount of bacteria, fungi, viruses and other microbes that make you, well, you. In fact,
you’re only 10 percent human; the rest is this microbial system that lives on your skin, in your mouth, nose, throat, lungs, guts….you get the picture.

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From potentially shaping our personalities to fighting obesity, our microbiomes play a much stronger role in our overall health than we once thought. And it varies from person to person based on diet, health history, ancestry, geographic location and climate. Even those you live with, including your pets, can influence your microbiome.

But there’s a lot that we don’t know about these microbes, which form the pervasive (yet practically invisible) infrastructure of life on Earth.

UC San Diego has created an interdisciplinary initiative on microbial sciences in order to understand microbiomes in a detailed way and to find methods of manipulating them for the benefit of human and environmental health.

“Getting an understanding of what microbial communities there are, how those microbial communities change naturally and how we can specifically alter them in order to benefit either the health of our own bodies or the health our planet holds tremendous potential for revolutionizing a wide range of fields,” biologist Rob Knight explains.

Studies Reveal How General Anesthesia’s Brain effects Differ in Older Adults and in Children

“We know even less about how anesthetic drugs influence brain activity in children, and the current standard of care for assessing the brain state of children under anesthesia calls only for monitoring vital signs like heart rate and blood pressure. This lack of knowledge is
especially troubling, given recent studies suggesting an association between early childhood surgery requiring general anesthesia and later cognitive problems.”


Patrick Purdon, PhD

Mass General Department of Anesthesia, Critical Care and Pain Medicine

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Quote from Dr. Szostak, 2009 Nobel Laureate

It’s important to recognize that despite all the problems we have, this is still a great time to be doing science. There are unbelievable advances being made, and incredible new technologies that allow us to make discoveries that we couldn’t even dream about 20 years ago. So it may be harder in some respects, but it is still a fantastic time to be involved in research.

Jack Szostak, PhD
2009 Nobel Laureate
Department of Molecular Biology
Massachusetts General Hospital

Newly Identified Gene Variants that Modify the Onset of Huntington’s Disease Could Lead to New Therapeutics

Researchers from the Mass General Research Institute have used an innovative approach to pinpoint two locations on the human genome that influence the rate at which Huntington’s disease (HD), a debilitating neurodegenerative disorder, develops in those carrying the HD gene defect.

By studying the samples from more than 4,000 HD patients, researchers were able to identify two genetic variants in areas distinct from the mutated gene that causes the disease.

These variants were more common in HD patients who developed symptoms at atypical times—either earlier or later than expected.

The findings imply that these genetic differences can alter the timing of the onset of the disease, which in turn could help devise ways to start treatment or preventative measures before symptoms appear.

James Gusella, PhD, director of the Center for Human Genetic Research at Mass General, is corresponding author of the report.

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