Category Archives: You are what you eat

Gut microbiota: more awesome than before

Bacteria with telephone, picture via NPR

Who are you gonna call???? (image via NPR)

After 15 straight days of bonus point summaries from students, today brings a special treat as it falls to me to fill the space with content. This was a cool story, spotted via Microbe World from a news story on NPR, detailing work by researchers at Georgia State University and published in the journal Science this week. We are aware in BIO230 of the critical importance of the normal microbiota in helping us to resist pathogens and disease, however much of this benefit is due to the fact that we have developed a state of peaceful co-existence with them (meaning that they do not generally cause disease), and they are able to out-compete the bad guys. On the face of it, this is a rather boring picture, however the research outlined here shows that it is much more interesting and complicated than we might think.

The researchers were interested in developing treatments for a common gastrointestinal infection due to rotavirus. Rotavirus is a highly contagious agent that causes vomiting and severe diarrhea that can last for up to a week. According to the Centers for Disease Control, prior to 2006 rotavirus infections in United States accounted for around a half million doctors’ office visits, with a large number (greater than 50,000) of hospitalizations. Worldwide, there have been about a half million deaths due to rotavirus annually, mainly in children under the age of 5, and indeed young children everywhere are the most susceptible to infection and have the most severe signs and symptoms. Since the deployment of a vaccine in the last decade, hospitalizations due to rotavirus have begun to decrease, and epidemiologists believe that the unvaccinated are now beginning to see some of the benefits of the vaccine through herd immunity.  Currently, there are no antiviral treatments for rotavirus infection, and of course antibiotics actually will prolong the disease course by eliminating the normal bacterial microbiota. The main treatments for rotavirus are to avoid dehydration caused by vomiting and diarrhea. Consequently, there is strong interest in identifying novel, oustide the box approaches for actually treating these types of infection when they occur.

The researchers introduced a bacterial antigen (flagellin), which is the major component of the prokaryotic flagella, under the skin into either healthy mice or mice infected with rotavirus, and observed that healthy mice did not subsequently develop rotavirus when infected (disease was prevented), and in the already infected mice the disease course was stopped (i.e. the mice were cured). The protection was independent of an adaptive immune response, meaning that no prior exposure to the virus was necessary in order to induce the response. The responses to the virus depended on two innate immune pattern recognizing proteins, Toll-like receptor TLR5 and NOD-like receptor NLRC4. The binding of flagellin to immune cells via TLR5 led to the production of a signalling molecule by those immune cells called Interleukin 22 (IL-22), which bound to intestinal epithelial cells and protected them from rotavirus infection. Production of a second Interleukin (IL-18) following stimulation by flagellin through NLRC4 actually eliminated rotavirus-infected cells.

The model being proposed is rather interesting. Bacteria in the gut do not normally cause disease, however components on their surface seem to have powerful immune stimulating capabilities in preventing infection by other, structurally unrelated pathogens. The researchers stress that this study demonstrates the protective nature of flagellin works in mice, which are not humans, and therefore a lot of work still needs to be done to show this holds true for us as well. Fortunately, the basic pattern recognition and signalling pathways are highly conserved between mammals, so there is no a priori reason to expect that these experiments will fail. As indicated in the introductory paragraph, we currently have a pretty good vaccine for rotavirus infection here in the US, which is starting to show real promise in reducing the numbers of rotavirus infection just since its introduction a few years ago. However, the vaccine seems to be poorly effective outside the US, possibly due to genetic variation between strains of the virus in different parts of the world. This approach, if it works in humans, will offer a way to circumvent this problem as it is takes advantage of a generalized innate immune response to a pathogen, as opposed to the specific adaptive immune response promoted by a vaccine. Since it is an innate immune response, there is also no reason to expect that it might not be effective against other virus pathogens that gain access via the gastrointestinal route..

BONUS:  Given the discussion above, list in the comment thread ONE microorganism that might offer this protective effect, along with where you found that information. No repeats. You may have to do some research to find this. Offer runs through the end of Thanksgiving Break!!!!

Is your weight really your fault?

gut-microbiomeAmanda Sherry (11 AM Micro) found an article in Science Daily describing research from King’s College of London. The normal microbiota of the human intestinal system have been implicated in things as sensitivities to various allergies, and the types of people we might want to hang out with. However, as you look at these types of articles, read them critically, and remember the important distinction between correlation and causation, as pointed out in this commentary from Nature earlier this fall. Here is Amanda’s summary; let’s see if this project passes the criteria outlined in that Nature article:

Obesity, illnesses and diseases, like Type 2 diabetes and heart disease for example, that may be a byproduct of excessive weight have been studied for centuries costing millions of dollars in research funding.  Moreover, the millions of dollars that goes into marketing, advertising, medicine, and diet pills to raise awareness and combat obesity is incredible. So, if scientists are able to link obesity and excessive weight to a family of microbes in a person’s gut, then incredible advantages and/solutions for the medical community and for the health of millions of people living with excessive pounds may be right around the corner.

The article posted in ScienceDaily shares the results of research conducted by scientists in King’s College London and Cornell University. The study researched the relationship between a person’s genetic makeup and how it influences their weight. The results of the study concluded that whether a person is fat or the presence and amount of microbes in their gut determine skinny.

A team of scientists studied hundreds of sets of twins at King’s Department of Twin Research and identified a specific bacterial family called Christensenellaceae. Christensenellaceae is influenced by genetics and found to be more common in individuals with low body weight. The results of the study showed a direct linkage between low body weight and this microbe, concluding that this specific group of microbes living in a human’s gut protects against obesity. And to add more credence, in a separate study with mice — mice that were treated with this microbe in laboratory experiments gained less weight than untreated mice, thus further substantiating the results.

Prior to this research, the variation in the abundances of gut microbes has been explained by diet, the environment, lifestyle, and health. This is the first study to firmly establish that certain types of gut microbes are based on genetics and not just influenced by our environment.

To promote the use of microbiome testing more widely, the United Kingdom has established a British Gut Project. This experiment would allow anyone with an interest in their diet and health to have their personal microbes tested. The individual will have to pay a small fee, but will receive some incredible information that he/she can use to make health decisions. The advantage of the Gut project is two fold. First, a person learns some information not currently available to him/her for only a small fee and the second advantage is that work can continue and future research results may provide other links that may exist between our gut and our health.

The results of this study may present some interesting and new ways and next steps to combat obesity. One next step may be to research ways to increase the amount of Christensenellaceae present in a person’s gut, whereby preventing or reducing obesity across the globe. This would be a new weight loss and/or weight prevention option. Not only would it reduce obesity, but it would also directly affect the illness and diseases that are byproducts of excessive weight.

A New Take on Clostridium difficile: “Poop Pills”

New Picture (6)

via the NIH Director’s Blog

Brittany Reichelt (11 AM Micro) is thinking outside the box with the treatment of Clostridium difficile infections. These infections are difficult to treat, in large part due to the fact that they can form endospores, and as a result are not easily eliminated by antibiotic treatment. This leads to many patients have long term gastrointestinal issues from the infection, and a generally unsatisfactory quality of life for the patients with these infections. Brittany found this summary via the National Institutes of Health news page (excellent choice!). FYI, the use of poop to treat C. difficile infections is not news to long time BIO230 fans–it is a topic near and dear to my heart (see here, here, or just search “poop” on the blog). Here is Brittany’s take and summary on this important topic:

The following summary is on an article from the National Institutes of Health on Clostridium difficile. We have heard about the genus Clostridium with infections, such as Clostridium botulinum and Clostridium tetani. Clostridium difficile has many of the same characteristics, such as endospore forming and is anaerobic. This bacterium C. difficile is most prevalent in people with prolonged use of antibiotics, since antibiotics kill the bad and good bacteria in the colon, it will be easier for C. difficile to make its home there. Normally for treatment, antibiotics are not effective in improving the symptoms. Instead, the recommended treatment is to transplant “microbe-rich stool samples from healthy people into the C. difficile patient to help improve the bacteria in their colon and improve their symptoms.”

In the study completed by National Institutes of Health funded researchers from Massachusetts General Hospital took a different approach. Rather than taking the poop of healthy individuals and transplanting it into the patients, they created a simple pill: “the poop pill, which is shown in the picture above.” Researchers completed this by first taking healthy poop samples, purifying them, and then concentrating the good bacteria it. The concentrated good bacteria was put into clear capsules and then froze, these poop pills were to be given to patients frozen. Researchers tested the effects of the poop pills on 20 patients who experienced “at least three C. difficile infections and did not respond to antibiotics normally used on this bacterium. Patients were given 30 pills over a period of two days. The results of this study showed in 2 days of treatment 14 out of 20 patients had a dramatic reduction in symptoms, such as frequent diarrhea went away. The resulting 8 patients were given a second round of treatment and 4 more patients had the same decrease in symptoms.

The results show that this may be a better alternative; it is much easier for a patient to take a pill then it is to transplant the poop from one human being to another human. Researchers say that someday, this treatment may even be beneficial for other gastrointestinal diseases.

(note added in proof by Singleton: this seems as good as an opportunity to bring out this old chestnut–any ideas why this graphic is completely relevant to Brittany’s story? First person to comment with the correct answer gets a free bonus point!)

"S#!t Sandwich"

Down with diet

noartificialsweetenersRebecca Donovan (11 AM Micro) is interested in the normal microbiota. I have had a long-standing interest in the role of the gut microbes, and how recent studies have implicated them in a variety of phenomena–see for instance this report about how gut bacteria play a role in mate selection, or this one about a dating service based on gut bacteria. Rebecca’s summary shows that what we feed those bacteria is as important as the types of microbes themselves. Here’s Rebecca’s story, and for those who read to the end, a BONUS opportunity:

A recent article, published on sciencedaily.com, discovered that artificial sweeteners may be doing more harm than good in your body. Originally marketed to be the ideal solution to those desiring a lower calorie, “sugar less” way to avoid diabetes, recent research has suggested that artificial sweeteners are actually promoting glucose intolerance in the body. If, by this point, I have not convinced you to put down that diet coke in your hand, please read on.

How does this happen?
According to Dr. Eran Elinav and Professor Eran Segal, both of the Weizmann Institute of Science, our gut microbiota, or the bacteria residing in our intestines, are the likely culprits. To confirm this idea, the scientists gave mice water that contained three of the most readily used artificial sweeteners, saccharin, sucralose (splenda), and aspartame (Equal). They found that giving these mice the artificial sugar water promoted development of glucose intolerance to a much greater extent compared to mice only given plain water (Weizmann Institute of Science, 2014). It is also worth noting that mice who were given water containing real sugar developed less of an intolerance to glucose compared to mice given artificial sweetener water. Next, the scientists “cleaned out” the microbiota in the mice through the use of antibiotics. This “clean sweep” of gut bacteria resulted in a return of tolerance to glucose in mice given artificial sweetener water, solidifying the claim of the researchers that gut bacteria are the “prime suspects” in glucose   intolerance brought on by artificial sweeteners.

How do these findings pertain to humans? (After all, we’re not mice!!!)
The scientists involved in this experiment “covered their bases” by gathering a group of human volunteers, who rarely consumed artificially sweetened products, to add them to their diets for a week. After this time, their blood glucose levels would be measured. Their gut microbiota would also be analyzed and measured. The results of this experiment were that most of the participants exhibited an intolerance to glucose after ONLY ONE WEEK of consuming artificial sweeteners. Further analysis of the gut bacteria of participants illustrated  that, with consideration to those whose intolerance levels towards glucose were not adversely affected, that there are two types of gut bacteria living within humans: a type that reacts negatively to glucose resulting in intolerance and a type that has no effect on glucose tolerance (Weizmann Institute of Science, 2014). The researchers involved in the experiment believe that the aforementioned “bad” gut bacteria “turned on” an inflammatory process in the body, negatively affecting the ability of the body to effectively process sugar.

What should this study teach us?
The ultimate question we should ask ourselves is: why would we want to put substances in our body that are proven to be harmful to us? Diabetes and obesity are still, and will continue to be on the rise, in America if we continue to do little to prevent these diseases from occurring. You can take the first step in preventing diabetes and obesity by eliminating  “diet” from your diet. Artificial sweeteners aren’t worth the risks associated with them.

BONUS added by Singleton: in the comment thread, give an example of an association that the normal microbiota has with ANY aspect of human health (good or bad). No repeats, so read what others have put in, and you must give a citation (URL). Don’t worry about formatting of names–I will fix–but do spell them correctly. Offer ends on the end of the day on Friday September  26th.

Food allergies and our normal microorganisms

Peanuts_with_skinA news article that made the rounds through the popular press this week caught my eye: “Commensal bacteria protect against food allergen sensitization,” which appears in the early access section of the journal of the National Academy of Sciences. I have been a big fan of this type of research for a while now. The basic premise is this: our modern lifestyle has potentially begun to diminish the numbers and variety of microorganisms that live on our bodies in the absence of disease (the normal microbiota), and as a consequence, benefits that these benign organisms can confer to us are being lost. So far, loss of diversity of the normal microbiota have been correlated with a long list of ailments including potentially autism and cancer.

An opinion piece in this week’s Nature warns against drawing too many conclusions from these studies, and suggests that over reporting of some of them by the press reinforces the need to ensure that the public understand the distinction between “correlation” and “causation”–these concepts are frequently confused, and the distinction is sometimes not clear. Indeed, the editorial in Nature suggests that reporting of microbiome analysis and human disease should be tempered by asking 5 questions:

  • Can experiments detect differences that matter? Characterization of microbiomes is generally accomplished by sequencing very highly related genes, and this analysis may hide real differences.
  • Does the study show causation or just correlation? Many of the cases of a disease association with certain microorganisms may be the result of conditions in the body becoming favorable for the microbe, meaning the disease caused the microbes to alter.
  • What is the mechanism? Demonstrating causation is important, however without an explanation of how a change occurs, it is not sufficient.
  • How much do experiments reflect reality? Many of the putative effects of the microbiome on health involve germ free mice; that is mice that have been raised to have no normal microorganisms of their own, as this makes interpreting the effects somewhat easier. However, mice and humans are not the same, and the microorganisms that live on each are not the same.
  • Could anything else explain the results? Many things can cause disease, and other factors should be considered and tested.

With this in mind, I read the article on food allergies linked up at the top. The authors carried out the study to address the hypothesis that the normal microbiota of the gastrointestinal tract are able to guide adaptive immunity at this site. The intestinal tract of animals hosts an incredible variety of organisms in the absence of disease. The immune system needs to be non-responsive to these organisms, as well as to all of the food antigens that enter the digestive tract. Immune cells in lymphoid tissue along the digestive tract modulate signals between the microbiota and the epithelial barrier of the digestive tract, which helps to prevent an ongoing inflammatory response, and thereby promote a homeostatic relationship between the microbiota and the host.

The researchers first experiment was to treat neonatal wild-type mice with an antibiotic regimen prior to weaning to eliminate intestinal microbiota, then sensitized by gastric administration of Peanut Antigen (PN). Three weeks later, the mice were challenged with the antigen and allergic responses were measured a day later by collecting blood. Control mice had essentially undetectable levels of allergic responses, while antibiotic treated mice showed highly elevated levels of IgE. Analysis of the bacteria from feces of mice at the same time intervals also showed that the antibiotic treated mice had lowered levels of fecal bacteria, and greatly diminished diversity of fecal bacteria. Specifically, members of the prokayotic phyla Bacteriodetes and Firmicutes, present under normal conditions, were essentially absent in the antibiotic treated mice. These bacteria were replaced with members of Lactobacilli, a result consistent with another recent report examining changes in the microbiota of antibiotic fed mice. The results outlined above were achieved using outbred mice strains housed in pathogen-free, but not germ free conditions; therefore this study addresses one of the critiques above with the use of outbred mice.

This paper was also significant, in that the authors also propose a mechanism for how the immune modulation occurs. Recolonization of antibiotic fed mice with a group of Firmucutes from genus Clostridium (the major genus of the Firmucutes from normal mice), prevented the allergic response produced by peanuts. Dissection of the intestines from these animals indicated that specific T cells involved in adaptive immune regulation are more prevalent in Clostridia colonized mice. Additionally, mice colonized with Clostridia in comparison to germ free mice and control mice exhibited high levels of an immune cytokine Interleukin 22 (IL-22). The authors propose that IL-22 (induced by the presence of Clostridia) causes the intestinal epithelial barrier to be reinforced, reducing the permeability to dietary proteins. To address this possibility, they then measured the levels of food allergens in the bloodstream after intragastric gavage. Colonization by Clostridia resulted in significantly lower levels of these allergens in comparison to germ free mice, supporting this hypothesis.

The major conclusions of this paper support the important role of the benign normal microbiota in promoting health. Their model argues that tolerance to food antigens is aided by the presence of those antigens along with specific components of the normal microbiota. To translate this work to human therapies, the role of Clostridia needs to be confirmed in humans. Indeed, other work has shown that Clostridia species isolated from human feces do induce the same immune regulatory cells discussed above when transferred to germ free mice, suggesting that they may be playing similar roles in both species.

Notes from the Field: Listeria from Soft-ripened cheese

 

some nice cheese, via Cheese.com

some nice cheese, via Cheese.com

Via the ever helpful Morbidity Mortality Weekly Report, another alert about the dangers of foodborne-illness! The Minnesota Department of Health reported in late July 2013 two cases of invasive listeriosis, for which molecular analysis indicated a sole-source for infection. As an aside, the Minnesota Department of Health seems to be the hardest working state department of health, as evidenced by this alert about Salmonella from Guinea pigs, and this alert about Salmonella from phlebotomy that I found in the BIO230 archives. Way to go, Minnesota Department of Health!

Once the Centers for Disease Control and Prevention were notified, further analysis indicated that the isolate was also identical to an environmental isolate collected from a cheese producer in 2011. With this in place, several other cases were also identified by the CDC in last summer’s outbreak, resulting in one death and one miscarriage. All patients were interviewed to determine their “cheese exposure.” All patients indicated that they had likely eaten one or more of Crave Brothers Farmstead Cheese varieties (Les Frères, Petit Frère, or Petit Frère with truffles) during the likely time frame for infection, at either grocery stores or restaurants in the region. All of the cheeses were shipped as intact wheels to the point of sale, where they were cut and repackaged.

The manufacturer issued a voluntary recall when news of the outbreak was made public. Conjecture by the CDC suggested that the contamination arose during the manufacturing process. The process of pasteurization very effectively eliminates Listeria monocytogenes from milk, however in the cheesemaking process contamination can occur after the original pasteurization. The CDC recommends that strict sanitation and monitoring of contamination steps always be in place for cheesemakers, regardless of whether pasteurized milk is used.

The CDC also reiterated standard precautions to protect against infection by Listeria, which again bear repeating. The organism does not generally pose a significant health risk to the general population, however immunocompromised individuals can become quite seriously ill. Additionally, pregnant women can pass the organism onto the developing baby, and fetal infection due to Listeria is a significant cause of miscarriage. Because of these risks, at risk individuals are strongly advised to avoid any food that carries the potential for infection by Listeria.

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