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Category: microbes

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Treating tumors with bacteria is very exciting and new.From Medical Express:

Injected bacteria shrink tumors in rats, dogs and humans

A modified version of the Clostridium novyi (C. noyvi-NT) bacterium can produce a strong and precisely targeted anti-tumor response in rats, dogs and now humans, according to a new report from Johns Hopkins Kimmel Cancer Center researchers.

In its natural form, C. novyi is found in the soil and, in certain cases, can cause tissue-damaging infection in cattle, sheep and humans. The microbe thrives only in oxygen-poor environments, which makes it a targeted means of destroying oxygen-starved cells in tumors that are difficult to treat with chemotherapy and radiation. The Johns Hopkins team removed one of the bacteria's toxin-producing genes to make it safer for therapeutic use.

For the study, the researchers tested direct-tumor injection of the C. noyvi-NT spores in 16 pet dogs that were being treated for naturally occurring tumors. Six of the dogs had an anti-tumor response 21 days after their first treatment. Three of the six showed complete eradication of their tumors, and the length of the longest diameter of the tumor shrunk by at least 30 percent in the three other dogs.

In a Phase I clinical trial of C. noyvi-NT spores conducted at MD Anderson Cancer Center, a patient with an advanced soft tissue tumor in the abdomen received the spore injection directly into a metastatic tumor in her arm. The treatment significantly reduced the tumor in and around the bone. "She had a very vigorous inflammatory response and abscess formation," according to Nicholas Roberts, Vet.M.B., Ph.D. "But at the moment, we haven't treated enough people to be sure if the spectrum of responses that we see in dogs will truly recapitulate what we see in people."

"One advantage of using bacteria to treat cancer is that you can modify these bacteria relatively easily, to equip them with other therapeutic agents, or make them less toxic as we have done here, " said Shibin Zhou, M.D., Ph.D., associate professor of oncology at the Cancer Center.  He and colleagues at Johns Hopkins began exploring C. novyi's cancer-fighting potential more than a decade ago after studying hundred-year old accounts of an early immunotherapy called Coley toxins, which grew out of the observation that some cancer patients who contracted serious bacterial infections showed cancer remission.

The researchers focused on soft tissue tumors because "these tumors are often locally advanced, and they have spread into normal tissue," said Roberts, a Ludwig Center and Department of Pathology researcher. The bacteria cannot germinate in normal tissues and will only attack the oxygen-starved or hypoxic cells in the tumor and spare healthy tissue around the cancer.

Verena Staedtke, M.D., Ph.D., a Johns Hopkins neuro-oncology fellow, first tested the spore injection in rats with implanted brain tumors called gliomas. Microscopic evaluation of the tumors showed that the treatment killed tumor cells but spared healthy cells just a few micrometers away. The treatment also prolonged the rats' survival, with treated rats surviving an average of 33 days after the tumor was implanted, compared with an average of 18 days in rats that did not receive the C. noyvi-NT spore injection.

Zhou said that study of the C. noyvi-NT spore injection in humans is ongoing, but the final results of their treatment are not yet available. "We expect that some patients will have a stronger response than others, but that's true of other therapies as well. Now, we want to know how well the patients can tolerate this kind of therapy."

It may be possible to combine traditional treatments like chemotherapy with the C. noyvi-NT therapy, said Zhou, who added that the researchers have already studied these combinations in mice. "Another good thing about using bacteria as a therapeutic agent is that once they're infecting the tumor, they can induce a strong immune response against tumor cells themselves," Zhou said.

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I've posted on whether probiotics can be used to treat mental disorders (see Probiotics and Psychobiotics- Part 1 and 2). But this article poses the interesting reverse question of whether the microbes are engaging in "microbial manipulations"? From NY Times:

Our Microbiome May Be Looking Out for Itself

Your body is home to about 100 trillion bacteria and other microbes, collectively known as your microbiome. We’ve come to appreciate how beneficial our microbes are — breaking down our food, fighting off infections and nurturing our immune system. 

But in the journal Bioessays, a team of scientists has raised a creepier possibility. Perhaps our menagerie of germs is also influencing our behavior in order to advance its own evolutionary success — giving us cravings for certain foods, for example. Maybe the microbiome is our puppet master.

The idea that a simple organism could control a complex animal may sound like science fiction. In fact, there are many well-documented examples of parasites controlling their hosts. How parasites control their hosts remains mysterious. But it looks as if they release molecules that directly or indirectly can influence their brains.

Our microbiome has the biochemical potential to do the same thing. In our guts, bacteria make some of the same chemicals that our neurons use to communicate with one another, such as dopamine and serotonin. And the microbes can deliver these neurological molecules to the dense web of nerve endings that line the gastrointestinal tract.

A number of recent studies have shown that gut bacteria can use these signals to alter the biochemistry of the brain.Compared with ordinary mice, those raised free of germs behave differently in a number of ways. They are more anxious, for example, and have impaired memory.Adding certain species of bacteria to a normal mouse’s microbiome can reveal other ways in which they can influence behavior. Some bacteria lower stress levels in the mouse. When scientists sever the nerve relaying signals from the gut to the brain, this stress-reducing effect disappears.

Some experiments suggest that bacteria also can influence the way their hosts eat. Germ-free mice develop more receptors for sweet flavors in their intestines, for example. They also prefer to drink sweeter drinks than normal mice do. Scientists have also found that bacteria can alter levels of hormones that govern appetite in mice.

Different species of microbes thrive on different kinds of food. If they can prompt us to eat more of the food they depend on, they can multiply. Microbial manipulations might fill in some of the puzzling holes in our understandings about food cravings, Dr. Maley said. Scientists have tried to explain food cravings as the body’s way to build up a supply of nutrients after deprivation, or as addictions, much like those for drugs like tobacco and cocaine. But both explanations fall short.

Take chocolate: Many people crave it fiercely, but it isn’t an essential nutrient. And chocolate doesn’t drive people to increase their dose to get the same high. Perhaps, he suggests, the certain kinds of bacteria that thrive on chocolate are coaxing us to feed them.

John F. Cryan, a neuroscientist at University College Cork in Ireland who was not involved in the new study, suggested that microbes might also manipulate us in ways that benefited both them and us. “It’s probably not a simple parasitic scenario,” he said.

Research by Dr. Cryan and others suggests that a healthy microbiome helps mammals develop socially. Germ-free mice, for example, tend to avoid contact with other mice. That social bonding is good for the mammals. But it may also be good for the bacteria. “When mammals are in social groups, they’re more likely to pass on microbes from one to the other,” Dr. Cryan said.

If microbes do in fact manipulate us, Dr. Knight said, we might be able to manipulate them for our own benefit — for example, by eating yogurt laced with bacteria that would make use crave healthy foods. The most important thing to do now, Dr. Knight and other scientists said, was to run experiments to see if microbes really are manipulating us.

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The following is from a presentation from The American Association of Diabetes Educators Annual Meeting August 6-9, 2014 by M.Jardin and C.Kafity. But the coffee and tea statement is different from what I've read elsewhere, specifically that coffee is beneficial, is a source of soluble fiber, and may keep pathogenic bacteria in check. From Endocrinology Today:

Plant-based diet helps grow healthy microbiota, halt diabetes disease process

With research mounting on the onslaught the body’s microbiota take from human eating patterns and the environment, making choices to maintain inner ecosystem health is essential, according to presenters at the American Association of Diabetes Educators Annual Meeting. Choosing a plant-based diet is one way people can increase the diversity of bacteria in their biome, reduce inflammation and begin to reverse the diseases processes involved in obesity and diabetes — often in just a few days.

“We know obesity and diabetes have increased tremendously in the last 20 years and we know that our genes haven’t changed, so that can’t account for the change,” Meghan Jardine, MS, MBA, RD, LD, CDE, RDN, of Parkland Health and Hospital System, said during a presentation. “Many scientists believe the changes in our diet and physical activity can’t really account for the change either, that there’s something else at work here.”

Weighing at least two kilograms in all and accounting for more than 3 times the amount of the body’s human cells, gut bacteria is colonized after birth, stabilized by age 3 years but influenced by a number of external factors, Jardine explained. Areas of influence include nutrition and immune function, both priorities in treating obesity and diabetes.

“Microbiota releases enzymes that digest food so we can absorb nutrients, produces vitamins, combats opportunistic infections and works with the immune system,” Jardine said. “About 70% of our immune systems are in our gut.”

People who consume plant-based diets have “healthy” gut microbiota in terms of global parameters and functional and compositional features, Christina Kafity, RN, BSN,CHC... “Children and elderly individuals who consumed more plant carbohydrates versus the typical standard American diet had rapid, reproducible alterations of the gut microbiota for the better, and this happened within 24 hours to a week,” Kafity said.

Growing good bacteria depends on creating an environment in which they can thrive, Kafity explained, including choosing foods that contain certain fibers intact in plants and probiotics; among them are soluble, insoluble and functional fibers as well as psyllium and inulin.

Intake of cruciferous vegetables including Brussels sprouts, kale and cabbage can help boost healthy microbes and, further, provide glucosinolates to help to reduce inflammation, Kafity said. Yogurt, kefir and probiotics also promote the growth of good bacteria, Kafity noted, while some popular beverages may not be much help. “We’re considering that coffee and teas may actually sterilize the bacteria.”

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I'm glad that there is interest in therapeutic possibilities of bacteria, but I'm worried (a lot) about the possibility of companies claiming rights to naturally occurring bacteria. The article simply said: "...intellectual-property rights for naturally occurring bacteria, may complicate the path of products to market."  From Scientific American:

Drugs to Be Derived from Insights into Body-Dwelling Bacteria

The human body teems with trillions of microorganisms — a microbial landscape that has attracted roughly $500 million in research spending since 2008. Yet with a few exceptions, such as the use of fecal transplants for treating life- threatening gut infections or inflammatory bowel disease, research on the human microbiome has produced few therapies.

That is poised to change as large pharmaceutical companies eye the medical potential of manipulating interactions between humans and the bacteria that live in or on the body.

On 2 May, drug giant Pfizer announced plans to partner with Second Genome, a biotechnology firm in South San Francisco, California, to study the microbiomes of around 900 people, including those with metabolic disorders and a control group.A day earlier, Paris-based Enterome revealed that it had raised €10 million ($13.8 million) in venture capital to develop tests that use the composition of gut bacteria to diagnose inflammatory and liver diseases.

Experts predict that the next few months will see a boom in such partnerships and investments, and that new microbiome-derived drugs and therapies will come to market within a few years.

Probiotics, or beneficial gut bacteria, have become a popular therapy in recent years. Television advertisements feature celebrities touting Bifidobacterium-laced yogurt, and consumers flock to buy pills that contain Lactobacillus to quell their gut disturbances and other ailments. But many physicians and scientists doubt the effectiveness of such remedies. 

But as scientists come to understand the mechanisms by which specific bacteria affect the body, many think that they can pinpoint the right combination of microbes to treat different conditions. Others aim to develop molecules that mimic a beneficial bacterium–host interaction, or block a harmful one. “Undoubtedly, the microbiome is a  little drug factory in our intestine,” says Justin Sonnenburg, a microbiologist at Stanford University in Palo Alto, California.

Changing the balance of ‘good’ and ‘bad’ bacteria in the gut microbiome can also influence health — inflammation, for example, or even depression and anxiety. 

Getting microbiome-inspired therapies to market presents a number of challenges, however. Small molecules such as those developed by Microbiome Therapeutics may be able to go through the normal drug regulatory pathway. But there may be a different or new set of regulatory hurdles for genetically modified bacteria — for example, those in development by Ghent-based ActoGeniX in Belgium and ViThera Pharmaceuticals in Cambridge, Massachusetts — that deliver anti-inflammatory agents to the gut. Other issues, including intellectual-property rights for naturally occurring bacteria, may complicate the path of products to market.

Pierre Belichard, Enterome’s chief executive, says that such investment has been a long time coming — but companies are now flocking to microbiome research.

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This was done in mice, so much more needs to be done. But...if it holds true for humans, probiotics (with IPA-producing bacteria) can be used as therapies for all sorts of diseases. From Medical Xpress:

'Normal' bacteria vital for keeping intestinal lining intact

Scientists at Albert Einstein College of Medicine of Yeshiva University have found that bacteria that aid in digestion help keep the intestinal lining intact. The findings, reported online in the journal Immunity, could yield new therapies for inflammatory bowel disease (IBD) and a wide range of other disorders.

The research involved the intestinal microbiome, which contains some 100 trillion . The role of these microorganisms in promoting or preventing disease is a major emerging field of study. Einstein scientists found that absorption of a specific bacterial byproduct is crucial for maintaining the integrity of the intestinal epithelium —the single-cell layer responsible for keeping intestinal bacteria  and their toxins inside the gut and away from the rest of the body. Breaching of the intact intestinal epithelium is associated with a number of diseases.

"Intestinal bacteria secrete a wide variety of chemicals known as metabolites," said Sridhar Mani, M.D., co-corresponding author of the paper. Dr. Mani and his colleagues suspected that bacterial metabolites exert their influence by binding to and activating a protein in the nuclei of intestinal epithelial cells called the pregnane X receptor (PXR). PXR was known to be activated by chemicals within the body (such as bile acids) as well as by drugs including steroids and antibiotics.

In a series of mouse studies, the researchers found that a metabolite called indole 3-propionicacid (IPA)—produced exclusively by so-called commensal bacteria, which aid in digestion—both strengthens the intestinal epithelium's barrier function and prevents its inflammation by activating PXR. More specifically, PXR activation suppresses production of an inflammatory protein called tumor necrosis factor alpha (TNF-α) while increasing levels of a protein that strengthens the junctions between adjacent intestinal epithelial cells. 

"By adding probiotics in the form of IPA-producing bacteria to the intestine or by administering IPA directly, we may be able to prevent or treat IBD and other inflammatory disorders that occur when the intestinal epithelium has been compromised," said Dr. Mani. "Such a strategy could also be tried for other health problems that may occur when the intestinal epithelium breaks down, including certain forms of liver disease, diabetes, asthma, allergies, obesity and heart disease."

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Two related articles, the first from a month ago, but both discuss eating fresh foods of summer and the effect on the microbiota. From Gut Microbiota Worldwatch:

Seasonal diet changes affect the composition of our gut microbiota

The mix of bacteria that live in our gut changes throughout the year, to match the food we eat in every specific season. For example, bacteria that process fresh fruit and vegetables are more abundant in the summer, and those that process fats are mode abundant in winter times. A group of scientists at the University of Chicago has found evidence of this seasonal shift in the gut flora, by studying the remote Hutterite population, in North America. The traditional diet and common meals of this community have allowed researchers to study the effect of one common diet in a large population over a long period of time.

Hutterites live in communal farms (colonies) and eat meals in common dining rooms, using traditional recipes that have been relatively stable over time and between colonies. They have little contact with the world outside their colonies, which translates into a very homogeneous genetic pool. Sixty Hutterites from six colonies answered questionnaires about what they ate over the course of a year. During the same period, scientists sampled their stool periodically, to find the genetic sequences of bacteria contained in their gut.

The Hutterites’ diet is relatively stable, except that in summer they eat more fresh fruit and vegetables, and in winter they eat less, and turn to frozen or canned food. Remarkably, their gut flora responded to these changes with massive modification in the abundance of certain bacteria. For example, during summer Bacteroidetes were more abundant: this group of bacteria contain complex carbohydrate digesters, which may be at work in processing fresh fruit and vegetables.

On the other hand Actinobacteria increased in winter: these microbes are associated with processing fat, and with a decreased content of fibre in food. Researchers also found seasonal shifts in other types of bacteria, whose associations with food are still unknown. Notably, the trends were almost identical in all six colonies, possibly a result of a very homogenous lifestyle carried on in a very similar environment.

Although Hutterites live in a relatively isolated way, they use technology and medicine, which makes their lifestyle closer to the general population than that of other more traditional communities. That is why the authors believe that these results may be extended to the general population.

This healthy living article promotes eating fresh fruits and vegetables (tomatoes, blueberries, asparagus, and leeks) as good for the gut microbiome. From Huffington Post:

4 Summer Foods That Can Help Trim Your Waist

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Future microbiome research and therapy will have to take into account that diet affects the gut microbes of men and women differently. From Science Daily:

Diet affects males' and females' gut microbes differently

The microbes living in the guts of males and females react differently to diet, even when the diets are identical, according to a new study. These results suggest that therapies designed to improve human health and treat diseases through nutrition might need to be tailored for each sex.

The researchers studied the gut microbes in two species of fish and in mice, and also conducted an in-depth analysis of data that other researchers collected on humans. They found that in fish and humans diet affected the microbiota of males and females differently. In some cases, different species of microbes would dominate, while in others, the diversity of bacteria would be higher in one sex than the other.

These results suggest that any therapies designed to improve human health through diet should take into account whether the patient is male or female.

Genetics and diet can affect the variety and number of these microbes in the human gut, which can in turn have a profound influence on human health. Obesity, diabetes, and inflammatory bowel disease have all been linked to low diversity of bacteria in the human gut.

Why men and women would react differently to changes in diet is unclear, but there are a couple of possibilities. The hormones associated with each sex could potentially influence gut microbes, favoring one strain over another. Also, the sexes often differ in how their immune systems function, which could affect which microbes live and die in the microbiome.

One notable exception in Bolnick's results was in the mice. Although there was a tiny difference between male and female mice, for the most part the microbiota of each sex reacted to diet in the same manner. Because most dietary studies are conducted on mice, this result could have a huge effect on such research, and it raises questions about how well studies of gut microbes in lab mice can be generalized to other species, particularly humans.

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The study was needed, but my first thought was "Duh! Of course." From Science Daily:

Fist bumping beats germ-spreading handshake

“Fist bumping” transmits significantly fewer bacteria than either handshaking or high-fiving, while still addressing the cultural expectation of hand-to-hand contact between patients and clinicians, according to a study published in the August issue of the American Journal of Infection Control...

In this study from the Institute of Biological, Environmental, and Rural Sciences at Aberystwyth University in the United Kingdom, researchers performed trials to determine if alternative greetings would transmit fewer germs than the traditional handshake. In this experiment, a greeter immersed a sterile-gloved hand into a container of germs. Once the glove was dry, the greeter exchanged a handshake, fist bump, or high-five with a sterile-gloved recipient. Exchanges randomly varied in duration and intensity of contact.

After the exchange, the receiving gloves were immersed in a solution to count the number of bacteria transferred during contact. Nearly twice as many bacteria were transferred during a handshake compared to the high-five, and significantly fewer bacteria were transferred during a fist bump than a high-five. In all three forms of greeting, a longer duration of contact and stronger grips were further associated with increased bacterial transmission.

“Adoption of the fist bump as a greeting could substantially reduce the transmission of infectious diseases between individuals,” said corresponding author, David Whitworth, PhD. This study expands on the recent call from the Journal of the American Medical Association (JAMA) to ban handshakes from the hospital environment. Healthcare providers’ hands can spread potentially harmful germs to patients, leading to healthcare-associated infections (HAIs). 

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This research illustrates how little we currently know about gut bacteria.But it did show the importance of diet. From Science Daily:

Monitoring rise and fall of the microbiome

Trillions of bacteria live in each person's digestive tract. Scientists believe that some of these bacteria help digest food and stave off harmful infections, but their role in human health is not well understood.

To help shed light on the role of these bacteria, a team of researchers led by MIT associate professor Eric Alm recently tracked fluctuations in the bacterial populations of two research subjects over a full year. The findings, described in the July 25 issue of the journal Genome Biology, suggest that while these populations are fairly stable, they undergo daily fluctuations in response to changes in diet and other factors...."To a large extent, the main factor we found that explained a lot of that variance was the diet."

There are a few thousand strains of bacteria that can inhabit the human gut, but only a few hundred of those are found in any given individual, Alm says. For one year, the two subjects in the study collected daily stool samples so bacterial populations could be measured. They also used an iPhone app to track lifestyle factors such as diet, sleep, mood, and exercise, generating a huge amount of data.

Analysis of this data revealed that dietary changes could produce daily variations in the populations of different strains of bacteria. For example, an increase in fiber correlated with a boost in the populations of Bifidobacteria, Roseburia, and Eubacterium rectale. Four strains -- including Faecalibacterium prausnitzii, which has been implicated in protecting against inflammatory bowel disease -- were correlated with eating citrus.

During the study, each of the two subjects experienced an event that dramatically altered the gut microbiome. Subject B experienced food poisoning caused by Salmonella, and Subject A traveled to a developing nation, where he experienced diarrheal illness for two weeks.

During Subject B's infection, Salmonella leapt from 10 percent of the gut microbiome to nearly 30 percent. At the same time, populations of bacteria from the phylum Firmicutes, believed to be beneficial to human health, nearly disappeared. After the subject recovered, Firmicutes rebounded to about 40 percent of the total microbiome, but most of the strains were different from those originally present.

Subject A also exhibited severe disruptions to his microbiome during his trip, but once he returned to the United States, it returned to normal. Unlike Subject B's recovery from food poisoning, Subject A's populations returned to their original composition.

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We know so little about the viruses in the human microbiome that a study just reported a newly discovered gut virus found in most of the world's population. From Medical Xpress:

Newly discovered gut virus lives in half the world's population

Odds are, there's a virus living inside your gut that has gone undetected by scientists for decades. A new study led by researchers at San Diego State University has found that more than half the world's population is host to a newly described virus, named crAssphage, which infects one of the most common types of gut bacteria, Bacteroidetes. This phylum of bacteria is thought to be connected with obesity, diabetes and other gut-related diseases.

The fact that it's so widespread indicates that it probably isn't a particularly young virus, either. "We've basically found it in every population we've looked at," Edwards said. "As far as we can tell, it's as old as humans are." He and his team named the virus crAssphage, after the cross-assembly software program used to discover it.

Some of the proteins in crAssphage's DNA are similar to those found in other well-described viruses. That allowed Edwards' team to determine that their novel virus is one known as a bacteriophage, which infects and replicates inside bacteria—and using innovative bioinformatic techniques, they predicted that this particular bacteriophage proliferates by infecting a common phylum of gut bacteria known as Bacteriodetes.

 Further details about crAssphage have been difficult to come by. It's unknown how the virus is transmitted, but the fact that it was not found in very young infants' fecal samples suggests that it is not passed along maternally, but acquired during childhood.