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(Re)Becoming Human

AS THE SUN set over Lake Eyasi in Tanzania, nearly thirty minutes had passed since I had inserted a turkey baster into my bum and injected the feces of a Hadza man – a member of one of the last remaining hunter-gatherers tribes in the world – into the nether regions of my distal colon. I struggled to keep my legs in the air with my toes pointing towards what I thought was the faint outline of the Southern Cross rising in the evening sky. With my hands under my hips – and butt perched against a large rock for support – I peddled an imaginary upside down bicycle in the air to pass the time as I struggled to make sure my new gut ecosystem stayed put inside me.

With my butt cheeks flexed and my, you know what puckered, I wondered if I had just made a terrible mistake. Could I really displace my western gut microbial ecosystem with that of a man, who, days before had dined on animals as diverse as zebra and monkey, possessed one of the most diverse gut microbiomes of any person in the world? Would my immune system soon freak out at the presence of what should be some familiar Old (microbial) Friends now setting up shop throughout the slimy vastness of my gastrointestinal tract? Or had I just unwittingly infected myself with some lethal bacteria or virus? The pros and cons – mostly cons – of my turkey basting activities raced through my anxious mind as I peddled my way into the evening.

Hadza hunter-gatherer

Hadza hunter carrying his share of a recent zebra kill.

My colleagues and I have been working and living amongst the Hadza hunter-gatherers of Tanzania for over a year now. Over the course of several field sessions, we’ve collected nearly 2,000 human and environmental samples in an attempt to characterize the microbes on and within the Hadza and the microbes in their environment. The human samples have mostly included stool (feces), but also swabs of hands, foreheads, bottoms of feet, tongues (some spit), breast milk from mothers, and so on. Environmental sampling has included swabs of the plants and other foods they consume – like berries, roots, honey, etc. – and a dizzying number of animals ranging from Greater Kudu, Impala, Dik Dik, Zebra, various monkeys and birds, and so on. For the animals, we collect feces and when possible swabs of the stomach contents of larger animals – all of which end up covering the Hadza sooner or later during butchering (see little blurb in Nature titled Please Pass the Microbes). We also swab their homes – inside and out – along with the various water sources. In short, we swab everything including the researchers while in the field.

The project includes a talented team of collaborators from New York University, University of Colorado-Boulder, Stanford, Mount Sinai School of Medicine, Western University & Lawson Health Research Center in Canada, and several researchers from the National Institute of Medical Research in Tanzania. Additional collaborators working on various analysis are scattered at universities in the US and Europe.

Twenty years of rainfall in Hadza Land taken at Kisema Ngeda.

Twenty years of rainfall in Hadza Land taken at Kisema Ngeda.

Among many things, we are interested in how Hadza microbes – along with their environmental microbes (water, homes, plants and animals) – shift between the wet and dry seasons. Due to some unique geography and global weather patterns, East Africa experiences a striking wet and dry season – essentially 6 months of on and off rain, followed by almost none (see figure). This reality means that during the dry season, as water holes dry up, the Hadza kill a lot more animals as dwindling water sources make the animals more predictable and easier to shoot with their poison arrows from hunting blinds (aka ambush hunting). An increase in protein and fat from animals means a drop off in other caloric resources, mainly plants, as the Hadza will often binge on meat when possible (note they have no storage so everything is eaten in a short period of time). During the wet season when Hadza Land is awash in greenery and flowers, the Hadza enjoy an abundance of wild honey (fat of the larvae included) and massive stands of sugary berries. With the coming of the rains larger animals are more scattered and thus harder to kill, so make up less of the daily calories (though its highly variable from day-to-day and week-to-week and from camp-to-camp). No matter the season, fibrous baobab fruit and subsurface tubers are a daily constant for the Hadza. Yes, they consume lots and lots of dietary fiber!

The impact of seasonality on the Hadza and their microbial environment is an interesting and possibly important question as it relates to what a healthier microbiome might have looked like before the niceties and medications of late whacked the crap out of our gut bugs in the so-called modern world. It’s not a stretch to say that nearly all of us in the western world are a hot microbial mess due to, well, just about every aspect of our daily lives – hence the emerging microbial connection to a staggering number of diseases and ailments in the twenty-first century including IBD, autoimmune disease, obesity, type 2 diabetes, and so on.

Should we really strive for a certain composition of gut microbes as many modern buggy-like products infer – such as those found in over the counter probiotics, various drinks and foods? Or does the reality of our seasonal past reveal that our gut microbiome is a shape shifting metabolic organ pulling the strings on our health and well being in a bi- or even tri-annual circadian-like rhythm? Said differently, and with all due respect to the brilliant Harvard researcher Richard Wrangham of fire made us human fame, is seasonality and its impact on our symbiotic microbes more responsible for what makes us human? I like to think it might – plus, Seasonal Homo is kind of catchy.

The Hadza are particularly (microbially) interesting over, say, remote groups in South America, as they still live in a part of Africa that purportedly gave rise to our genus Homo. However, Lee Berger and his colleagues working new fossil sites in South Africa are giving East Africa a run for its money for the prize for which part of Africa holds the honor to the geographical cradle of humanity. Regardless, being only a stones throw from famous paleontological sites like Olduvai Gorge of Leakey fame, the Hadza literally hunt and gather many of the same animals and plants that humans and our ilk have subsisted on for millions of years – not too mention they are covered in the same dirt, drink the same water (save the occasional cow turd floating about), and practice the same central-based foraging that has brought people together in microbial-sharing camps/communities for the better part of the Pleistocene. It is this foraging lifestyle that has endowed the Hadza with an extraordinary diversity of bacteria. And its the diversity they carry is what is most fascinating when compared to our less diverse western gut.

Hadza women lightly cooking //ekwa roots before eating. Hardly a day goes by that Hadza women don't dig these fibrous (and delicious) roots from the hard ground. Note also we suspect the consumption of these roots "may be driving" the abundance of Treponema bacteria in the Hadza gut - a group of bacteria that are also found in other African and South American populations but all but absent in our western guts. The Hadza harbor a larger number of species of Treponema.

Hadza women lightly cooking //ekwa roots before eating. Hardly a day goes by that Hadza women don’t dig these fibrous (and delicious) roots from the hard ground. Note also we suspect the consumption of these roots “may be driving” the abundance of Treponema bacteria in the Hadza gut – a group of bacteria that are also found in other African and South American populations but all but absent in our western guts. The Hadza harbor a larger number of species of Treponema.

While the Hadza are not living fossils, nor in anyway represent a perfect referent population for early human evolution, their hunting and foraging lifestyle and constant contact with the natural microbial world, natural births, extended breast feeding and limited access to western medications, makes them one of the better populations in the world for trying to understand what our ancestral microbes may have once looked like, where we got them and at what point in our life history we acquired them, before the rest of us ran gut first into the buzz saw of globalization. (I am also aware that “ancestral microbiome” is a loaded term. I could just as easily say “natural microbiome” or “non western/minimally impacted microbiome” and so on. Clearly there is no ONE ancestral microbiome. My point is that ancestral equals diversity in the context I use it). Again, it’s important to point out our project is in no way trying to argue that the Hadza diet – or the diet of any minimally westernized population (present or past) – is what we should be eating today. We will leave those discussions up to others as its not a focus of our research. We are simply interested in how a free living population that is still intimately connected to nature acquires microbes and potentially most interesting of all, is the greater diversity of microbes they carry compared to western populations.

On the original question of whether or not the gut microbiome composition of the Hadza changes between wet and dry seasons, our initial – though unpublished data – suggest yes. To our knowledge this is the first study to document this pattern among rural and remote populations. Ecologically speaking, this suggests there may not be one steady state – or equilibrium – for the human gut. It’s moving target with multiple steady states.

Though we see seasonal shifts in the composition of the Hadza gut microbes across the same individuals, we are currently trying to determine if there exists any functional shifts as well. In other words, even if the members shift around from season to season, are the metabolic capabilities – or ecosystem services – of the entire community conserved between seasons or do they change as well? We should know this in the near future.

If we squint for a moment and consider the Hadza and the seasonality of our ancestral past and its impact on our shape shifting gut microbiota as relevant to populations in the western world – and no reason we shouldn’t, though some may argue otherwise over hair splitting details – then we might need to start rethinking an entire industry of probiotics and the like that suggest we need a certain set of bugs in this drink or that slimy yogurt.  And since we are on the subject of probiotics, some significant and dominant players on the market today include characters with names like bifidobacterium and lactobacillus. Interestingly, while the Hadza harbor bifidobacterium and lactobacillus while still breast-feeding, these bugs are essentially absent in Hadza post-weaning (i.e., more or less absent after age 5).

This begs the question: should we really consider these groups of bacteria as essential and necessary to human health despite what a multi-billion dollar industry tells us? Clearly, mountains of research suggest these lactic acid bacteria are good for us, but are there other – more ancestral – groups of bugs that may be more in tune with our seasonal gut post-weaning? More importantly, does the persistence of bifidobacterium and similar bugs in our western gut – mainly due to continued consumption of cow’s milk, ingestion of some probiotic/prebiotic foods, and so on into adult life – nudge out or blunt down other members of our gut ecosystem that would otherwise flourish and provide important ecosystem services? We are currently trying to understand this as we perform various co-occurrence analyses of the Hadza data. Stay tuned.

Swabbing the forehead of a Hadza man for microbes.

Swabbing the forehead of a Hadza man for microbes.

It’s also interesting to note that while the most dominant group of bacteria in the American Gut is the genus Bacteroides – by a country mile – this group of bacteria is a minor, minor player in the Hadza gut. Almost non-existent. The prevailing wisdom is that these bacteria are driven by our high protein-fat and sugary diet. However, I think it has a lot more to do with our absence of dietary fiber and resulting alkaline guts (see Going Feral). As my own self-experiments have shown, I can turn my Bacteroides up or down with the amount of fiber in my diet irrespective of the amount of other macronutrients like fat. To me at least, I think the dominance of Bacteroides in the western gut has to do with pH levels, which is “mainly” driven by fermentation of dietary fiber (fermentation of fiber equals more SCFAs and thus a more acidic colonic environment which strains of Bacteroides don’t like). So with the average American eating less than 20g of fiber a day – pitiful – we are likely lugging around the most alkaline guts in human history which in turn is allowing certain species of Bacteroides (and some opportunistic pathogens) to flourish. Again, if we squint for a moment and lean on the gut of the Hadza, then maybe we shouldn’t let Bacteroides dominant our gut – and by doing so, who else is getting nudged out or down and potentially dragging us closer to ill health? Who knows at this point and will be exciting to see how this turns out with more data over the coming years. I suspect the Hadza keep Bacteroides levels low with their high, daily levels of dietary fiber which keeps their colonic environment very acidic (but this is more of a hunch than something we know for sure at the moment – more data needed). In addition the high protein-fat and sugary argument doesn’t hold with the Hadza either as they will often gorge on meat-fat and eat piles of sugary honey for weeks on end during the wet season – and we see no blooms in Bacteroides when we sample during these periods. It’s the Fiber, Stupid!

Some of our initial sequencing data on the Hadza reveal extraordinary diversity of certain groups of bacteria – one that sticks out, among many – is the genus Prevotella. Currently there are only two described/sequenced species of Prevotella derived from the human gut: P. copri and P. stercorea. Strikingly, the Hadza appear to harbor dozens of species! This is interesting as Prevotella have been linked/correlated to enhanced susceptibility to arthritis and some other issues. So, is the diversity of Prevotella species in the ancestral Hadza beneficial, benign, or possibly even problematic? It’s exciting to think that we all once harbored this diversity of Prevotella but have lost it through our western diet and lifestyle. At the moment we don’t know what to make of the Hadza diversity of this important genus, but we are working on it. Stay tuned.

Oxalobacter formigenes is another species of bacteria that most of the Hadza carry and that the rest of us in the western world have more or less lost. Oxalobacter, as an oxalate-degrading gut microbe, has gained attention in recent years for its ability for preventing calcium oxalate kidney stones. Graduate students Amanda PeBenito and Lama Nazza in Marty Blaser’s lab at NYU have been looking at Oxalobacter levels in our Hadza samples and have found that most of the Hadza still carry this important microbe – and acquire it at a young age. Conversely, Oxalobacter seems to be disappearing from our western guts and may be at the root of rising levels of kidney stones. Less the 15% of Americans still carry this important microbe and almost no kids are acquiring now – according Amanda and Lama’s research. Since Oxalobacter is sensitive to penicillin’s, our overuse of some western medications may be the problem. (Click here for a PDF of a poster recently presented at an NIDDK conference by Amanda and Lama showing some of the Hadza data)

The hands of a Hadza male following the butchering of a large animal. Note the Hadza will often clean the blood off their hands with the acidic stomach contents of the deceased animal (as seen in the picture above). The microbes from the butchering and subsequent hand cleaning in the microbial-rich stomach contents is a significant source of microbes for the Hadza as the men then move the microbes socially (aka horizontally) among other community members. We also collect time series samples whereby we swab hands of hunters several times a day before and after a butchering even to see how long the animal acquired microbes persist on their hands.

The hands of a Hadza male following the butchering of a large animal. Note the Hadza will often clean the blood off their hands with the acidic stomach contents of the deceased animal (as seen in the picture above). The microbes from the butchering and subsequent hand cleaning in the microbial-rich stomach contents is a significant source of microbes for the Hadza as the men then move the microbes socially (aka horizontally) among other community members. We also collect time series samples whereby we swab hands of hunters several times a day before and after a butchering even to see how long the animal acquired microbes persist on their hands.

As the examples of Prevotella and Oxalobacter reveal – and note there are others emerging in the Hadza samples – we have potentially lost an extraordinary diversity of microbes that may have once contributed to our proper functioning and the reason I found myself peddling an imaginary bicycle under a Baobab tree this past August.

When we started working with the Hadza during the summer of 2013, we would live near them but not in their camps. And though I lived in their environment while working with them, I continued eating western food all the while collecting my stool samples as well as theirs. Other than the occasional taste of wild meat and some baobab fruit, my diet consisted of pasta, some canned meats, fruits, veggies, booze, etc. I was interested in seeing whether or not simply being in their environment would change my gut microbes in any meaningful way. And it did – but only so slightly. The next field session I not only lived in their environment, but drank their water and ate their food – giving up my normal, western camp food. But I did smoke weed on occasion as the Hadza are big pot smokers (they trade honey and meat for weed with the local Datoga). As with my previous experience, the combination of environment plus Hadza food altered my gut microbe composition as well. However, my gut bugs still did not match that of an age-matched Hadza male. Granted, I did not stay on the Hadza diet long – only 6-8 days at a time. The experiment of “going Hadza” was to see if I could catch or acquire their consortium of microbes through diet and lifestyle changes. Clearly my changing microbiota suggested yes. Since I did not have the time to live amongst the Hadza for months on end – a time I felt would be necessary to make my gut look more Hadza-like – I thought something more radical was needed.

Fecal microbiota transplants – or FMT – have become all the rage. And as the name implies, it entails taking a small amount of fecal matter from one person and putting it another. While the promise of this therapy is hard to overstate, the science is still a long way down the road from being a simple thing for everything that ails us in the western world. FMT has been proven again and again as a successful treatment for C. Diff infections – where antibiotics have been unable to clear the infection and in many cases, only make matters worse – its use in IBD and other issues is still a work-in-progress. But everyone – including me – is hopeful that the idea that you can restore microbial diversity or otherwise improve dysbiosis in a sick gut with a donor stool is breathtaking.

When I first considered the idea of doing a fecal transplant between a Hadza hunter-gatherer and myself, I discussed the idea with a number of colleagues working in various areas of microbiology and medicine – and others who specialize in fecal transplants. If memory serves, one hundred percent of the experts I consulted said don’t do it. Concerns ran from it’s too risky or you’re not sick so why do it, and so on. But it was comical to hear more than a handful of experts warn against doing it, but if I did, it sure would be interesting to see the data! So I carefully weighed the advice and decided to move forward.

While for ethical reasons I cannot disclose the donor, I can say it’s a Hadza male, in his mid 30s, with a wife and handful of kids (the donor provided Informed Consent). Before the poo swap took place, I knew more or less what microbes he carried as we had sampled him several times over the months prior and that he harbored at least twice the amount of species (OTUs) that I carried – including all those crazy Prevotella and those oxalate eating Oxalobacter. We also took the donor to a small hospital in the town of Haydom and had him tested for Hep A-C and a few other things. For HIV, we used rapid field test strips and repeated the test multiple times over several days. While it’s not possible to catch everything, we were being cautious. However, I had no data on the parasites he might carrying at the time of the transplant as those analysis were still ongoing at the University of Chicago. Oh well, parasites be damned, onward with the science! (Side note: even though parasites get a bad wrap – and rightfully so given that there are some bad guys out there – I am not overly concerned with acquiring them given that they “likely” play in an important role – past and present – is shaping our gut microbiota).

Since I wasn’t sick and in need of a transplant for those reasons, why was I taking the risk? To that advice – which I greatly appreciated from my colleagues – I responded that while I don’t technically have a diagnosed disease like a refractory C. diff infection for which a fecal transplant was the best cure, I did have a western gut microbiota – one I was given when I passed through my mother’s vaginal canal and that I had spent a lifetime of knocking the crap out of with chlorinated tap water, the occasional antibiotic, mountains of shitty (and good) food, living more or less the sterile life of an American male – devoid of the kind of microbes my donor had grown up with – and last but not least, a semi truck load of booze I had consumed as an average American male (I’m 47 so I have seen the bottom of my share of tequila bottles). Therefore I did consider my gut sick even if I had not been diagnosed as such. But that’s not the whole reason.

Don't be grossed out. Days leading up to the transplant - and the days after - I took blood, urine, and stool samples (all frozen in liquid nitrogen) to monitor any changes following the transplant. Note I am taking stool samples everyday for the next few months as well.

Days leading up to the transplant – and the days after – I took blood, urine, and stool samples (all frozen in liquid nitrogen) to monitor any changes following the transplant. Note I am taking stool samples everyday for the next few months as well.

The bigger reason or hypothesis I wanted to test was one of microbial extinction, something I believe we all suffer from in the western world and may be at the root of what’s making us sick. Maria Gloria Dominguez-Bello and Marty Blaser at NYU estimate from their decades of work in the US and among Amerindian populations in South America, that us modern humans have lost a third (or more) of the microbial diversity we once enjoyed. The Hadza data thus far suggest this number could be as high as half. So for me, and my little transplant experiment with a Hadza hunter gatherer still living at microbial ground zero for all humans, I wanted to know if my western diet and lifestyle could rapidly destroy this newly acquired diversity in a short period of time. Since the human genome contains ~23,000 genes and our whole-body microbiome accounts for another staggering 5-10 million genes – most of which our deep in our gut – my distal gut ecosystem restoration project attempted to replace 99% of the genes in my body. Said differently, I was not interested in acquiring some exotic microbiome from the donor – and this would some how be protective for me in the years to come – just to have this different microbiome, but rather I wanted to acquire a large diversity of microbes [which the Hadza carry] so that I could attempt to reduce that diversity once transitioning back to a western diet and lifestyle. That is, I’m not really suggesting the Hadza have a more ideal microbiome – we, of course do not know this at this point in time – but we do know it’s much more diverse).

**It has been suggested from several folks that it isn’t entirely clear why I did the FMT – many think it’s because I was seeking to acquire a more healthier microbiome and thus be healthier. Which is NOT the experiment. So to be clear, the goal was to 1) acquire the diverse microbes from a Hadza and then 2) attempt to WIPE THEM OUT. Yes, the goal is to try and wipe out my newly acquired microbiome. It is the diversity of microbes the Hadza carry in their gut that I’m interested in and the role of diet and lifestyle in reducing that diversity. I’ve added/strengthened this point in a number of places in this post where it wasn’t sufficiently emphasized.

Again, if you squint with me for a minute, could I simulate 10,000 years of human history – from the transition of hunter-gatherer to agriculturalists, to crowded conditions of civilizations, to indoor plumbing, to the introduction of antibiotics and antimicrobial soaps, to Lady Gaga – all in a short few months with my fecal transplant?

But underlying all of the scientific reasons for doing the transplant and the extraordinary effort it takes to work in East Africa for months on end with the endless stream of set backs, is my daughter. As anyone who reads this blog on a regular basis knows, she was diagnosed as a type 1 diabetic at ~2 yrs of age – she’s 14 now. It is her disease that drives me everyday to try understand why she acquired such a terrible autoimmune disease. Was it because she was born via c-section, and thus skipped the time-honored seeding of microbes from her mothers birth canal? Was it because she was not breast fed for 2+ years like her ancestors? Was it some medication or the hyper-sterile environment that kids now grow up in the US? Is it because she had a lower diversity of gut microbiota than the ancestors who came before her – that is, is she a casualty of unintended consequences of the Anthropocene we all now live? As any parent knows, there is nothing more heart wrenching than to watch your child suffer day in and day out with a disease. So yes, I do understand and accept the risks and the many unknowns involved in performing such a fecal transplant with a hunter-gatherer – but in no way does this undermine the emerging importance of fecal transplants for certain ailments and the developing science that underpins it. I do not in anyway take this lightly nor am I cavalier about it. But for me and my daughter – and for other families – I feel I have no choice but to do everything I can to try and understand the role of our disappearing microbiota in diseases such as hers. I hope you understand. (With a sample size of exactly one, I’m aware of the limitations of the Self Experiment).

So once the fecal transplant had been completed that warm, August night – with the aid of a turkey baster (note also I’m pretty sure my colleagues who brought me the turkey baster purchased the largest one made and sold at Walmart) – I immediately went back to camp and started back on my western diet (note I had been on a pure Hadza diet for a few days leading up to the transplant).

A new coffee-table-like book about our work in Africa will be available soon. Click here (http://eepurl.com/7X8YX) is you want to receive an e-mail when the book is available. 100% of the proceeds go to the research.

A new coffee-table-like book about our work in Africa will be available soon. Click here if you want to receive an e-mail when the book is available. 100% of the proceeds go to the research.

Before and after the transplant I took stool, blood, and urine samples (note I’m still taking stool samples weeks after the experiment). We also took several samples of the donor stool. At the writing of this blog post I’m not sure if the fecal transplant took – that is, whether my body successfully took the transplant and if so, what percentage of my donors bugs populated my distal colon. I was able to “hold in” the donors sample until 11AM the next morning, a period of 16 hours, before having my first bowel movement. So I am hopeful. I should know by early November, when all the samples are sequenced, whether or not the procedure took.

So, if I was able to acquire and keep a portion on my donors ancestral microbial ecosystem, how much of it could I wipe out as I transitioned back to the US and then back to Tanzania this coming Fall? When I arrive back in Tanzania, I will go back on the Hadza diet – and of course, live in their environment – to see how much of the original donor sample I can get to spring back to life. If my transition back to the US results in a loss of my newly acquired diversity, then in essence – if you squint with me for a moment – I was able to recreate the epidemiological transitions we’ve all experienced in the last 10,000 years in a few short months. Regardless of the outcome, it will be interesting. I will also do another transplant or two when I return in the Fall, but this time I will stay on the Hadza diet to see if I can hold onto whatever ecosystem I acquire at transplant.

So how did I feel after the transplant? Not that much different other than – as it was pointed out to me by my girlfriend – I seemed to be farting a lot less – a lot less! Didn’t really notice any change in my mood or my bow hunting skills either! But it is interesting that I started shedding a few pounds for no apparent reason. Hmm. Stay tuned.

Don’t try this at home.

***
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American Gut: Please consider joining the American Gut project as well as we attempt to map the microbial diversity of the human gut.
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