I'm Professor Rob Knight. Let’s talk about the lessons we can learn from poop...I mean, the millions of marvelous microscopic creatures inhabiting your gut. AMA!

You get a poo sample and a metadata sheet from every person on the planet. Amazon grants you all of their EC2 servers to process it, and every analysis just came in. What is the first thing you look at?

I think the most promising (and understudied) area is linking the gut microbiome to mental health. Interestingly, this was one of the things Francis Collins suggested at the launch of the Human Microbiome Project -- at the time, a lot of people thought that perhaps his own mental health was in need of checking, but evidence of the roles microbes play in the gut-brain axis has accumulated remarkably rapidly since then (although human studies are still rare).

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There's some really nice work that's been done in mice, e.g. by John Cryan's group at University College Cork and by Chris Lowry's group here at Boulder, suggesting that there are specific probiotic strains of bacteria that can improve outcomes with mouse analogs of stress and depression. Connections between diet and mood are also well established, and the microbiome likely plays a role in at least some of these (most of the serotonin in your body is in your gut, not in your brain). However, it's important to remember that the same microbe often has different effects in different host species. For example, Salmonella typhimurium, which just gives you food poisoning, causes the equivalent of typhoid fever in mice and is often lethal. So there are large risks involved in just assuming that what's beneficial in mice will help you. Waiting for clinical trials to be done is the best plan.

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It's a really good idea, and we had a grant from C2B2 (the Colorado Center for Biofuels and Biorefining) on this topic a few years ago. Many people are studying this in the context of different species' guts. Most focus is on herbivores that can digest wood, ranging from cows to termites to shipworms. The tricky part is not getting it to work in the lab but scaling up to commercially viable systems, though.

What do you recommend for the average person to improve our digestive health/bowel movements?

Well, a lot of the evidence pre-dates studies of microbiome involvement but studies of the microbiome help us understand why things work. For example, there's a lot of evidence that fiber is good -- in part this is because bacteria ferment it into butyrate in the large intestine, and then the butyrate helps feed the cells that line the gut. Special considerations apply if you have specific conditions such as irritable bowel syndrome (and then it depends which subtype). One of the main things we're learning about the microbiome is that everyone is different, so it may be that the right advice on diet depends a lot on the individual (and that individual's microbes). But the general guidelines that are supported by evidence are things you'd expect: lots of leafy green vegetables, lots of brightly colored vegetables (these contain carotenoids, anthocyanins, lycopenoids, and other beneficial plant compounds), fermented foods, no fries or artificial sweeteners, or highly processed foods, etc.

does beer count as a fermented food?

Yes but it's also high in sugars, which tend to have a less good effect.

How do artificial sweeteners affect the microbiome? Please use as much jargon as is necessary in your answer. I'm not afraid to google.

Later this week (looks like it is not online yet), you'll want to google essentially the question you're asking.

I assume you're referring to a paper that will be published without a paywall. Do you have a title?

Sorry, I shouldn't have said anything, but searching for microbiome and artificial sweeteners later this week should pull it up.

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Yes, that's what I had in mind, and it has just been posted online. Here's a direct link (regrettably behind a paywall): http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13793.html

Thanks for doing this AMA, I hope more people turn out. Here is my question. I had chemo last year for testicular cancer. What type of effect did that have on my gut flora? I still (a year later) feel like things aren't completely back to normal in that regard.

Research on this is very recent (mostly in the last couple of years) and it probably depends on which specific drug you had. There's a recent review of the literature here:

http://www.ncbi.nlm.nih.gov/pubmed/25040088

...which suggests that there are some consistent changes with chemotherapy, especially decrease in beneficial microbes such as Faecalibacterium prausnitzii, and increase in proteobacteria (which tend to be inflammatory). The research is still in too early a stage for specific guidelines in my opinion, but the field is developing rapidly.

Same here, I had chemo 8yrs ago and now suffer from acid reflux and wheat/gluten intolerance.

Wonder if this is related?

Thanks for being a scientist and researching this stuff!

It's possible. There's very little information on long-term effects of chemo (or antibiotics) although many people have anecdotes like yours. The challenge is to get enough people with similar stories to turn them into usable information. Thanks for your kind comments!

Hey Dr. Knight! Thanks for doing this AMA.

What are your thoughts on fecal transplants for treating all manner of diseases from crohn's and IBS to cancer?

Also, what goes into selecting donors for fecal transplants (i.e. what constitutes a healthy persons gut biome)?

Thanks! There's a lot of promise in fecal transplants although as noted elsewhere, the FDA guidelines make it hard to do research on this in the US.

Donors are usually selected as family members (relatives or spouses), although there is no evidence that this helps as far as I know -- it just makes the transplant more culturally acceptable. A very good reason not to use relatives or spouses is that they might actually harbor microbes that are harmful to the person who has the disease but are harmless in the context of their own microbiomes and genetics. On the other hand, family members, whether related or just living together, tend to have more similar microbiomes, see for example the papers below, so that decreases the risk of introducing problematic microbes.

http://www.ncbi.nlm.nih.gov/pubmed/19043404 http://www.ncbi.nlm.nih.gov/pubmed/22699611 http://www.ncbi.nlm.nih.gov/pubmed/25170151

The AGA has some material on fecal transplant here (disclosure: I am on their Microbiome Center Science Advisory Board)

http://fmt.gastro.org

What does a "good poop" look like? Is it firm, soft, a certain color or consistency?

The Bristol Stool Scale (http://en.wikipedia.org/wiki/Bristol_stool_scale) provides some guidance on this. Alternatively, the National Folk Museum of Korea currently has a special exhibit in the children's wing dedicated to the topic of poop, including what it should look like: http://www.kidsnfm.go.kr/nfmkid/viewPage.do?screenId=SCREEN_ID_ENG_SPEC#NONE

Thanks so much for doing this AMA! I had a C-section when my daughter was born about 5 years ago. I had, of course, a large dose of antibiotics that day, and then a course of them shortly after her birth because of an issue with my stitches. Since then I have suffered from dyshydrotic eczema on my hands. Someone recently suggested to me that it may be due to a yeast overgrowth in my gut. My dermatologist poo-poo'ed the idea, but I've been wondering about it. The only other time in my life I suffered from eczema was as a child when I was on antibiotics frequently for ear infections. Do you think they could be related?

It's plausible, and it's been reported killing off the bacteria in the mouth, the vagina and the gut can cause yeast overgrowth there, although evidence is mixed to date. Studies of fungi on the skin are still very recent although Julie Segre's lab has been doing some really nice work there, e.g. http://www.ncbi.nlm.nih.gov/pubmed/23698366

Thank you so much for answering. I hesitate to try to "fix" my gut on my own. Do you have a recommendation for the type of doctor I might visit to address this? I haven't had much luck with dermatologists or my general practitioner.

Gastroenterologists tend to be most interested in this sort of thing but it's still very much an emerging field. We're doing a lot of outreach through the AGA.

From my experience most gastroenterologists will look at you like you're a nutcase and tell you you're a hypochondriac who reads too much online if you mention stuff like this to them. If you come up clear for chron's/uc/cancer and try to push for further investigation from your gastro you'll be advised to go back to your GP and ask for anti-anxiety pills.

Most but not all, and knowledge in this area is expanding rapidly.

Why is the lesson my poop always tries to teach me-Do not eat at Taco Bell?

I don't think you need your poop to teach you that lesson...

Whats this about the "Biological dark matter" that's in our tracks? Seems wild too me.

There are two main ways "biological dark matter" is used:

(i) The vast majority of microbes in the environment belong to groups that we don't know how to culture. This used to be true for microbes in the human body, but is a lot less true now than it was 5 years ago due to improvements in culture techniques. So the "dark matter" can refer to microbes that we know are there (because we see their DNA) but no-one has seen under a microscope or grown in culture.

(ii) Many genes isolated from the environment can't be linked back to a specific genome. In part, this is because a lot of genomes (especially viruses) haven't been sequenced yet, but there might also be new kinds of life out there, or "in there", that don't fit into our existing classification scheme.

there might also be new kinds of life out there, or "in there", that don't fit into our existing classification scheme

Do you, personally (gut-feeling if you like) think this is likely? I have sequence data (published) from a sponge sampled from 2900 m depth and a cluster of sequences neither falls in the domains Archaea or Bacteria. I personally trust the rigourous quality filtering of the data and I have to believe (with healthy scepticism) what I am seeing.

Yes, I think it's likely, but as you note the evidence has to be really good as a lot of incorrect papers have made it into the literature (e.g. the infamous arsenic bacteria).

Do babies start out with "blank slates" as far as microbiomes go, or do they receive microbes from their mother?

Good question! Babies receive their first major dose of microbes as they travel (often slowly) through the birth canal. In 2010, we showed that babies born via c-section have different microbial communities than babies born through the birth canal. You can find that paper here. http://www.colorado.edu/eeb/EEBprojects/FiererLab/Dominguez-Bello_etal_2010.pdf

Understanding how birth mode, breastfeeding, and antibiotics affect a babies microbial development in active area of research spearheaded by our collaborators Maria Gloria Dominguez-Bello (NYU) and Elizabeth Costello (Stanford)

Have you come across any info on home-made kefir? Is it beneficial?

Most studies focus on commercial preparations because they're reproducible. Although the costs of studies have come down a lot, they're still expensive enough that you probably can't do it on your own home-made preparation.

What are some things we can do to be nicer to the good bacteria in our gut?

Avoiding unnecessary antibiotics is probably the largest effect. Eating fiber is good for the butyrate producers, which are generally beneficial. As noted above, eating a variety of fresh plants is good (in American Gut, how many kinds of plants you eat seems to have one of the largest effects on the diversity of your microbiome -- this is not to say that high diversity is necessarily good, but on the other hand obesity, diabetes, colon cancer and inflammatory bowel disease have all been reported to be associated with low diversity).

How long does it take for your microbiome to return to normal after a course of antibiotics? I avoid them as much as possible but I was forced to take them for a while last year due to Lyme disease. Prior to that I hadn't taken them for maybe 10 years and I am wondering if my gut flora may still be altered.

It varies a lot. Les Dethlefsen in Dave Relman's lab at Stanford looked at three people and saw totally different responses in all three of them: http://www.ncbi.nlm.nih.gov/pubmed/19018661 http://www.ncbi.nlm.nih.gov/pubmed/20847294 We need larger-scale studies but it's really hard to get ethical approval for them if they involve giving antibiotics to healthy people, and if you look at people who took antibiotics for a reason you don't know what's due to the antibiotics and what's due to the disease.

how do cigarettes effect your micro biome, and also alcohol..?

Alcohol is associated with increased gut microbiome diversity (at least in the American Gut population), which is consistent with the idea that moderate drinking is healthier than abstaining completely (this is supported by a fairly large number of different studies). Cigarettes have mostly been studied in the context of the airway and lung microbiome, where as you'd expect they have a negative effect. I haven't seen anyone looking at the effect of cigarettes in the context of the gut microbiome, although it's a logical study to do given the different effects of smoking on ulcerative colitis and Crohns disease (both linked to the microbiome).

I stand corrected, it has been done:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597605/

Thanks to Mr. Heisenbug for the link:

https://mrheisenbug.wordpress.com

What's the word on probiotics? I've heard some people call them bullshit, but others say that there's actually some peer-reviewed literature supporting their effectiveness.

In the same way that most drugs don't work for most conditions, most probiotics don't work for most conditions. However, there are specific probiotics that work for specific conditions, just like drugs. So you want to choose the ones where there's good scientific evidence supporting the idea that they'll work for the condition you're interested in.

Have you heard anything of the B. fragilis probiotic that seemed to temporarily reverse some autism symptoms in mice? Last year I heard they were looking into a pilot study in people, but I haven't seen anything since.

Yes. That study (by Sarkis Mazmanian's group at CalTech) is still in progress and what I've heard is very promising.

Could you speak a little on the co-evolution of humans and our digestive bacteria? I know that we evolved with these bacteria but I am curious as to how long this symbiotic relationship has existed. Is there any indication that we at one point did not have bacteria in our digestive tract?

Edit:grammar correction.

It is likely that the relationship between gut microbes and humans has existed for a very long time since we see gut microbes inhabiting hosts that are distantly related to us (e.g. insects). That means the gut microbe-animal relationship likely existed even before humans did. Work that Katie is currently doing in collaboration with Steve Leigh and others suggests that there may be something special about human gut microbes that contributed to our ability to grow large brains and inhabit new environments with distinct diets.

Do you study coprolites? If so, how does the microbial content differ between hominid species such as H. neanderthalensis and H. sapiens? And is there a significant dietary difference?

We study coprolites, which occasionally preserve the hosts gut microbes. See our open-access research with Cecil Lewis' group here http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051146 No Neanderthal coprolites yet that we've looked at!

Are you interested in different individuals level of digestive abilities? For example I seem to be able to eat basically anything in any quantity and not feel sick, ill, get diarrhea, have a stomach ache, or any of those negative things. My wife on the other hand can barely eat dinner without her stomach being in awful pain.

Is this because of our microbiome? Could someone like me donate microbes to someone like her to help with those types of digestive issues?

Also, where does our microbiome come from? If I understand, our gut is sterile in the womb. Are we basically just infected as soon as we are born and that is our microbiome? Could new borns be infected a certain way to give them a better/healthier microbiome?

I'm very interested in this subject. I've just started my master's in cellular and molecular biology. If you need a PhD student in a couple years let me know ;)

Yes, this is a very interesting topic. We think it's the type of thing that might be best answerable through crowdourced/crowdfunded projects like American Gut, which everyone is welcome to sign up for. And we're always looking for talented people to work on the microbiome -- because the area is so new, there are a lot of great questions that are tractable and exciting as student projects. Many of our best papers have graduate students and/or undergraduates as coauthors.

Very interesting thank you. And could you answer this part of my question?

"Also, where does our come from? If I understand, our gut is sterile in the womb. Are we basically just infected as soon as we are born and that is our microbiome? Could new borns be infected a certain way to give them a better/healthier microbiome? "

see my answer to speezo_mchenry

Are the claims of this cholesterol lowering probiotic (Probiotic strain: Cardioviva™ (Lactobacillus reuteri NCIMB 30242) Colony-forming units (CFU): 2 x 109 (2 billion) (80 mg)) anywhere near true or is it a waste of money?

The clinical trial data seem to suggest that it has a statistically significant but modest effect: http://www.ncbi.nlm.nih.gov/pubmed/22990854

I don't know what their marketing claims are.

So I took a look at their web site: they seem to be accurately reporting the results of their clinical trial, which is refreshing (the claims for many probiotics are overstated, which must frustrate the companies that actually do proper clinical trials and report the results). Whether it is a waste of money probably depends on what other treatments are available to you, which is really a conversation between you and your doctor.

What is your take on "colon cleansing" products?

There hasn't been much research on the effects of colon cleansing on the gut microbiota. Here is one paper that was published on the topic showing that colonic lavages (the pre-treatment before colonoscopy) reduce the diversity of bacteria in the colon. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289660/

We've all heard about the benefits of live active culture foods like yogurt. When I consume a cup of yogurt, do its microbial denizens actually take up residence in my guts for any significant amount of time, or are their beneficial functions carried out as they are "just passing through?"

It depends on the yogurt. Many of them have strains that are specifically selected not to establish in the gut (for regulatory reasons, and/or because they want to keep selling you the yogurt). However, even bacteria that don't establish in the gut may have a beneficial effect on their gut bacteria while passing through.

What bacteria should we be trying to establish in our guts and how can we go about it.

As noted elsewhere, there's probably no "one size fits all" answer to this.

Thanks for doing this AMA!

I have an, odd, question.

When I am ill with a cold or flu, I notice that my poop, and gas that gets passed, smells uniquely different, almost stronger. If I am not imagining things, does this mean that my gut bacteria are also 'sick', or does me being sick just alter their production of gas? And to build on that, do you think it's possible to use gas to detect illnesses or other problems in the body, given you know what to smell for?

It's very plausible but there has been relatively little research on this topic. However, mass spec techniques for looking at small molecule metabolites (including those that produce smells) are getting much better.

What are the best foods for my microbes?

I know this sounds evasive, but it depends which microbes you have (and whether you want to keep those ones happy or change them). Some of the foods that have been reported to have large effects are fiber, garlic, and turmeric (the last two of those have antimicrobial activity against proteobacteria, which usually cause inflammation). In the long term, the ratio of plant to animal sources in your diet (also correlated with the ratio of carbohydrates to protein) makes a big difference. A lot of effects of individual foods are just starting to be investigated now. But diet is a very complex question, especially because foods you might consider the same (say, "a potato") can have completely different metabolites in it depending on where it was grown, how it was stored, how it was cooked, etc.

What are your thoughts on probiotic drinks such as this one - http://www.yakult.co.in/whyyakult.php ?

Some probiotics have good peer-reviewed evidence supporting them. For yakult specifically, you can search pubmed and see results here:

http://www.ncbi.nlm.nih.gov/pubmed/?term=yakult+AND+%22clinical+trial%22

However, most work on yakult has been done in infants, as you can see from the search results. Different probiotics work for different conditions, just like different drugs work for different conditions.

My employers restrict the times at which I may poop... is holding it in bad for me?

There's no data on whether it's bad, but experimentally altering transit time (how long it takes the food to pass through your GI tract) does affect the microbiome in mice:

http://www.ncbi.nlm.nih.gov/pubmed/23380084

What are the benefits that can come from studying microbes?

There are many, as Jess, Katie and I will describe in the course. However, a few of the major ones are: a better understanding of the majority of the genes and the majority of cells in our own bodies; microbes that can be used in different industrial processes (not limited to food/beverages but also biofuels), better understanding of disease (chronic diseases as well as traditional infections), better understanding of how we metabolize our food and which food/drugs are best for which people, etc. A lot of this research is in early stages right now but the field is very promising.

What data analysis programs does your lab use for determining the population makeup of a sample? Which programs do you recommend for the best accuracy?

We develop the open-source software package QIIME:

http://qiime.org

...and, perhaps unsurprisingly, recommend it. This is an open-source project -- what's on github is exactly what we use in our own lab, and we welcome additional developer involvement both in that project and on scikit-bio, the library that it depends on:

http://scikit-bio.org

One of the things that has really made the remarkable advances in microbiome science possible is the availability of open platforms and open protocols, and the contribution of time from a large number of students and postdocs both on the development side and in answering questions on the QIIME forums.

What benefits can we obtain by studying the human microbiome more closely?

Over the past decade, the cost of DNA sequencing has dropped by orders of magnitude, which has allowed much better characterization of the microbiome of each person and allowed a lot more people to be studied. What we've found so far is that microbes are associated with all sorts of diseases and processes that no-one knew they were involved in -- obesity, inflammatory bowel disease, colon cancer, heart disease, and in mouse models even analogs of multiple sclerosis, autism and depression (there is some encouraging but preliminary human evidence for these last three as well). Additionally, we know much more now about how microbes metabolize the food we eat and the drugs we take, leading to large individual differences in how we respond to the same food or drug. Where the field is going next is moving beyond understanding who lives in a particular person's gut (in terms of which species live there) but the genes they have and the functions they perform. This is what will help us move beyond describing the microbes associated with a particular disease and towards understanding how to change them.

How can I increase the "good" bacteria in my insides?

See other answers on this topic.

Thanks for your time! I have three questions.

1. People of different ethnicities have different genetic makeup, implying there's a difference in their enzyme and other protein composition. Do people of different ethnic backgrounds have different microbial makeup as a result?

2. Genetic conditions like celiacs must have an effect on your microbes. Is there anything you could teach me about different genetic conditions and their effect on microbes inside human body?

3. I forgot what I was going to ask.

1. Yes, see here: http://www.ncbi.nlm.nih.gov/pubmed/22699611 However, we don't yet know which differences are due to genetics, which to diet, which to environmental exposure, etc. as all these factors differ among populations.
2. Evidence for links between celiac, and, more generally, gluten intolerance, and the microbiome is relatively equivocal at present. It's also somewhat hard to draw the line about whether a disease is "genetic" as many complex disease require some combination of host genetic factors, environmental triggers (including microbes), etc. However, if we take a clear-cut case of a genetic disease, like Down Syndrome (caused by having an extra copy of chromosome 21), there has been some work showing differences in the oral microbiome (nothing in the gut yet to my knowledge though):

http://www.ncbi.nlm.nih.gov/pubmed/23855174

The more general question about whether host genes affect the microbiome has been fairly extensively studied in mice and plants but the interesting information for humans I've seen presented at conferences is mostly unpublished unfortunately.

I recently read an article that correlated a person's mood with type of gut bacteria they have. It also said the mechanism it affects a person's mood (and mental health) is not known, but it definitely does. Anything more I can learn about this?

You probably read this article, which is the only one published to date on this topic that I know of:

http://www.ncbi.nlm.nih.gov/pubmed/24888394

You might be interested in these reviews, although what you really want to do is keep an eye on new work coming out as it's a hot area:

http://www.ncbi.nlm.nih.gov/pubmed/23910373 http://www.ncbi.nlm.nih.gov/pubmed/23384445 http://www.ncbi.nlm.nih.gov/pubmed/22507593

Already signed up for the class and bought a kit from AGP. So, besides the course, are there any other resources (books, youtube videos, etc.) that you would recommend for people looking to learn more? As it seems like there is a lot of different interactions between the different species of bacteria, the food and liquids we ingest (and their components), so wrapping my head around it is difficult.

How do you determine what genes and interactions the individual species of bacteria have? Could you give us an overview of the techniques that are used.

We have several suggested readings and links to videos on our coursera course page https://www.coursera.org/course/microbiome. These are a good place to start and will probably link you to additional resources.

What would you recommend to have a healthy colon? Are there any foods that I should avoid and others that I should eat more?

See other answers on this topic.

So I went to South America earlier this year and now I'm lactose intolerant; realized about a month later. I'm pretty darn sure its related to my week in Peru for my friend who stayed down there also has stomach problems. I didn't get sick or anything, and the things I was eating weren't too far out of my normal diet (very healthy, a lot of greens and a mixture of fish and non-red meats). Why is it that most people feel "Montezuma's revenge" or just a general discomfort when travelling to other countries?

It's very plausible that there could be a microbiome link to this, but there's little data. Travelers' diarrhea has been a much lower research priority than other diseases, perhaps understandably, so there's not a lot of data. However, in mice, the gut microbes have a large impact on susceptibility to other microbes. See for example Brett Finlay's elegant work on FMT in mice in this context: http://www.ncbi.nlm.nih.gov/pubmed/22046427

I was prescribed Cipro and feel like I've fallen into the worst depression of my life. Many others have experienced the same thing

Finding physicians that understand this is seemingly impossible. Most I talk to dismiss it and diagnose me with major depression. I believe the depression is a symptom of what damage the antibiotic did.

What can I do or begin doing right now that will help restore balance in my gut? I've been drinking Kiefer, eating various yogurts, taking probiotics, etc. I'm 3 months into this now and am not feeling at all like I did prior.

You're correct that others have experienced this: there's very little research to date, although it's a very interesting area for study. Unfortunately there's no evidence that would support a specific recommendation about what to do.

How does or will long read sequencing, like from PacBio, help you with the work that you do? Do you think that will have an impact on microbiome research?

Long-reads from sequencing technologies such as PacBio are useful for assembling genomes of bacteria, and improving taxonomic resolution.

What exactly makes a persons stomach more sensitive than others?

Also, can eating too much spicy food permanently alter your gut in a negative way? How else does spicy food impact your stomach?

I haven't seen any research on this but it's an interesting question, especially because many spices have high levels of antimicrobials (potentially part of why they taste good). If they target some microbe that's a key player in your gut ecosystem, that could cause all kinds of other effects.

Do you have any thoughts on the potential of using fecal matter transplants to treat IBS? As far as I know, it's currently only allowed for treating C. Diff., but as someone who has experienced significant changes in my digestion after a course of antibiotics a few years ago, I'm still looking for potential solutions (and yes I'm seeing a physician about this, I'm just curious about your opinion).

It's a really interesting idea but there is little evidence right now, see more extensive answer to the other question on this topic.

What is your opinion on gut microbiota studies using Germ-free mice? Do you think they are a good model organism to use when doing metagenomic studies and comparing them to the gut microbiota of humans?

Any chance you or anyone at CU Boulder is looking for a graduate student to mentor? I'm a senior Bio major with a big appetite for bioinformatics/genomics/microbiology type research

I think that germ-free mice are very important for establishing causality (if you can transfer the phenotype, even partially, by transferring the microbes, that proves that the microbes are involved in the phenotype). They are also very useful for mechanistic studies, primarily in establishing that the mechanism is plausible in mammals, although they do have numerous immunological and other differences from conventionally raised mice so some caution is warranted in interpreting the results (and, of course, you shouldn't get too excited about treatments until they have been demonstrated in humans in randomized placebo-controlled clinical trials, at multiple sites).

As noted elsewhere, we're always looking for great people to work on the microbiome. Note that Boulder does not have a germ-free mouse facility so if you want to focus on that in your own research you'll need to look elsewhere.

I've heard that probiotics have to be taken repeatedly to have any effect, as they can't colonize the gut due to their lack of numbers. So why is it that a single "fecal transplant" seems capable of having tremendous benefit for people with conditions like IBS?

That's a good question. First, I should mention that the best evidence on fecal transplant is for C. diff-associated diarrhea. As far as I can tell, there is nothing published on fecal transplant for IBS, just a desperate plea that more research is needed:

http://www.ncbi.nlm.nih.gov/pubmed/24119331

However, given that we now know that when IBS is appropriately subtyped there are clear microbiome links, it's certainly a promising area for research:

http://www.ncbi.nlm.nih.gov/pubmed/23766444

...but given the regulatory burden of obtaining an IND (Investigational New Drug application, from the FDA), it is likely that this research will happen outside the US.

There are several reasons why fecal transplants could be different from probiotics in their ability to establish. First, the doses of bacteria in fecal transplant tend to be much higher. Second, most commercial probiotics are microbes that come from food, whereas fecal transplants are all bacteria that came out of the gut, so success rates for establishing are likely much higher. Third, fecal transplants also carry along a lot of the metabolites in the stool, which may help establishment. Research to untangle these different factors is just beginning.

However, although we don't understand fully why fecal transplants are so effective, it's an empirical fact that they are (at least for C. diff, which kills 14,000 people a year in the US alone), with success rates typically in the 90-95% range.

How do our bodies ensure that our microbiomes do not reproduce too quickly? With cells with our own dna in them, we give a signal and the cell kills itself, but I doubt our gut microbes would let us do that.

There are thousands of papers on this topic, and it's very complex. However, briefly, the immune system has a strong presence in the gut, and it is constantly monitoring the gut microbiota. In a general sense, this is what keeps the gut microbiota in check. For example, the immune system has the ability to influence the composition of the gut microbiota by excreting certain compounds. The immune system will also launch an attack on any microbes that escape the gut. We'll talk about this a little bit in the course, but I would recommend a web search for literature on immune system-gut microbe interactions if you are interested in all the details.

People like Robb Wolf and Mark Sisson have been promoting a primal/paleo diet, in part by touting its benefits to gut bacteria. What's your take on those claims, specifically the claims that grains and soy have severe negative effects on the gut?

The evidence on soy is mixed: in Asian populations it has health benefits, but this may be because more Asians are equol producers, whereas non-producers seem to have more negative effects. Similarly, grains increase the amount of Prevotella, which is often thought to be good but may have a pro-inflammatory effect. So I'd say that the evidence is mixed right now but a lot of studies are in progress. It may also depend on what microbes you have and on your genetic makeup. It's also important to remember that different "traditional peoples" have totally different diets from each other, and that even within a group the diet an vary a lot seasonally -- the Hadza in Tanzania get most of their calories from honey that they forage at certain times of year, for example.

Thanks for doing this!

What do we know about the ability of the microbiome to influence our behaviour? Is it just speculation for now or are there any facts?

And second related question: is there a link between the microbiome and mood disorders like depression? Could depression be a symptom of an 'unhealthy' gut bacteria population?

There's a more detailed answer elsewhere on this topic but briefly, the evidence is excellent in mice and some evidence in humans is starting to accumulate. So it's a very exciting research direction.

I was diagnosed with ulcerative colitis when I was 8. I've had periods of very horrible years, but also years of near complete remission. What is research on gut flora fluctuations and remission/flare up of UC?

The largest study to date (mentioned above) is here: http://www.ncbi.nlm.nih.gov/pubmed/24629344

Do yakult help our body?

See the other answer on yakult. Most research has been done on colic in infants; there's little information on effects on adults yet, although it's plausible that it has a beneficial effect given the types of microbes it contains.

Taking Metamucil once per day - good or bad for gut microbes?

No published data to my knowledge (or easily discoverable on pubmed).

How different are the microbial environments in people who have restrictive or abnormal diets? Examples: Vegans, people who eat low/no carb diets, people with gluten intolerance.

Self-reported dietary categories tend not to produce statistically significant links to the microbiome, in part because variation within each category is very large (you can be a vegan and eat mostly potato chips, for example). There's a National Registry of Picky Eaters that we'd love to link up to but haven't yet. Interestingly, the diversity of plants people eat seems to have a large effect, and in the long term the balance between carbohydrates and protein (especially animal protein) seems to make a large difference in Western populations.

What are your thoughts on red meat?

A Western diet, which often includes more meat has been linked repeatedly to differences in the gut microbiota (when compared with diets based more heavily on plant material). See, for example: http://www.nature.com/nature/journal/v486/n7402/abs/nature11053.html http://www.ncbi.nlm.nih.gov/pubmed/24336217

Also, a study by Stan Hazen's group (http://www.nature.com/nm/journal/v19/n5/full/nm.3145.html) was published last year that showed that when gut microbes metabolize a certain compound (L-carnitine) found in red meat, they produce another compound (TMAO) that can lead to a hardening of the arteries.

So red meat affects both your gut microbiota and your health, and gut microbes appear to be playing a role in determining how red meat affects your health.

Why is it when I eat very spicy foods sometimes I just get one shot of diarrhea and my ass feels the spice? What can I do for my gut health to prevent that?

See answer elsewhere, although some of the receptors (e.g. for capsaicin, the active ingredient in most peppers) are found on multiple mucous membranes, not just in your mouth, so that could be a non-microbial explanation.

What is the most unhealthy thing that a person can do to increase bowel movements, as in a certain dietary supplement?

This is essentially impossible to answer as research funding for techniques that are thought a priori to be bad is understandably limited.

I'm a nurse and we often give acidophilus by mouth a few times a day when we have a patient on multiple antibiotics (I'm presuming the rationale is that you want to restore normal flora to the gut in order to prevent an opportunistic resistant organism from causing things like enterocolitis).

How well do these things really work? I'm not in there changing shitty bed linens all the time, so I'm considering that a huge win...

The evidence that some probiotics reduce diarrhea is excellent, although how well a specific probiotic works likely depends on the patient population (age and geographic location). Note that a lot of this is by modifying the function of bacteria already in the gut rather than necessarily establishing.

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As noted elsewhere, some probiotics are likely good for specific conditions. The evidence on probiotics for C. diff treatment is mixed, although some seem to have beneficial effects in clinical trials.

thoughts on IBD?

Our most recent work on this is here:

http://www.ncbi.nlm.nih.gov/pubmed/24629344

This is by far the largest study done to date and, importantly, includes treatment-naive subjects (so we can separate the effects of IBD from the effects of treating it).

Are gut microbes nature or nurture? My parents are from the Middle East but I eat a fair amount of American foods ( the healthier side of American foods). Am I closer to my husband whom I share meals with or my family I share DNA with?

Bonus question: what are your thoughts on enzyme tablets that help digest foods like cheese? I started taking them about 6 months ago and now they don't seem to work. Does your body adapt?

Studies to date have mostly focused either on sharing a household or on genetic relatedness but not both. Because these are subtle effects and the studies differ in methodology (which cause differences as noted elsewhere), this question is difficult to answer. Note that the relative amounts of foods matter a lot, so even if you and your husband have the same items on the table if you eat them in different proportions your microbiota can be quite different (although likely more similar than the microbes of people who don't live together).

It's possible that your microbes and immune system adapt to the effects of added enzymes but I don't think there is a lot of research on this to date.

not sure if a relevent question but...

My house-mate suffer's with terrible IBS, so i guess my question is - are those microscopic creatures all messed up and not working, or working overtime, or is it all something completely unrelated?

thanks by the way :)

There are several studies showing links between the microbiome and specific forms of IBS, including the one I linked above. Several probiotics including VSL#3 have some clinical trial data suggesting that they help for IBS, so that might be worth trying (although they don't work for everyone).

Could there be a link between the human microbiome and immune system health?

I know there are devastating immune system diseases for which the origins are not well understood (rheumatoid arthritis, multiple sclerosis, etc). Maybe the microbiome has something to do with this since it is the intermediary between our bodies and outside material.

This is currently an active area of research, but there's some exciting findings. For example, Dan Littman's group published a paper last year (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816614/) showing that Prevotella copri is associated with disease onset in untreated rheumatoid arthritis patients.

What made you interested in studying poop? was it this toy

No, although my 2-year-old might enjoy that.

Hi, thanks for doing this post! I am an oddish duck in that I no longer have a colon. I have a jpouch. Because of this, my diet is drastically changing. While fiber like citrucel seems to help me, fiber like leafy greens is almost impossible to eat (at least for now). Do any of the thoughts of keeping a good bacterial balance and the ways to achieve it change in the absence of a colon?

It's likely that this is true (similar considerations apply to e.g. gastric bypass surgery) but relatively little information is available right now. It's an active area of study by several labs, although not my lab.

Where do you see the greatest impact might be in the future for microbiome research? Will there be a disease or condition we could manage by manipulating the microbiota, and if so, how might that be achieved?

Additionally, how do we deal with the current problem of reproducibility - different studies and different analyzes lead to different results (and often due to insufficient/inappropriate statistical approaches).

As far as reproducibility goes, we're engaged in a project called MBQC (MicroBiome Quality Control -- http://www.mbqc.org ) to test cross-lab variability. Among the labs that participated, the preliminary results suggest that the reproducibility isn't as bad as you might have expected. This is the great advantage of using open protocols. Essentially, all bets are off when companies or labs use proprietary protocols where the differences might or might not make a difference, but no-one really knows. Whether the technical effects are a problem for interpretation depends a lot on how big the biological effect you're looking at is. Cathy Lozupone, who was the lead developer on UniFrac when she was a grad student with me, led a really elegant paper on what you can and can't do combining studies with different protocols last year: http://www.ncbi.nlm.nih.gov/pubmed/23861384 . Essentially, if you're looking at a large effect, like age or some kinds of IBD, you'll find it no matter what, but if you're looking at something subtle the differences in techniques matter more. And you're correct that the computational techniques can have an even greater effect than the lab techniques on what you believe is in your sample -- again, why open source and open, reproducible protocols are important -- but consistency among the taxonomy databases and other resources has, through concerted effort, been getting much better in recent years.

The question on impact has been answered elsewhere in this discussion.

How do infants come to have gut microbes? I assume they come from the mother somehow but seeing as I've read that the digestive system is in many ways isolated from the rest of the body I can't imagine how they get transferred.

see my response to speezo_mchenry

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See other answers on gut-brain axis and fecal transplants. Briefly, there's great evidence in mice that you can alter behavior by altering the microbiome, e.g. http://www.ncbi.nlm.nih.gov/pubmed/21683077

Whether this can also be done in humans is an active area of investigation (complicated by IND requirements) but potentially very promising. You're exactly right that mental illness has been very challenging to treat, and NIMH is actively looking for new treatment modalities. However, NIMH is currently avoiding observational research and focusing on research that establishes links to specific neural circuits. Although you can certainly see their point (observational studies that lack mechanistic underpinnings have had limited success over the last few decades), it also raises the bar for studies that are trying to look for completely new mechanisms.

How important are plasmids to understanding the microbiome? Are we finding that effects are more often because of particular species populations or from the plasmids that infect them?

Great question. There's little data as it's a lot more expensive to look at the plasmids specifically, but it's a very interesting area of research. See here, for example: http://www.ncbi.nlm.nih.gov/pubmed/22431592

I've heard people say that without the help of our colonizing microbes we would not be able to live. But what about the "boy in the bubble" -- the kid with no immune system who lived in a hermetic bubble? Certainly microbes are useful, but are the essential?

Useful but not essential. For example, germ-free mice actually live longer than conventionally raised mice, but they have a very difficult time breeding (remember that both survival and reproduction are essential for fitness on an evolutionary timescale). For obvious reasons, no one has raised humans germ-free and tested the effects on reproductive success...

Ever since I moved to college I've been pooping like crazy. I literally have been shitting more than I feel like I've been eating. TONS of people have been saying the they've been doing the same. I suspect it's the dining hall food. But really though, is there a reason this is happening to us? And will it solve itself on its own? ( weird question I know, but it's like this synchronized mass pooping phenomenon at my school)

It's certainly possible that this is due to a transmissible microbe (or due to the food itself), but it would be fairly expensive to study the food and the gut microbiology of the student population.

Do you have a favourite species of bacteria? If yes, why?

No, a lot of different species are really interesting.

Let's just say that I came off of a series of broad spectrum antibiotics.

What's the best way to repopulate my gut biome to safely get it into a healthy state? Probiotics? Eat some dirt, maybe via unwashed veggies? Fermented foods? From other humans in certain, likely gross, ways? Etc.

At this stage, there's no clear advice as comparative studies haven't been done using the same subject population and techniques. Sorry.

OK, here are a couple of questions I've had for a while, since I read that serotonin is one of the more potent neurotransmitters, especially for regulating moods/happiness, and 90+% of your body's serotonin is found in your GI tract.

Are you familiar with any studies on how varying diets can affect the production of serotonin and other neurotransmitters, and correlated mood issues?

Do the current shockingly high rates of depression and other mental health issues have anything to do with the modern highly processed diet?

These are really good questions: as noted elsewhere, studies on microbes and depression are still in very early stages.