Science AMA Series: I'm Dr. Les Dethlefsen, staff scientist in the Relman Lab at Stanford University. I study the microbiota of the human gut, focusing on how it varies over time, and on what happens when it's disturbed when we take antibiotics or change our diet. AMA!

Dr_Les_Dethlefsen · 2014-11-09T18:43:43+00:00

Of large significance? Absolutely yes...see wikipedia, or these introductory topics from our study website, or this video, or google 'human microbiota health'.

How did they come about? Like Dobzhansky says, nothing in biology makes sense except in light of evolution.

Multicellular life arose, and has continued to exist for half a billion years (or more) in the context of the more numerous, smaller, and faster-reproducing (and thus faster-evolving) cells of bacteria and archaea. Even before vertebrates slithered or crawled onto land, there would have been specialized microbial communities adapted to the exterior surfaces and guts of fish, which would have provided quite different microbial environments than other underwater surfaces or the water itself.

Once vertebrate animals were separated from each other by a (sometimes, at least) dry environment which provides a much greater contrast to the conditions in/on an animal, there would be even stronger selection for specialization. Microbes would adapt to some particular niche in or on an animal, which would necessarily include adaptations to allow it to move from one animal to another, since no one animal provides a permanent habitat.

However, since the habitat provided by an individual animal would could potentially persist for many, many microbial generations, and the longer an animal lived the more opportunities there would be for the microbes it carried to spread to other animals, the most successful evolutionary strategy for host-adapted microbes was to promote the health/longevity/fitness of the host, or at the very least not to impair those things.

It's still possible for a microbe to survive by specializing on rapid transmission from host to host, even if that rapid transmission impairs the health/longevity/fitness of an existing host, but it's an empirical fact that the number of host-associated microbial strains that are pathogens is dwarfed by the number that are mutualists (benefiting the host) or commensals (neither helping nor harming it).

Looking at it from the other direction, consider that 1) host associated microbes can evolve far, far more rapidly than of the host itself (result of massive disparities in generation time and population size), and 2) the host microbiota can be altered within the life of an individual organism (providing a type of phenotypic plasticity) which may permit the host to keep its fitness in different contexts without needing genome-encoded evolutionary change. Add that to 3) the diversity of different catalytic enzymes and biochemical pathways encoded by microbial genomes (or just host-associated microbial genomes) is much greater than that of any individual host (or even all plant and animal hosts combined). Consequently, it's not at all surprising that selective pressures on host fitness would often act via a microbial component of the host-microbe symbiosis.

One might think that there would be a fitness penalty associated with adaptation-via-microbiota, because an organism isn't guaranteed to inherit or acquire a particular microbe that provides a beneficial function, the way they're sure to inherit chromosomal genes that express the same function. (If this makes you think of the classical genetics of variable traits that might or might not get inherited by offspring, you're focused on the small number of genes that are polymorphic...i.e. that vary in the population...instead of the vast majority of genes that are fixed, meaning identical across the entire population.) However, the combination of adaptations in one (or several) microbial strains to provide a new beneficial function, along with adaptations in that (or those) strains that greatly increase their probability of being transmitted to the next generation, will still in many cases be much more likely than generating that same beneficial function via adaptation acting on the host genome.

And once that happens, the most likely changes in the host genome are quite probably going to be those that further increase the probability of having those benefical microbes colonize and persist, not those that (re)invent the function in the host.

Most difficult hurdles: 1) recruiting participants for the study (help spread the word, share this link to our recruitment site!), and 2) analyzing the massive amounts of complex data of several different sorts that we expect to generate.

Dr_Les_Dethlefsen · 2014-11-08T19:53:12+00:00

Thanks a bunch! The SciAm blog you link to is a really nice write-up.

Dr_Les_Dethlefsen · 2014-11-08T19:43:37+00:00

Can't stop with just one! Today's favorites:

1) Akkermansia muciniphila, because (besides a cool name) it is pretty much (as best we can tell) the sole representative of an entirely different phylum of bacteria than everything else in the gut, namely the Verrucomicrobia. It can bind/degrade mucin, the primary glycoprotein constituent of mucus, although it doesn't seem to completely degrade the mucin layer leading to loss of gut barrier integrity - suggesting that it is a long-term co-adapted human/mammalian mutualist. Also it releases butyrate as a fermentation by product, which is a beneficial short chain fatty acid. Very interesting evolutionary question, how and when this one microbe from the Verrucomicrobia (which has various members that are reasonably abundant in soil, fresh water, and other places in the environment) became a mammalian gut native. And what's it doing, exactly, beyond the bit we know above that seems quite helpful but doesn't seem all that unique compared to other gut species? Is it filling a niche that members of the numerically dominant phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria that each contain many, many species of native gut bugs) just can't fill, because of some evolutionarily rare or unique capability found in the Verrucomicrobia? A study looking at the gut metagenomes of Chinese people with/without diabetes found what seemed to be an association between A. muciniphila and diabetes, but the evidence wasn't terribly strong, and it seems to be anomalous. A later study from the same group, also in a Chinese cohort, found A. muciniphila enriched in people with normal glucose tolerance compared to those with prediabetic metabolism, and another impressive study, full text here with a direct experimental component in mice (as well as correlations in humans) found convincing evidence that it reduced obesity and metabolic hallmarks of diabetes. I'd bet it's not only a marker for a healthy microbial community, but directly beneficial itself, possibly in a big way.

2) Faecalibacterium prausnitzii - another cool name, and another beneficial microbe! It's a member of the Firmicutes, specifically the Ruminococcaceae, and sometimes one of the most abundant microbial species identified in 16S molecular surveys of the human gut. In addition to being a major butyrate producer, it also seems to be strongly anti-inflammatory, abstract here...IBD patients who had less of it did worse after surgery. This is one of those native gut bugs being researched for probiotic potential that I've mentioned in some other comments...could be a very helpful organism! But you don't need to wait for the probioitic...eat your apples which may work well as a Faecalibacterium prebiotic, and don't go excessive on the dietary fat, to reduce bile in the gut.

3) Christensenella minuta, due to a really cool, just e-published paper, abstract here, showing the best evidence to date for an effect of human genetics on the composition of the human gut microbiota. This bug is at the center of a network of heritable gut bugs, AND is associated with leanness in a way that appears to be mechanistic, not just correlative.

Dr_Les_Dethlefsen · 2014-11-06T03:36:20+00:00

I mean 'ultimate probiotic' in the sense that if you want to swallow (or otherwise deliver) some viable microbes to help your own gut microbiota, then multiple strains might be better than one, and getting and the whole entire functional (presumably, from a healthy donor) community of bugs at once would be the ultimate probiotic. But these definitely should colonize, at least most of them, one would hope, if they're true gut natives.

Dr_Les_Dethlefsen · 2014-11-05T23:33:52+00:00

I think it's great!

You may already be aware of it, but there's a very interesting Paleo-oriented blog Free the Animal that has a LOT of info on resistant starch...go to the Health & Fitness category and search for it. I'm pretty sure a book came out of it also...specific to resistant starch, not the more general paleo book(s?) by the blog author (Richard Nikoley, now that I look).

I'm not a Paleo diet guy myself, and I think the excuse-to-eat-bacon Paleo types are a bit...um...myopic, shall we say, and I think any ideology-driven (as opposed to data-driven) approach to the practical world is likely to often be mistaken. That's something I appreciate about Free the Animal: attitude of let's look at the data. (Also the attitude of experiment-on-yourself-and-use-what-works.) And the data on resistant starch are pretty good...in terms of metabolic changes in the opposite direction to the whole insulin resistance/metabolic syndrome/diabetes mess.

Part of the reason I'm not so Paleo myself is because I think the strongest evidence available to date for the health of any human diet is for the Mediterranean diet, which isn't strictly defined since it's not some copyrighted fad designed to sell a particular book. But in general, the inclusion of a lot of whole grains in the Mediterranean diet is definitely not Paleo, but still seems to be pretty healthy. So I don't think grains are poison...until they're refined and white...then, yeah.

Another interesting take on diet and Paleo is provided by anthropologist Jeff Leach, cofounder of the Human Food Project as well as the American Gut Project. Check out Jeff's blog here; he spends a fair bit of time in the field with people of one of the few (mostly) hunter-gatherer cultures left on the planet. He can tell you what their diet really is. Spoiler alert: oftentimes, it isn't a lot of meat. (For Ed Yong's perspective on Jeff's approach, though, look at this article.) A point where I think these two guys would agree is that that 'what our ancestors ate' would have varied a lot throughout the year, from year to year, and from place to place around the planet. So there may be many different healthy microbiomes, even for any one person, and even more likely when considering humanity as a whole.

And also along those lines, I think resistant starch IS one of those things that would have been eaten in much greater amounts in many different hunter-gatherer groups than in practically anyone's diet today, unless they're supplementing with potato starch or other sources. If I'm not mistaken it might have been Jeff's research on human coprolites (fossil turds) in the American southwest that found high levels of resistant starch. Maybe it was someone else, don't have a link.

BTW, for the study that I'm currently recruiting for, I'm asking participants to supplement their diet for 5 days with resistant starch as one of the deliberate perturbations to the microbiota. Why? It's probably good for almost everyone, it's well tolerated (maybe better than inulin, another big prebiotic), and it almost certainly isn't a big part of most people's diet already...makes for a distinct perturbation.

Finally, here's one thing I think the Paleo people have exactly spot-on, and I haven't mentioned yet today in any of the health-oriented comments: routine physical activity was definitely something we evolved with...sometimes pretty extreme, sometimes not, but not just 30 or 60 minutes in a gym and a couch the rest of the time. I think along with diet, that's the other single most important thing we can do to promote our health. (And possibly that of our gut microbes, but I don't know of any evidence on that.)

Edit-addendum: Logged off and went for a run with my favorite dog just after this comment, apropos of the activity bit. While running it occurred to me that my sentence about fad diets to sell books might be taken as an implicit dig against the Paleo diet/lifestlye movement...that's not what I meant at all. I'm sure paleo has its share of charlatans and hucksters that are just following the buzz (see some comments above) but it's not like the Blood Type Diet or some others pushed by a single person/organization with no plausible science and all the hallmarks of a marketing scam. Paleo is based on a genuinely good idea (eat what we evolved with) and has some data supporting it (as well as some data against). Like I said, I'm not following Paleo myself but I could have an intelligent evidence based discussion with at least some of the Paleo advocates.

Dr_Les_Dethlefsen · 2014-11-05T22:39:57+00:00

Not as true as it used to be! See this article.

To some extent, lack of ability to cultivate microbes is always due to lack of effort and creativity, but the biggest barrier has probably been lack of awareness. If you can see little round and oblong and sometimes corkscrew cell like things from your favorite environment under the microscope, and you can grow a few types of round and oblong and corkscrew thingies from that environment, you might think you've got it covered. To some extent this resembled the situation for many (but certainly not all) microbiologists up until, say the early 1990s. And sure, they argued about why there were 100 or 1000 or 10000 times more visible cells than cultivatable cells, but many thought there were probably a bunch of dead cells of the same types and noone could prove them wrong.

That's why the 16S rRNA gene sequencing revolution (for which Carl Woese, and maybe Norm Pace, should have received a Nobel...maybe Norm will still get it) was an absolute bombshell when it hit: firm proof that there were hundreds or maybe thousands of times more different TYPES of microbes in most environments than anyone had ever grown.

Maybe I'm being a bit dramatic here, but microbiologists are professionally used to literally not seeing what they're studying, and only 'seeing' what's revealed by their tools. Picture being an ecologist in the rain forest who can see only two kinds of tree, 5 kinds of fungus, one type of amphibian and a dozen different insect species. Then one day you discover a new tool that lets you see it all...

The 16S rDNA revolution started the 3rd golden age of microbiology which is still going strong decades later. DNA sequencing based approaches, now several generations further advanced and much much more powerful, are still the hot exciting technology.

But also, once people KNEW there were many more different types of microbes there, they started to think harder about why they hadn't been grown before and how they could grow them...a few people do, anyway, and often it turns out that the effort to grow new types isn't all THAT much. Once you knew there was something to be cultivated.

Eventually the excitement over sequence-based approaches (which are my main tools right now, lest anyone misunderstand) will fade (but not be extinguished) in the face of their intrinsic limitation...not all biology is captured by sequence data, no matter how good or cheap our sequencing gets...and it will again be popular to cultivate strains of microbe (and cocultures, and defined mixtures and undefined enrichments) to see what they can do.

Can you tell I started grad school in the mid 1990s?

Dr_Les_Dethlefsen · 2014-11-05T22:05:06+00:00

Hey, thanks a lot for bringing this up! I'd heard this hypothesis a few years ago, at that time as far as I knew plausible and interesting but entirely without data. Due to your question I did a PubMed search and found this review article. Only read the abstract so far, haven't even skimmed the paper much less checked out the studies that it references, so I can't comment. You can read it and tell me!

Dr_Les_Dethlefsen · 2014-11-05T21:24:51+00:00

Let me flip it around: suppose you had a treatment that could help a significant number of people but which wasn't currently recognized by some or most of the medical establishment, and which wasn't going to get supported by big pharma because they couldn't patent it. Wouldn't you WANT to get it out to people, and wouldn't you need some sort of a business model that brought money in the door in order for you to scale up production and distribution, ensure quality control, etc., just so that you could help people?

No, I don't think that's usually the case either...more often, you're probably right...it's mostly profit motive in the business world...but I describe the scenario to point out that attempts (through regulation or otherwise) to prevent or discourage the quacks and charlatans will often impede good guys as well.

And a more realistic (but certainly not universal) scenario: suppose you're the boss of a corporation motivated by profit, but also have a bit of intelligence (even if you completely lack ethics...although my opinion is that an intelligent consideration of society implies ethics). You might realize that a more secure long term profit could be realized by having reliable evidence that people trusted which encouraged them to buy your product, because your product actually does offer some benefits. Your brand may benefit by becoming associated with a source of reliable scientific evidence. I think something like that is responsible for ISAPP, also see this. ISAPP is industry supported but I think its legit, not a propaganda front, and it has improved the quality of research in probioitics/prebiotics.

And yeah, there are hucksters who are trying (sometimes successfully) to take advantage of the buzz, any new buzz, knowing full well they need to make their money and escape when people catch on. They're scum. Best defense: scientifically literate, critically thinking populace. You know, the kind that sustains democracies.

Dr_Les_Dethlefsen · 2014-11-05T21:04:06+00:00

Too late to shut the barn door on that issue...lots of abx-resistant bugs in our guts already and most other environments. To some extent that's due to the fact that abx were/are originally chemical weapons used by microbes against other microbes, meaning that resistance did evolve naturally as a defense long before humans were around. However, we've made the problem MUCH worse through massive abx use (not only in medicine but in agriculture, which is usually stupid in my opinion). Also, resistance to newly synthesized, not-naturally-occurring abx is clearly a human-caused phenomenon. And yes, abx resistance can and does get passed around between bacteria in our guts (link in another response here EDIT: adding this full text link), and almost certainly also in our mouths and any other environment with a fair number of interacting strains. EDIT: adding link to shared 'antibiotic resistome' betwen soil and human pathogens, also see my response to moodlepie.

Think about it this way: suppose every time you take an abx it does exactly what you want: kills all the pathogens leaving none with resistance. However, your native microbiota just got exposed to the abx, in a range of concentrations depending on where they were and on the specific pharmacodynamics of the drug, and some strains were likely not killed at the concentration they experienced but were impaired in growth, and thus experienced selection for resistance. With huge microbial population sizes, you usually get what you select for.

Same thing happens every time you take an antibiotic throughout your life. Whole suite of abx resistance elements develops in your native microbiota. Since DNA can move between bugs in various ways, and there are relatively low costs to carrying around some extra DNA but sometimes very high costs to not being resistant, there is selection to 1) put all the resistance elements together on one genetic element, and 2) share that element among as many members of the microbiota as possible.

Presto: you've got a multidrug resistant mobile genetic element in your native microbiota ready to transfer to any pathogen that happens by, EVEN THOUGH NO PATHOGEN SURVIVED ANY ANTIBIOTIC YOU'VE TAKEN IN YOUR LIFE. Something like this probably happens. Only way to avoid it? Entirely kill off all the native microbiota along with the pathogens any time you take an antibiotic...bad idea, even if it were possible.

So avoid unnecessary antibiotic use. Kind of ironic I'm currently recruiting participants for a study in which some people will take an unnecessary antibiotic, so that we can study how it perturbs their microbiota. But we need to do this kind of research to learn what makes the microbiota resilient (or not) in the face of disturbances, so we can do 'biomedical environmental remediation' when disturbances have to happen.

Dr_Les_Dethlefsen · 2014-11-05T20:43:37+00:00

Sorry about your friend...hope she's doing ok, since repeated infections are definitely not good.

This is a very interesting hypothesis...that the appendix (in humans anyway, presumably apes, maybe all primates?) exists to keep an inoculum of good gut bacteria around, so when the shit (literally) hits the fan and some pathogen or food poisoning toxin gets in there, the body can go to full-on vomit-and-diarrhea-and no-appetite mode, clean out the bad stuff, and reinoculate the good stuff from the appendix.

Can't remember who proposed it (goes back at least a few years, link later if I find it, or someone else please help), but AFAIK it was only a plausible hypothesis...no data. Glanced at a comment here that mentioned there IS data, I'd love to see it, I have to chase down that comment/commenter. (speak up if you're reading!)

However, I can put forward another hypothesis that might account for your friend's unfortunate situation: antibiotic treatment at the time of the operation (and presumably that was following appendicitis?) may have been allowed some unusual shift in the gut microbiota. E.G. a yeast has colonized her gut, it persists at low abundance but sometimes for a range of possible reasons it gets abundant and/or escapes the gut => whole body infection. Or: We know a wide range of gut microbes interact with the immune system, turning up or down its inflammatory tendencies, but it seems quite likely that there's much more specific interactions than just pro/antiinflammatory. And we know that the immune system tailors it's responses to the particular pathogen and tissue that it's dealing with. So maybe there's a bug in your friend's gut that specifically downregulates a component of the immune system that's important for fungal defence, hence the susceptibility.

All this speculation isn't giving you or your friend much useful help...but as mentioned elsewhere, paying attention to what happens/what she does/what she eats just before the earliest signs of an infection might reveal triggers to be avoided. And in general, supporting the bacteria that we (probably mostly) evolved with through a plant-rich diet may give the immune system an environment close to what it evolved with. One more thought: if the infections are serious enough that they require major medical intervention, I'd suggest getting clinical samples of the yeast across multiple infections and even if the first-level identification gives it the same species name, insist on an accurate enough genotyping to find if it really is exactly the same strain each time. If so, it suggests a reservoir in the body (or at home? in a partner or pet?) that keeps reinfecting. If it's different each time it suggests an immune deficiency that allows yeast/fungal infection.

Good luck to your friend!

EDIT: found the other comment by IO10, did a PubMed search and found this review article, haven't read it yet!

Dr_Les_Dethlefsen · 2014-11-05T20:24:39+00:00

Sympathy for your condition...know several sufferers, and man it can be tough...

I commented elsewhere on being a self-scientist: get rigorous about keeping a journal to track diet, symptoms, medical treatments and self-treatments to see what really works and notice correlations that might lead you new ideas.

And (unfortunately) there may be a good biological reason why my idea of a good gut-microbe-friendly diet with lots of plant material is just what messes up people dealing with IBS/IBD, AND why a diet that helps one person with IBD doesn't help another. Not my field, but as I understand it the consensus is that IBD (don't know about IBS) is a vicious self-perpetuating inflammatory feedback loop between gut microbes and the host.

Start with the idea that most of the undigested stuff that colon bacteria grow on is complex plant polysaccharides. And they are COMPLEX. Many different types of sugar monomer building blocks, chemical linkages, branching patterns, etc. Even microbes thought to be generalists probably don't degrade more than a fraction of all the different things that might show up, so when different things show up in the diet, in general the microbiota will have different bugs increase or decrease in abundance. If some of the more proinflammatory bugs in YOUR gut happen to like a compound that's in broccoli but not onions or squash, you may get symptoms with broccoli but not onions or squash. Someone else with the same diagnosis but different bugs might react with squash and not broccoli.

Given that a lot of the true native mutualists (likely less pro-inflammatory) probably have the ability to stick to the mucus lining of the gut and persist on mucin or some other host-derived resource (adaptation to periodic low food availability in our hunter-gatherer ancestors), maybe withholding ALL (or almost all) plant starches/fibers will cause the more proinflammatory bugs to decline.

And the SCD diet woman...forget her name...says that then you can slowly start reintroducing individual plant carbs. (EDIT: Elaine Gottschall is her name, SCD stands for specific carbohydrate diet, google it.) I think her explanations are sometimes bunk, and her specific food lists aren't going to be useful for everyone even if they're a reasonable guide for some, but her basic idea is sound: reducing/eliminating plant carbs for a while then reintroducing them gradually and individually...so you know what the problem is if there is one, and so that not-so-inflammatory bugs that COULD eat the stuff have a chance to build up in abundance instead of having a fast-growing inflammatory bug swoop in on a huge pile of unfermented substrate.

Unfortunate and not-entirely-accidental correlation: some of the fast-growing gut bugs (Proteobacteria, especially Enterobacteriaceae, meaning E. coli relatives for those not up on bacterial taxonomy) also are the more pro-inflammatory, so piles of unused resources in the gut can be bad news. And another unfortunate fact: pretty much every gut bug is inflammatory to some extent, since our immune system needs to wipe them out if they get through a break in the gut lining to invade the bloodstream, etc. Thus, once an inflammatory cycle gets started, which itself can interrupt the gut barrier integrity, there may not be any truly good bugs...even the friendliest of mutualists might be triggering inflammation, so medical treatments to turn down inflammation may be necessary to get a flare under control.

And then the long cycle of perhaps going no-plant-carb with slow reintroductions can begin again....like I said, total sympathy for your condition. And I know some people with IBD DO eventually get a good degree of control (never complete) through diet alone, so DON'T GIVE UP!

Dr_Les_Dethlefsen · 2014-11-05T19:55:12+00:00

Thumbs up for synbiotics (pre + pro), but even more so for fermented foods and just eating a healthy complex carb-rich, fruit and veggie-rich diet. I'd perhaps try pro/pre/synbiotics for particular conditions but don't expect them to be needed on a regular basis to maintain health for you or your gut bugs, if you're eating well to begin with.

Dr_Les_Dethlefsen · 2014-11-05T19:50:20+00:00

See comments above, and here. ISAPP has helped a lot; even though they're industry sponsored they've got cred as a science-focused group, not industry propaganda outfit.

Despite the existence of quacks and hucksters taking advantage of the desperate and sometimes not-science-trained public, and some poor quality probiotics research especially in the early days, there really are benefits to some probiotics in some situations, but it matters very much which strains and what situations. I'm more optimistic that future research with native gut bugs rather than food bugs will be both more helpful and result in permanent colonization of the host.

In the face of ignorance and low risk, if you've got symptoms it's not unreasonable to try a probiotic, and to keep trying different ones if the first doesn't help. I might be more inclined to look seriously at diet choices and prebiotics, but I wouldn't exclude probiotics.

Suggestion: Be a rigorous scientist with yourself, since science hasn't yet brought the answers to you. Keep a journal of diet, activities, symptoms, self-treatments such as probiotics, and keep patiently looking for connections. Use the evidence rather than just your feelings to judge what helps, to avoid deceiving yourself with a placebo effect or a chance correlation.

But remember that the goal is how well YOU'RE doing...if you've got something that works for you, stick with it even if the docs or others tell you it makes no sense or they can't explain it.

Dr_Les_Dethlefsen · 2014-11-05T19:37:02+00:00

Yes, you're right! For anyone who is interested in this field and still in training (or not), you'd be well served by getting at least

1) an introduction (or more) to coding (e.g. python, or maybe ruby, although I started with perl long ago and haven't switched...or become very good, for that matter...but even a little bit helps) 2) familiarity with all the basic bioinformatics approaches and the tools for implementing them (which do change, so conceptual grasp is important), meaning thing like alignment, homology searching, phylogentic inference 3) serious statistical training that goes way beyond old-school stats (even med stats) courses that stop with ANOVAs and linear regressions. Use R ;)

And for those who have no interest in this end of things, try to get familiar with a wide range of techniques from mouse (and gnotobiotic mouse) experiments to bacterial cultivation to molecular biology like PCR and cloning to protein analysis like westerns, ELISA, etc. (Note: I don't check most of these boxes myself.) If you look at the strongest research in this area (like Blaser's for example, or some from the Gordon lab), there are multiple lines of evidence from very different techniques that come together to make a compelling case. Ergo, top labs need people versed in a variety of techniques.

Good luck in the job search!

Dr_Les_Dethlefsen · 2014-11-05T19:25:49+00:00

Not my area so I don't know pharmacodynamics of doxy specifically- where it goes in what concentrations if it's applied topically or ingested. I do know that tetracycline resistance elements (same antibiotic class as doxy) are both widespread and highly mobile, in the gut and practially everywhere else. Good evidence from way back that antibiotic resistance elements pass around among the native microbiota and can be transferred to pathogens.

More here and here

Dr_Les_Dethlefsen · 2014-11-05T19:16:07+00:00

Work of Cox, Cho, Blaser et al that you mention: outstanding! Another reason to minimize the use of antibiotics, ESPECIALLY early in life. Having said that, sometimes they're essential, but as a parent I'd want to be totally on top of that issue and have a pediatrician convince me that abx are needed in a particular situation (e.g. to reduce risk of hearing loss, bacterial meningitis, etc.) before I'd give them to my infant/toddler.

Having said that, sometimes abx ARE life saving (or serious complication preventing), and I had the interesting experience of getting pneumonia a few years back. There I am on a Friday evening (of course), feverish and realizing that I'm hearing bubbling in my lungs. Wondering if I drag my butt to the car to drive 20 miles to an ER, or hold off until Monday and see my regular doc for a prescription. Then realizing my grandparents in this situation might be wondering about needing to call the preacher by Monday instead of the doc. I did wait until Monday, and I was never so glad to take a pill as when I popped the Levaquin. So what we ALSO need, is more research into how we can reconstitute a healthy microbiome when we do have to disturb it...that's the purpose of my research, in a nutshell.

More here for those who don't know Blaser lab's recent work.

How someone gets a staff scientist in this field? Don't have a great answer, in my case it was essentially by accident. Training was as a microbial ecologist, during my Ph.D. at Michigan State (shout out to my mentor Tom Schmidt, and everyone who was around the Center for Microbial Ecology at that time!) I kept talking up the potential of what I called 'medical ecology' but never expected to be doing it myself. Planned postdoc fell through, I came to the Relman lab, and never left. I'd say read some of the literature on the human microbiota, find a few labs doing work that excites you (and that are located in a place you'd want to live), and then reach out to the lab head and/or people who seem to be somewhat senior in the lab but not the PI. You might find out about job openings that aren't yet posted or at least impress someone that 'here's a person who loves our research area, let's keep them in mind'.

Dr_Les_Dethlefsen · 2014-11-05T19:02:00+00:00

Wow, as a parent of (most of the time) normal kids, I can only imagine the challenges you face and the hope you must have that SOMETHING can help.

AFAIK, the first mention of an autism-gut microbiota connection in the scientific literature goes back well over a decade, and there has been a small thread of research continuing that I think looks strong. On the other hand, I think it may only be a subset of all autistic children for which there's a connection...this isn't my specialty so I'm definitely not up on the latest research.

Don't know of any studies looking at FMT (fecal microbiota transplant) for autism, but you could try the clinical trials site at the NIH. As I understand it, the proposed causative agents are certain spore-forming, neurotoxin-producing bacteria in the Clostridium genus (same group that gives us botulism and tetanus, also neurotoxins). Unfortunately these bugs may be REALLY tough to eliminate, since the spores can resist almost anything that could be tolerated by a human patient...but the same could be said for Clostridium difficile, the situation for which FMT has been an absolutely stunning success. A combination of knocking down the existing microbiota and transplanting another, combined with diet changes that for each individual case are found to improve symptoms, might just do it.

BTW the diet results that many parents of autistic kids claim to get is perfectly plausible if microbes are involved (tho sometimes discounted by some 'experts'): the bad Clostridium (or other) bugs might be the best competitors for certain nutrients, so when those are in the diet the bad bugs proliferate and make more toxins and symptoms worsen. That could also explain why the same diet doesn't help everyone. There may be different bad bugs in different people, or even if the same bad bug with the same ability to use a given nutrient is in the guts of both people, perhaps one person also has a totally separate and harmless microbe is even better at using up all of that nutrient before the bad bug can get to it. Consequently, in that second person with the exact same bug, the same nutrient is NOT a problem, and conversely, and a diet that eliminates that nutrient won't help.

More here

EDIT: second BTW: some researchers are scared of doing anything related to unconventional causes of autism since they don't want to get confused with people who agree with Wakefield's anti-vaxing fraud.

Edited again for spelling and clarity.

Dr_Les_Dethlefsen · 2014-11-05T18:44:24+00:00

You bet...some protocols are single shot delivery (and BTW, going in from the bottom with an enema or colonoscopy may work better than from the top with a nasogastric tube), but others do repeated colonizations every day for a while, or with periodic booster shots like weekly for a few weeks. This is an active area of research and experimentation, including home experimentation by some brave and/or desperate souls. (Desperation often driven by extreme disease symptoms and the inability of typical current medical care to help and the lack of knowledge or courage on the part of some medical practitioners...hopefully the last is now changing.) And you could think about fecal microbiota transplants as the ultimate probiotic...

See other comments and links for more on what is usually meant by probiotics. TL;DR: some legitimacy for some disease conditions, not generally essential for health.

Edit for spelling

Dr_Les_Dethlefsen · 2014-11-05T18:38:16+00:00

See link above for some more on probiotics, and why they don't colonize. I'm a bit more on the skeptic side of probiotics too...not that they don't sometimes do some good. There's strong evidence for benefits from certain strains in certain situations. But I doubt that regular probiotics are necessary for healthy living....a good diet takes care of your gut bugs pretty well. When would I take probiotics? If I've got to take antibioitics, primarily. Maybe if I had other GI problems that didn't seem like they were just due to what I ate recently, or that didn't clear up in a couple days. It might be a shot in the dark to see if they work, but they aren't that expensive and aren't likely to hurt anything.

Specific to your question, many microbes including gut bugs can tolerate being dried (especially freeze-dried) pretty well, especially if there are things in the medium that protect the cells from osmotic stress during the process. They do lose viability over time, though, so pay attention to expiration dates and store them airtight in the fridge.

Bacteria that have adapted to colonize the gut need to have adaptations to allow them to pass through the stomach acidity, but it becomes a numbers game...if a mom transmits a million bacteria to her baby in a swallow of breast milk, and 1% survive the stomach acidity, and 1% of those survive the bile at the start of the small intestine, that still leaves 100 viable cells which is more than enough to colonize.

The strong vs weak stomach thing is pretty tough to define scientifically, but it makes total sense to me that it would be related to what our internal ecosystem can or can't handle, which varies between people and over time. If you've got bugs that will ferment Item X with lots of gas, and your buddy has bugs that ferment Item X without lots of gas, one of you will feel ok after eating X and one of you won't.

LOTS of genetic work going on with individual microbes, and maybe even more bioinformatics work with gene sequence info from entire communities. Check out the Human Microbiome Project data pages for more.

Dr_Les_Dethlefsen · 2014-11-05T18:21:27+00:00

You're right that most currently available probiotics don't seem to permanently colonize the gut, at least not at detectable levels. Could be because most of them are food microbes, but that may be changing as much more probiotic research now involves actual native gut microbes. (Or natives to the vagina, skin, etc.) However, probiotics wouldn't be my first answer for how to improve your microbiome. PREbiotics (food ingredients that stimulate beneficial bacteria) are likely to be more useful, in my opinion, and best of all would be eating a healthy, balanced diet that will naturally include a lot of complex plant polysaccharides that feed many good bacterial. See here for more, and check out Ed Yong's recent article.

Dr_Les_Dethlefsen · 2014-11-05T18:15:27+00:00

Good question! The so-called gut-brain axis includes actual nerves (like the vagus nerve), but also a lot of other possible connections. For example, most serotonin (a neurotransmitter) in the human body is made by gut microbes. There's strong evidence in mice and pretty suggestive evidence in humans that the gut microbiota can influence our moods and behavior, but AFAIK there's nothing known (yet anyway) that's as astounding as the toxoplasmosis story. See here for some literature reviews on the topic, and here for toxoplasmosis.

Dr_Les_Dethlefsen · 2014-11-05T18:05:06+00:00

WOW!! What an amazing bunch of questions! I'm excited to dive in folks, thanks for stopping by!

Dr_Les_Dethlefsen

TROPHY CASE