Thursday June 7, 2012
3:01
Elizabeth Pennisi:
Hi. Welcome to this afternoon’s Live Chat. Our twitter connection is #sciencelive. Today we’re talking about the trillions of microbes that live in and on our bodies. Collectively known as the human microbiome, these “bugs” are usually our friends, helping us to digest food, strengthening our immune systems, and keeping dangerous enemy pathogens from invading our tissues and organs. Researchers are trying to learn how changes in this community of microbes can lead to disease.
With us today is Lora Hooper, an associate professor of immunology at the University of Texas Southwestern Medical Center in Dallas and an investigator of the Howard Hughes Medical Institute. Her group studies how friendly bacteria shape intestinal immunity in the gut and how the immune system prevents these bacteria from invading host tissues and causing disease.
Our second guest is George Weinstock, associate director of The Genome Institute at Washington University in St. Louis. He is one of the principal investigators in the NIH Human Microbiome Project and leads numerous other metagenomics projects that study human disease.
Thanks for joining us, George and Lora. I’d like to start off with a question. How similar is my microbiome to your microbiomes?
3:02
George Weinstock:
We know the microbiome is flexible both in being dynamic but also variable between people. Some studies focus on the taxa that are present, some the genes, and it may be that some taxa are replaceable by other organisms with similar genetic functionality, which could give variability but it is really flexibility. There is a growing understanding of the host involvement in microbiome structure as well, the papers on the immune system in the Science collection for example. So host genotype may be another factor in the variability. We are all familiar with comparisons of the human genome between people – it is usually simplified that we differ in about 1 nucleotide out of 1000 in our sequence. Well, the microbiome is much more complex, and if we wanted to try to put a number on similarity between “microbial genome sequences” between people, it would be hard but it would be much lower than 99.9%.
3:05
Comment From KEITH
How damaging to children is the anti-dirt fetish of today
3:05
Lora Hooper:
This is a really interesting and important question: do our children get enough immune stimulation from bacteria in the environment and in their bodies? At this point we know precious little about exactly how the microbiome influences immune system development in babies and children, but this is being actively investigated in several labs. I think we'll know much more about this in the coming few years.
3:05
Comment From c_ve
The genome project has been a costly adventure with very few leads towards translation. Moving towards individual patients, we are finding that our old population-based "safe" statistical methods are inadequate and that our study designs are not really geared towards interpretation from data on individuals. There have been many new developments in statistics and computational biology and yet, there is hesitation on the part of prominent molecular epidemiologists to explore these methods for personalized translation. Rather unfortunately, in the narrow focus to replicate older studies, more money keeps getting thrown into repeating the same tests over and over, with not many translatable goals. Does this problem exist in the microbiome field as well? How receptive are senior researchers in this field to moving out of the vice-like grip of "simple" but sadly inadequate and inappropriate statistics? How will the field tackle the challenges of translating to a single patient or individual? Are we at a point yet where we could be confident about manipulating our microbiota to counter other infectious agents? If not, how far ahead do you foresee us coming to this point in translation?
3:05
George Weinstock:
There is a lot of activity in terms of new methods for analyzing data in the microbiome field. Things as basic as how to do power calculations and experimental design are being improved and made more accurate. Much from ecological analysis is being integrated with appropriate changes for microbiome work. The existing data sets will continue to be analyzed and new studies will be more refined than in the past as a result.
3:10
Comment From Clinton
I am interested in learning more about how the microbiome works in conjunction with the robust presence of immune cells in the gut. Immune tolerance and cues must be associated with the cross-talk between these two very different cell populations and probably have links to local and systemic maladies. Has there been any progress in identifying specific microbes that coincide with autoimmune disorders and other pathologies of the gut? Also, do we know how the microbiome facilitates or disrupts digestion and metabolism?
3:10
Lora Hooper:
You have identified some of the major burning questions in the field! Of course the answers to your questions are very complex. There has been a lot of progress in the past year or so in beginning to tease out how different intestinal bacterial species impact the immune system, and I think that understanding how and whether these microbes elicit pathologies will flow from this work.
3:12
Comment From JavierCabello
Does killing the natural biota on the skin by showering everyday have an uhnealthy effect, as does killing the microbiota in the gut?
3:12
George Weinstock:
Our civilization has made many wholesale changes in our lifestyles that likely affect our microbiomes. Showering is certainly one, but things like air conditioning and controlled environments, carpeting, and other modernisms change the environments that collect microbes as well as our exposure to microbes and what microbes get selected for colonizing us. We are a very adaptive species so even though we have a different microbiome than the caveman, it is still doing us a lot of good although there may be some downside such as higher incidences of respiratory diseases like asthma.
3:15
Comment From KEITH
why have anti bacterials such as bezalkonium chloride been difficult to obtain over the counter?
3:15
Lora Hooper:
The question of whether our resident intestinal bacteria engage in quorum sensing is a fascinating one, as quorum sensing is typically associated with pathogenic bacteria. As far as I know, no one has reported definitive evidence of quorum sensing among members of the microbiota, but that's not to say it doesn't happen. It's an extremely difficult experimental problem because of challenges in detecting the molecules that mediate quorum sensing behavior.
3:16
Elizabeth Pennisi:
Oops,. we posted the wrong question...hold on
3:16
Comment From Ben G
What relationship/partnership does our immune system share with quorum sensing of bacteria of our microbiome, if any?
3:16
Elizabeth Pennisi:
That's the question that Lora just answered above. Thanks.
3:17
Comment From Mark Denny
Could we function efficiently without our microbiome (did we co-evolve with it)? What fraction of the microbiome is purely parasitic?
3:17
George Weinstock:
The general belief is we would not be very healthy without a microbiome. For example, we would be much more susceptible to infection by pathogens. We definitely co-evolved. Our gut and mouth are essentially organs that evolved to house large numbers of bacteria who could be beneficial without causing damage. That's quite a feat.
There are some summaries of the gut microbiome in infants in the Science collection, but actually besides vaginal and caesarean delivery, there are also pre-term babies who are put on antibiotics for the first days to a week of life. They are close to germ-free when the antibiotics are removed and their initial colonization seems more a matter of chance. Yet they will eventually converge on the same community patterns that are found in all children. And these are not the predominant organisms in the air or water or the environment. They are selected somehow. The microbiome is both flexible both also highly restricted in the end.
We shouldn’t only focus on the bacteria. The viruses and eukaryotic microbes are going to play an important role as well. There’s a nice paper in the Science collection by Underhill and colleagues that emphasizes the importance of fungi. And viruses, both animal viruses and bacteriophages, are ubiquitous but certainly not passive.
3:18
Lora Hooper:
We can raise animals (such as mice and pigs) without a microbiome, so life without microbes is certainly possible. However, we did co-evolve with a microbiota, and this was probably very important for maximizing efficient extraction of dietary nutrients. So life without a microbiota might be possible, but not as pleasant!
3:21
Comment From Cathie
I have read that lean people have more bacteroidetes than firmicutes and that in obese patients it is the opposite, suggesting that the healthy combination would be more bacteroidetes than firmicutes, but then diabetic patients also seem to have more bacteroidetes that firmicutes suggesting that more than considering just the proportion of this two groups is the strains that form part of them that have to be determined in detail, is it so? Also what do you think about some elements of our diet that we have been told are good for our proper intestinal function but probably we have been wrong all this time, for instance fiber, in particular the non soluble one like that from grains, because it could damage our gut cells and feed and make proliferate the "wrong" bacteria, leading us to gastric problems like chronic constipation, irritable colon syndrome, colitis etc...?
3:21
George Weinstock:
There have been some studies that showed a correlation between Bacteroidetes and Firmicutes and obesity, particularly in mice but also in humans. However other groups have either found no correlation or the opposite correlation. This is a difficult area to study, given that the subject's in the studies have different diets, genetics, etc. The mice studies showed that you can transplant the microbiome and the obesity trait goes with it. But we also know mice are not humans. So there is a feeling that the verdict is still out and it may not be this simple.
3:24
Comment From ahmad2bala
are destruction of beneficial microbes lead to an increase in autoimmune disorders and obesity
3:24
Lora Hooper:
It is certainly possible that alterations in the normal communities of beneficial microbes can lead to autoimmune and metabolic disorders. After all, we co-evolved with these microbes. There have been a number of studies out of the Gordon lab showing that the ratio of Bacteroides versus Firmicutes can be a factor in determining whether an animal (or human) becomes fat/obese. Less is known, I believe, about how and whether such alterations predispose to autoimmunity.
3:25
Comment From Nathan S Ivey
What accounts for the discordance in bacterial populations between twins? Would you agree that this divergence in genetically identical individuals points to an increase in nurture (environment) vs. nature (genetics) in human health and disease?
3:25
George Weinstock:
Great question Nathan. This gets at the issue of variability in the microbiome between people. I gave some thoughts earlier on variability but here is some other issues to think about.
I think one area where we need more definition is in the dynamics of the microbiome, and this has relevance also to understanding variability in disease: when is a variant microbiome due to disease perturbation and when is it a transient state that’s part of the regular dynamics in a healthy person. We know there is a certain level of stability – some things that are there repeatedly. But we also know the microbiome is not static. Wide variation has been seen in a longitudinal study and we know it changes after antibiotics are removed or when diet is changed. And one important distinction between microbes and communities of plants or animals is that microbes can grow very fast. E. coli increasing in numbers by one million-fold in a test tube is no problem. But we don’t have a consistent model to explain both how it can be conserved as well as not be static. We need to understand that better to accurately assess healthy and diseased states from limited sampling.
3:29
Comment From Maria
I understand that some bacteria are "good" and some are "bad", and that this depends on many aspects sucha as location, number of cells, state of the host, etc. But, is there a clue on what makes our bodies accept some of these microorganisms and not others?
3:29
Lora Hooper:
Great question, Maria. I think it depends on many things, but a big factor is the location of the bacteria. This is actually a very simple but important concept. Most of the bacteria that are non-pathogenic are highly adapted to the environment of the intestinal lumen, and are able to quickly and effectively extract nutrients from the diet ingested by their hosts. However, some pathogens (Salmonella for example) are not able to compete effectively with resident bacteria from these nutrients and instead adopt a strategy of invading our tissues in order to get nutrients. Obviously, this is a bad thing for us, and we tend to mount a vigorous immune response against such bacteria.
3:30
Comment From tamara
Does it appear to you that this line of study could lead to a future where a patient with a bacterial infection, rather than being prescribed anti-biotics to kill all similar bacteria, could be given a balanced suite of microbiotics to ‘out-compete’ the offending bug? This is the concept we utilize in soils with compost addition. What about increasing the use of compost in the production of food? Could that increase the micro-diversity in the consumers of the produce?
3:30
George Weinstock:
This is one of the grails of microbiome research, so the answer is definitely YES. There's much interest in looking at ecological approaches to manipulating the microbiome, instead of "nuking" it with antibiotics, and there are several reports in the Science Collection about this thinking. It is very intellectually exciting to see the marriage of ecological thinking with microbiology and human physiology. This is certainly one very fresh approach to the science of human disease, although I’m sure its been around for a while. We may not have had quite the extensive data sets or sophisticated thinking drawn from decades of developing ecological concepts. The Costello paper in the Science collection moves this approach along and provides some specific ideas for models of how we might understand ecological mechanisms in the body.
3:35
Comment From Seyi
Hello! Do you have any opinion on the effects hygiene products such as aerosols and soaps have on our natural flora? Also what do you think of a project which aims to document the progressional change in the microbiome of individuals over a lifetime?
3:35
Lora Hooper:
A very interesting study from Rob Knight's group from a couple of years ago looked at the effects of hand-washing on microbiome abundance and composition of skin bacteria. Obviously, there were profound effects immediately following hand-washing but an interesting finding was that most of the bacteria bounced back after a fairly short period of time. I think it's less clear what the long-term effects are of soap use on overall natural flora composition, but definitely an important thing to find out. In answer to your question about progressional change of the microbiome: I think that there are several projects already underway to address this question, so stay tuned....
3:36
Comment From tim
What is your view regarding bacteria causing cancer? The famous bacteria probably is Helicobacter pylori but recent metagenomic approach also identified Fusobacterium nucleatum in colorectal cancer patients. Since cancer is a multi factorial disease, could it be possible there will be more findings supporting the bacteria cancer? Most researchers don't really believe in bacteria cancer. Thanks!
3:36
George Weinstock:
There's been work done in the past about microbes and cancer but it seems like its all getting a fresh look now that there's so much interest in the microbiome. No question that Helicobacteria is involved in gastric cancer. And you point out the recent finding of Fusobacteria in colorectal cancers. There are other studies ongoing looking for bacteria associated with tumors both outside and inside. And there is considerable interest in bacteria who excrete potential carcinogens as an end product of their metabolism, thus putting the surrounding tissue at risk. And let's not forget about viruses. So there is a renewed interest in this area and there is likely to be continuing new observations to follow.
3:39
Comment From Dieter Schifferli
Much of the work done is dealing with correlation studies. It will be difficult to study causality when so many individual bacteria of the microbiome can't be cultured. Any thoughts about new approaches to handle this bottleneck?
3:39
George Weinstock:
Hi Dieter. There is an arm of the microbiome research that is focusing on developing new culture media or methods for sorting single cells without culturing them, with the intent of measuring their numbers. So there is some movement in this area.
However, this brings up the larger issue of making connections between disease and microbiome. Despite the huge amount of the work that has been done on the human microbiome, the number of rigorously proved connections between disease and microbiome are few to none. There are some very interesting articles in this context in the June Science collection. So far, we mainly look for connections with single organisms or genes, and often only those that are most abundant. One wonders if there will be some low-hanging fruit in terms of disease causation to discover among single abundant organisms. But if it is more complex, and I think the whole idea of community-oriented effects is that it is complex, then we may need to take our data collection and/or analysis to another level before we find effects. Maybe we need larger subject cohorts, or deeper sampling of the communities and their genes, or longitudinal studies to sort out the conserved from the transient. In any case I am very optimistic that we are very close to a bonanza in disease-related microbiome discoveries.
3:40
Comment From Dieter Schifferli
Lora, isn't it simply because quorum sensing is mainly studied (and funded) in pathogens?
3:40
Lora Hooper:
That could be, but there have been a number of labs looking actively at the question of quorum sensing in commensals as well. Hopefully some more information on this will be forthcoming.
3:44
Comment From Deuke
How do you know for certain that our present-day microbiome, and its set of "instructions" is not the same as those of the "caveman?" I understand that the belief exists that environmental changes may contribute to differences - but what is the evidence of such a belief?
3:44
Lora Hooper:
Well, there's ample evidence that diet is an important determinant of microbiome composition. This evidence is derived in part from studies in animals where diet and microbiota composition can be well-controlled. Our diets, generally speaking, are likely to be enormously different from that of a prehistoric caveman in that we tend to eat a lot of agricultural products such as grains that weren't in existence during paleolithic times. So I would be willing to bet that our microbiome is very different.
3:45
Comment From c_ve
The HMP started out as a pilot to demonstrate feasibility of data collection and analyses. Now that the pilots are coming to an end, do you think that feasibility been amply demonstrated? In which domain do the crucial challenges in this field like - is it laboratory methods, experimental systems, population related recruitment, data analyses or something else? If you were to rank these research domains from most challenging to least challenging in terms of microbiome research, what would your order be?
3:45
George Weinstock:
You're right that the NIH Human Microbiome Project was a "feasibility" study and it has produced large datasets, produced methodology for large-scale sampling of many body sites in an individual, contributed analysis methods, etc. This was its goal, along with infrastructure development for the NIH and the research community. Probably the main marker to its success is that there are now microbiome projects in many of the NIH institutes: at least NIDCR, NHLBI, NIAID, NHGRI, etc with other institutes planning to get into the fray. The HMP still has a component that is ongoing - the Demonstration Projects - which are the projects looking for disease correlations. They will be the ones that determine which of the areas you mention are the ones that need more development, and their results will be in over the next year.
3:47
Comment From Maria
I recently read that we are born with some bacteria in our gut. Is this true? and if so, how can this happen?
3:47
Lora Hooper:
Human babies develop in utero without any bacteria, but they acquire bacteria from the mother during passage through the birth canal. The type of bacteria that colonize a newborn infant depends on whether the mode of delivery was vaginal or whether the infant was delivered via C-section.
3:51
Comment From Jim Goedert
Could you please address the challenges of estimating absolute (rather than relative) differences among and within individuals' gut (fecal) microbiomes? Are there (relatively) good standards that could be used?
3:51
George Weinstock:
It has been difficult to get the kind of absolute numbers of organisms that you allude to, although this is pretty important. Part of the problem is that the samples are not uniform. When you analyze a stool sample you are really looking at just a subsample of the specimen, and it is often hard to make things homogeneous. For this or other body sites you have a range of materials: more fluid with saliva, more tissue for skin, etc. Trying to get the same volume of sample from each person is hard. Nevertheless, it would be worth effort in this area since a measure of the absolute amount of organisms is important.
3:53
Comment From Sparkenstein
Is there any clear distinction or set of properties that differentiate the bacteria that live in your gut and those that live on your exterior -- or are the ones in your gut just the bacteria that have been able to "get in"?
3:53
Lora Hooper:
The communities of bacteria in the gut and on the skin are quite distinct, but there is certainly some overlap. The bacteria in the gut appear to be well adapted to harvest nutrients from the host diet. For example, Bacteroides species are well-equipped to digest all sorts of complex carbohydrates that we ingest as part of the plant-based portion of our diet. Another special feature of many microbes is their ability to thrive in an anaerobic environment. The organisms in the gut have to be able to live without much oxygen, whereas those on the skin tend to be adapted to an aerobic environment.
3:56
Comment From Dieter Schifferli
Has there been any study administering orally a gut virome to modulate the microbiotas of different individuals (animals or humans) ?
3:56
Lora Hooper:
Not to my knowledge, but there are efforts underway to look at bacteriophage that are associated with resident bacteria of the gut. Some of these are lytic towards particular bacterial species and strains. This suggests that there may be opportunities to use bacteriophage to shape microbiota composition.
3:57
Comment From ahmad2bala
what are the role of bacterias in current epidemics of early life obesity and type2 diabetes
3:57
Elizabeth Pennisi:
oops,. wrong question....
3:57
Comment From ahmad2bala
how related the microbiome are to each other on or inside aperson s body
3:57
George Weinstock:
In general, the microbial communities you have in the different sites of your body are distinct (e.g. gut vs mouth vs skin) and do not appear to overlap too much. Also, not everyone is the same in terms of their gut microbiome for instance and there may be classes of communities people have.
3:58
George Weinstock:
Thanks to everyone for great questions. Sorry I couldn't answer more of them. I think June 2012 will be remembered as Microbiome Month. There's a plethora of significant publications coming out. This important collection in Science, the wonderful article in Scientific American, another landmark collection of articles from the NIH HMP will appear this month, and I know of at least one other major magazine that is preparing a signature article. It feels like a coming of age party for the human microbiome field and it's very exciting.
3:58
Elizabeth Pennisi:
Before we sign off for the day, I would also like to thank everyone for their great questions. There were many more than we could answer.
3:59
Elizabeth Pennisi:
Join us next week for a live chat on paternal bonding--just in time for father's day!
