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Category: microbes

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This is part 3 of a 4 part series by Katherine H.  Courage. It's a good description of what goes on at a lab that does state of the art genetic analysis of microbes making up the human microbiome (the community of microbes that are part of us). These analyses (especially of fecal samples) are done for the American Gut Project which anyone can participate in (go to americangut.org for more information about this crowd-sourced project). From NPR News:

Behind The Scenes At The Lab That Fingerprints Microbiomes

The gut microbiome may soon reveal important answers to questions about our health. But those answers aren't yet easy to spot or quick to obtain.The week after I mailed off my family's microbial samples to be analyzed for the American Gut Project, I followed them down the road from my home to the University of Colorado, Boulder. They — and I — came to a massive, futuristic science complex there. Daniel McDonald, a doctoral student studying quantitative biology and computer science, greeted me and brought me up to the workspace, where rows of researchers worked on computers outside of a small lab room.

 Inside the lab, where the sealed samples were received, a lone technician sorted through new arrivals, snipping off intentionally fouled swab heads. Each sample kit contains two cotton swabs. One swab head goes directly to the freezers for safe keeping (in case the first sample doesn't provide clear results or for the near future, when sequencing technology is better). The other gets dissolved in a solution so its contents can be carefully analyzed for genetic traces of microbes.

Just down the hall is one of the lab's boxed-in robots, charged with loading samples into individual wells on a tray that will later get fed through the sequencers. The task might seem mundane for such a high-tech tool, but the bot works much faster and more accurately than a human lab helper can.

Still, this is where some of the work can be slow going. The team must wait for hundreds of fecal, oral or skin samples to process together. A single sample could go through the full analysis process in a week, but it would cost thousands of dollars, Rob Knight, a co-founder of the project, estimates, rather than the $99 members of the study pay. For the project to be cost-effective for participants, the research team must wait to collect large groups of samples and analyze them together.

This robot in the Knight lab can handle many samples simultaneously. To avoid contamination, the lab only processes the same kind of samples at the same time together (fecal with fecal, skin with skin and pet with pet). Credit: Katherine Harmon Courage for NPR

Most of the human microbiome is uncharted territory because many of the microbes that live in our guts can't be grown easily in the lab. Oxygen is toxic to them. Using the tools of genetics to probe the human microbiome has already uncovered many new species, each of which has a full genome of its own.

We're still far from getting quick full genomes from each of the inhabitants. Instead, scientists rely on microbes' telltale 16S gene, a marker that helps identify bacteria from one another. Finding the base pairs —the As, Cs, Ts and Gs — for this gene can help scientists sort out which species are present.This is where a nifty machine that performs PCR (polymerase chain reaction) comes in. It makes thousands of copies of the genetic material so that the pattern in the genetic code is easier for the sequencers to find.

These sequencers are located on a lower floor of the building in a room that smells a bit like a photography darkroom. Here, each tray of samples takes about 20 hours to process. On a nearby screen, I see a readout of bright genetic points against a dark background, which looks more like a telescopic image of a night sky than the code to microbial life from someone's stomach.

Deciphering this code is just the first step in understanding what is going on in the jungle of your gut. Like many things in biology, it is not just the organisms present — plants, animals or bacteria — but how these organisms interact that is important.

The dynamics among the characters make a play — not just the cast.For instance, research has shown that many of us are walking around with E. coli in our guts but show no ill effects. In much the same way that weeds or hungry insects might not harm a thriving field or forest but could wreak havoc on an unbalanced ecosystem, we depend on a healthful mix of good microbes to keep the bad ones from taking over.

And to see what our intestinal forests are composed of, we need more than just a few points of genetic data. So after the sequencer spits out the genetic code it has assembled, the data needs to get turned back into intelligible (or at least semi-intelligible) patterns.

To do this, our microbial code gets run through a supercomputer nicknamed Compy, which hums safely in the building's basement beyond two sets of doors and a sticky, dust-collecting floor mat. When I meet her, Compy is busy crunching away on base pairs with her 1,000 processors...The research group is testing using new software to analyze and display these many layers of information.

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More research is needed, but looking at the "microbial signature" of a criminal definitely has potential. From Science (American Association for the Advancement of Science):

Bacteria on pubic hair could be used to identify rapists

When it comes to identifying a rapist, one of the main pieces of evidence police analyze are pubic hairs found at the crime scene. But most of these hairs are missing their roots and thus don’t harbor enough DNA for a proper match. Now, a new study suggests there may be a better way to finger the criminal: Look at the bacteria he left behind.

In addition to hair, police have relied heavily on semen samples to identify potential rapists, notes Silvana Tridico, a forensic biologist at Murdoch University in Perth, Australia. But criminals have gotten wise to genetic testing, she says, and are increasingly wearing condoms, which they take with them after assaults. She hoped to find a way to get around this problem by comparing bacteria that are present in the pubic hairs of the victim and suspects and then creating a microbial fingerprint that could nail the culprit.

Tridico and colleagues asked seven individuals—two of whom were living together—to collect their scalp and pubic hair for 5 months. The researchers then analyzed these samples in the lab, looking for bacterial populations present after 2 and 5 months. The scalp hair showed that 50 different varieties of microbes in males and 55 in females are found in this part of the body, but many of the microbes that were found were not specific to the individual carrying them. The pubic hair bacteria, however, turned out to be more distinct; in addition, each individual’s “personal” pubic bacteria stayed roughly the same during the 5 months. More kinds of bacteria live in these hairs: approximately 73 in males and 76 in females. A larger combination of different bacteria means it is more likely for people to carry a unique microbial signature on them, Tridico says.

Although each person’s pubic hair bacteria were distinct, the couple who were living together had greater similarity of bacteria on their pubic hairs at 5 months than detected after 2 months. The couple later revealed that they had sexual intercourse 18 hours before the collection of their hairs, the researchers report online today in Investigative Genetics.

Because the study included only one couple who were living together and only seven participants in total, the results are “far from conclusive,” Tridico cautions. However, the findings are encouraging, she says, and show that “it may be possible to differentiate between individuals on the basis of their bacteria.”

Max Houck, a lead forensic scientist at Consolidated Forensic Laboratory, a government organization based in Washington, D.C., agrees. But he also points out that it might be more difficult to use this method if there has been previous sexual contact between the victim and the subject, in the case of abusive ex-spouses, for example. “Human pubic hairs could be of potentially significant use in cases where the victim and subject have not had previous sexual contact.”

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Of course! From Science Magazine:

Guts of obese dogs look similar to those of obese people

Obese people have a less diverse array of bacteria living in their guts than do thin people—and the same holds true for dogs. In a new study, researchers fed seven beagles unrestricted amounts of food for 6 months, during which each dog gained an average of 4.93 kilograms—about 67% of their initial average weight of 7.37 kilograms. The investigators fed another seven beagles controlled food portions, and, as expected, this group did not gain weight.

When the researchers examined the fecal samples collected from both groups after 6 months, they found that the guts of obese beagles contained a smaller diversity of bacteria than those of the other dogs. What’s more, microbes from the phylum Firmicutes were the predominant group in the lean dogs, whereas Gram-negative bacteria called Proteobacteria were prevalent in the obese group, the team reported online this month in the Journal of Veterinary Internal Medicine. The researchers speculate that an abundance of Proteobacteria may lead to an increase in lipopolysaccharide, a major component of the cell wall of Gram-negative bacteria, which has been linked to weight gain in mice. More research is needed to examine what role gut bacteria may play in the development of obesity, however, the authors say.

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Interesting research using probiotics (beneficial bacteria) to treat a nickel allergy. What other allergies could be treated with probiotics? From the American Microbiome Institute:

Treating severe nickel allergies with probiotics

Systematic nickel allergy syndrome (SNAS) is a severe reaction to nickel, a metal that is found in nature and most human food sources. An allergic reaction to nickel can manifest cutaneously, causing inflammation and irritation of the skin, or it can be gastrointestinal, causing diarrhea. Studies in which balanced diets are used as a way of reintroducing nickel to SNAS patients have been conducted to find possible treatments of this allergy; however no cure has been found. Research by a group in Italy was  published last month in the Journal of Applied Microbiology that examined the use of probiotics such as Lactobacillus reuteri to treat SNAS patients.

A double blind study was performed using twenty-two adult women who had both systematic and cutaneous reactions to nickel. A control group received a placebo, while an experimental group received the L. reuteri probiotic. Fecal sampling and clinical evaluations were performed at the start of the study, before any pills were taken, as well as after two weeks of supplementation and two weeks after the end of the trial. Throughout the entire evaluation period the patients followed a low-nickel diet.

Both groups prior to experimentation had low diversity of lactic acid bacteria (LAB) communities in their gut.  After the trial, they found that the control group had stable LAB communities while the experimental group resulted in greater diversity of LAB than prior to the study. They found that only the experimental group showed the presence of L. reuteri meaning that the bacteria in the probiotic had successfully colonized and survived in the gut, an essential feature if a probiotic is to be used in a clinical setting.

They also found a significant improvement in cutaneous symptoms after two weeks in both the group being given the probiotic with a low-nickel diet, as well as the strictly low-nickel diet patient group, however the improvement was more pronounced in the group getting the probiotic. Only patients receiving the supplementary L. reuteri showed a significant reduction in gastrointestinal symptoms. Eating a diet low in nickel will cause less averse reactions than an uncontrolled diet; however, this study strongly suggests that probiotics can significantly decrease the severity of allergy symptoms in SNAS patients. The study also suggests that a combination of diet and probiotics could increase bacteria’s ability to colonize in the intestines.

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Considering all the antibiotics that the typical sinusitis sufferer takes over the years, reading this article was depressing. One wonders, can the gut microbiome (community of microbes) recover from many rounds of antibiotics and how long does it take? Please note: CD is Crohn's disease, UC is ulcerative colitis, and IBD is inflammatory bowel disease. Dysbiosis means that the community of microbes (microbiome) is out-of-whack. From Medscape:

Antibiotics Associated With Increased Risk of New-onset Crohn's Disease but not Ulcerative Colitis

The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing inflammatory bowel disease (IBD).A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. 

Conclusions: Exposure to antibiotics appears to increase the odds of being newly diagnosed with CD but not UC. This risk is most marked in children diagnosed with CD.

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Environmental factors have a key role in the pathogenesis of inflammatory bowel disease (IBD)...Furthermore, the incidence of IBD has been increasing worldwide over time. Developing countries have seen an increase in IBD incidence as they have Westernized.

Emerging evidence suggests that certain medications are associated with an increased risk of new-onset IBD. In particular, antibiotics have been linked to the development of both Crohn's disease (CD) and ulcerative colitis (UC).Growing research suggests that the microbiome and its interaction with the mucosal immune system are important in the pathogenesis of IBD.Antibiotics can cause alterations to the microbiome that may potentially contribute to the dysbiosis and dysregulated immune response seen in IBD.

Previous studies have investigated the association of antibiotic exposure with newly diagnosed IBD in both adult and pediatric populations. CD has been more consistently associated with antibiotic use, with some studies demonstrating an increased risk of CD but not UC. It also appears that patients who receive more frequent courses of antibiotics have a higher likelihood of developing IBD.

The results of this meta-analysis suggest that exposure to antibiotics increases the risk of new-onset IBD. When stratifying by type of IBD, antibiotic exposure was associated with an increased risk of developing CD but not UC. We found that the magnitude of risk of new CD is greater for children than for adults. All classes of antibiotics studied, with the exception of penicillins, were associated with new diagnoses of IBD. Interestingly, the types of antibiotics showing the strongest association were fluoroquinolones and metronidazole.

Although it is impossible to draw causal links on the basis of these data, there are some possible implications and explanations for our findings. First, our findings may support the importance of disruptions in the microbiome in the pathogenesis of IBD. The link between antibiotic exposure and new IBD seems biologically plausible. It is known that the microbiome likely has an important role in the pathogenesis of IBD. Studies have shown a decrease in the diversity and stability of both mucosa-associated bacteria and fecal bacteria in patients with CD and UC.For example, the largest cohort microbiome study to date recently found that newly diagnosed CD patients have increased Enterobacteriaceae,Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae, and decreased Erysipelotrichales, Bacteroidales, and Clostridiales.

Antibiotics have been shown to alter the composition of the human gut microbiota by decreasing taxonomic richness and diversity....Although the microbiome may recover to its initial state within days to weeks after antibiotic treatment, some studies have shown a longer-term impact of antibiotics on specific microbial populations that can persist for months to years.

It is unclear as to why antibiotic exposure was associated with new-onset CD and not UC. Studies have suggested a difference in the microbiota between CD and UC patients....Our finding that pediatric populations appear to have an increased association of antibiotic use with new-onset CD compared with adults may reflect the less stable nature of the microbiome earlier in life. During the first 3 years of life, the microbiome appears to undergo marked changes and significant maturation toward an adult-like composition with greater interpersonal variation. It is possible that antibiotics may therefore have a greater impact during childhood when the gut microbiota composition is still developing.

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The numbers are amazing. Researchers found all these microbes because of state of the art genetic analysis such as 16S rRNA gene sequencing (because most microbes can not be "cultured"). From Science Daily:

Cataloguing 10 million human gut microbial genes: Unparalleled accomplishment

Over the past several years, research on bacteria in the digestive tract (gut microbiome) has confirmed the major role they play in our health. An international consortium has developed the most complete database of microbial genes ever created. The catalogue features nearly ten million genes and will constitute a reference for all research on gut bacteria.

Research on the gut microbiome (all of the bacteria in the digestive tract) has multiplied over the past several years, helped in great part by new sequencing technologies. The gut microbiome, which scientists have labelled a "new organ" that is composed of tens of trillions of bacteria -- ten times as many as the number of cells in the human body -- is directly linked to the immune system and brain. It is a major player in chronic illnesses such as obesity and Type 2 diabetes. However, research in the field depends on access to reference gene databases (or catalogues), which is particularly important when identifying the functions of microbial genes. Few and far between, existing catalogues were created using samples from a limited number of people and geographical origins.

Most of the genes (around six million) are shared by just 1% of the population, making them quite rare. While there is substantial data today regarding the most common genes, future research will focus on determining the importance and role of these rare genes.

Thanks to this catalogue, the most clinically significant genes can be described, most notably those related to illnesses such as Type 2 diabetes, cirrhosis of the liver, cardiovascular diseases and some cancers. It will also provide a more complete picture of imbalances in the gut microbiome (dysbiosis), particularly those caused by medication.

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Much discussion about the link between gut bacteria and liver cancer, as well as the link between inflammation and cancer. Gut microbiome imbalances can cause health harms.

Bottom line: Try to improve your gut microbiome by eating a diet rich in fruits, vegetables, seeds, nuts, legumes, and whole grains.

From the Dec.4, 2014 issue of Nature: Microbiome: The bacterial tightrope

Imbalances in gut bacteria have been implicated in the progression from liver disease to cancer. The team's research, published last year, suggests that gut bacteria — which are part of the microbiome of bacteria and other microorganisms that live in and on the body — can play a crucial part in liver-cancer progression.

There are trillions of microorganisms in the human microbiome — they outnumber their host's cells by around ten to one — and their exact role in health and disease is only now starting to be explored. Studies have found that people with non-alcoholic fatty liver disease have a different composition of bacteria in their gut from healthy individuals2, 3

 Instead, she sees an emerging picture of liver disease and cancer as a process in which various factors — including a high-fat diet, alcoholism, genetic susceptibility and the microbiome — can each contribute to the progression from minor to severe liver damage, and from severe liver damage to cancer.

Flavell's research suggests that the liver has an important role in immune surveillance and helps to maintain bacterial balance in the gut. Specialized cells in the liver and intestines monitor the microbiome by keeping tabs on bacterial by-products as they pass through. These cells can detect infections and help to fight them.

But they can also pick up on subtler changes in the bacterial populations in the gut. When certain types of bacteria become too numerous — a state called dysbiosis — the immune system becomes activated and triggers inflammation, although at a lower level than it would for an infection... Now, research is emerging that suggests that dysbiosis and the immune reaction it provokes can even contribute to cancer.

He thinks that at least part of this mechanism involves disruption in the balance of the various species of bacteria in the gut. An out-of-balance microbiome promotes a constant state of inflammation, which can contribute to cancer progression, Schwabe says. This aligns with the picture that is emerging of cancer, in general, as an inflammatory process: the same immune reactions that help the body to fight infection and disease can also promote unchecked cell growth.

Some of the earliest research on the human microbiome, published in 2006, demonstrated that the balance of gut bacteria in obese people is different from that in people of healthy weight. In particular, obese people tend to have greater numbers of the bacteria that produce DCA (deoxycholic acid) and other secondary bile acids.

This line of research points to the microbiome as one potential link between obesity and liver-cancer risk . And, much like Schwabe's work, Hara's results indicate that several factors converge to promote cancer: in this case, bacteria, diet and carcinogen exposure. Here, too, the ability to stave off the disease seems to depend on maintaining the appropriate microbial balance. Overweight mice and people have a different composition of gut microbiota from their lighter counterparts, and they have higher levels of DCA, too.

However, not everyone is convinced that individual bacterial species are to blame. Some researchers point out that dysbiosis, and therefore cancer risk, involves multiple strains of bacteria. And the bacterial mix can vary from person to person, meaning it is unlikely that scientists can pin all responsibility on a single species.

Others are looking for ways to promote the growth of healthy bacterial strains rather than target the bad ones....There is also some early clinical evidence that specially formulated probiotics — cocktails of good bacteria — can bump the microbiome back into balance. Hylemon and his colleagues gave people with cirrhosis a probiotic containing Lactobacillus bacteria and found that their blood markers of inflammation decreased along with their cognitive dysfunction (a common symptom of cirrhosis)6. Although the study was not designed to evaluate cancer risk, it does show that delivering bacteria to the gut can have positive therapeutic effects on the liver.

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Please note that the study was of people living in the Baltimore, Maryland area - so it is unknown if this would hold true for people living elsewhere. From Medical Xpress;

Virus may affect mental abilities, study reports

People with an algae virus in their throats had more difficulty completing a mental exercise than healthy people, and more research is needed to understand why, US scientists say. A study in the Proceedings of the National Academy of Sciences showed that the virus was present in about half of 92 human subjects studied, and those who had it performed worse on certain basic tasks.

The virus, known as Acanthocystis turfacea Chlorella virus 1, or ATCV-1, also appeared to limit the cognitive abilities of mice.The mice had a harder time navigating a maze and noticing new objects in their surroundings after they were infected.

It remains unclear if the virus was truly driving the drop in mental functioning. Researchers have not yet shown the cause and effect between the virus and the intelligence results."At this point we do not think that this virus should be considered as a threat to individual or public health," said lead researcher Robert Yolken, a virologist at Johns Hopkins University in Baltimore, Maryland. The virus was found by accident while scientists were analyzing microbes in the throats of healthy humans for a different study.

Experts have been studying viruses similar to ATCV-1 for 35 years, said senior author James Van Etten of the University of Nebraska, an expert on algal viruses. Van Etten joined the research four years ago when Johns Hopkins scientists found ATCV-1's DNA sequences in the brain tissue of people who had died with mental disorders such as schizophrenia.

"These viruses are ubiquitous in fresh water ponds and streams throughout the world," Van Etten said. He noted that the virus—previously thought to only infect algae—could make its way into the human body when people swallow water while swimming.There might also be another host in nature, such as mosquito larvae, he said. But the nature of the disease is still in the early stages of analysis.

It is also unknown if the virus's effects on the brain are lasting or temporary. Scientists have long understood that viruses interact with DNA, and further studies could shed more light on the role of the virus on cognition.

"As more studies like this are conducted, I believe we'll find out there's even more interaction between viruses, bacteria and fungi that are either ingested or breathed into our noses and mouths and the overall human condition," said Jordan Josephson, ear nose and throat specialist at Lenox Hill Hospital in New York, who was not involved in the study.

Further information on this study and the virus. From Medical Xpress:

Researchers identify algae-virus DNA in humans

From Newsweek:

American Researchers Discover 'Stupidity Virus'

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Natural ways that may help GERD symptoms without drugs : eating smaller portions, losing weight, not lying down for 2 hours after eating, and avoiding alcohol, cigarettes, and "trigger" foods.From Health Day News:

Could Popular Heartburn Drugs Upset Your 'Good' Gut Bugs?

Heartburn drugs such as Prilosec and Nexium may disrupt the makeup of bacteria in the digestive system, potentially boosting the risk of infections and other problems, a small new study suggests.

According to Harvard Medical School, billions of dollars are spent annually on antacid drugs in an attempt to combat heartburn, ulcers and gastroesophageal reflux disease, also known as GERD. Old standbys such as Maalox and Mylanta have been supplanted by more effective, more expensive drugs, including proton pump inhibitors. These include Prevacid (lansoprazole) and Protonix (pantoprazole) in addition to Prilosec (omeprazole) and Nexium (esomeprazole).

Long-term use of proton pump inhibitors has been linked to infection with a germ called Clostridium difficile, which causes severe diarrhea, he said. Researchers have also connected the medications to vitamin deficiencies, bone fractures and pneumonia, among other conditions.

In the new study, researchers sought to understand what happens to the trillions of germs in the digestive system when people take omeprazole, the generic name for the drug best known as Prilosec.Ten participants, aged 18 to 57, took 20 or 40 milligrams of the drug a day for 28 days. Researchers analyzed the study participants' stool samples to understand the germs in their guts.

"These microbes have evolved with us to participate in our normal development and metabolism, and perform certain functions that we would not be able to accomplish without their help," DiBaise said. Many scientists believe that people's risk of disease goes up when their normal germ makeup changes, he said.

The researchers found evidence that the medications disrupted the balance of bacteria in the digestive systems of the participants, and the changes lasted for at least a month after they discontinued the drug. It didn't seem to matter whether they took the higher or lower dose, DiBaise said.

DiBaise cautioned that the study doesn't prove that the drug causes users to become more vulnerable to C. difficile infections. However, it shows that the drug "creates a situation in the gut microbial environment that may increase an individual's susceptibility," he said.

What should users do for now? According to DiBaise, proton pump inhibitors are "the most effective medications to treat gastroesophageal reflux disease." If patients don't have the most severe symptoms, he said, other types of heartburn drugs might help. Also recommended: eating smaller portions, losing weight, not lying down for two hours after eating, and avoiding alcohol, cigarettes and "trigger" foods.

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Are probiotic bacteria the reason?

From Medical Xpress: Does a yogurt a day keep diabetes away?

A high intake of yogurt has been found to be associated with a lower risk of developing type 2 diabetes, according to research published in open access journal BMC Medicine. This highlights the importance of having yogurt as part of a healthy diet.

Type 2 diabetes is a chronic condition that occurs when the body doesn't produce enough insulin, or the body's cells develop resistance to insulin. There is an increased risk of developing it if a relative has the condition or if an individual has an unhealthy lifestyle. 

Researchers from Harvard School of Public Health pooled the results of three prospective cohort studies that followed the medical history and lifestyle habits of health professionals. These studies were the Health Professionals' Follow-up Study (HFPS), which included 51,529 US male dentists, pharmacists, vets, osteopathic physicians and podiatrists, aged from 40 to 75 years; Nurses' Health Study (NHS), which began in 1976, and followed 121,700 female US nurses aged from 30 to 55 years; and Nurses' Health Study II (NHS II), which followed 116,671 female US nurses aged from 25 to 42 years beginning in the year 1989.

Within the three cohorts 15,156 cases of type 2 diabetes were identified during the follow-up period. The researchers found that the total dairy consumption had no association with the risk of developing type 2 diabetes. They then looked at consumption of individual dairy products, such as skimmed milk, cheese, whole milk and yogurt. When adjusting for chronic disease risk factors such as age and BMI as well as dietary factors, it was found that high consumption of yogurt was associated with a lower risk of developing type 2 diabetes.

The authors then conducted a meta-analysis, incorporating their results and other published studies, up to March 2013, that investigated the association between dairy products and type 2 diabetes. This found that consumption of one 28g serving of yogurt per day was associated with an 18 per cent lower risk of type 2 diabetes.

Previous research has suggested calcium, magnesium, or specific fatty acids present in dairy products may lower the risk of type 2 diabetes. It has been shown that probiotic bacteria found in yogurt improves fat profiles and antioxidant status in people with type 2 diabetes and the researchers suggest this could have a risk-lowering effect in developing the condition.