Unless you’ve been holed up in a cabin in the Siberian outback, it’s been hard to miss the avalanche of research and associated press coverage ballyhooing the connection between microbes and human health and disease in 2013 – and 2014 will be no different, as fecal transplants become the new black!
But reading between the lines of the near breathless and optimistic reporting on the human microbiome, sits a sobering fact: scientists know very little about the connection between disease and the potential microbial culprits (these are early days). Science is hard and the human gut is a vast and diverse ecosystem. As with any ecosystem, it’s the community as a whole that’s likely more important, not single members per se. Connecting the dots when there are lots of them – and they are shape shifting all the time – is proving to be tough (a similar reality has slowed our understanding of the role of human genes in disease). This will take some time – but the writing is on the wall.
That said, projects like American Gut (think about joining the project!) are trying to map the diversity of the human gut. By sequencing the gut microbes of tens of thousands of regular folks – of all shapes, sizes, and of diverse diet and lifestyles – we hope to see coarse-grained patterns shaped by disease state, age, diet, lifestyle habits, and so on. These broad strokes will then allow researchers from all over the world (yes, de-identified American Gut data is open source and made available to the research community – thanks good folks over at Earth Microbiome Project) to dig a little deeper to see what might matter the most when it comes to maintaining a healthy microbiome at different stages of life (yup, a 2 year old harbors different microbial compositions than grandpa).
In addition to a large sample of westerners, we will also able to compare these tens of thousands of samples to other data sets – including groups from Africa, India, South America, and so on. Excitingly, our work with the Hadzabe hunter-gatherers in Tanzania will allow us to compare our western selves to people who still hunt and gather the majority of their food, have limited access to western medications, are all born naturally and breastfed for 2+ years, live outside more or less 24/7, are covered in microbial-laden soil (natures blanket), and that have an intimate connection to a vast (natural) microbial world that we in the so-called developed world have moved away from. We don’t know what we will learn over the coming years, but it’s a given we will be a little smarter when it comes to modulating and nudging our gut microbes in a healthier direction with diet and lifestyle choices (I sure hate to see Big Pharma drug our microbiome into compliance – lets not let it happen folks!).
As researchers continue to build the scientific case for the microbe-health connection in 2014, I’m embarking on a little self-exploration. On January, 1, 2014, I began the first of many diets that I hope will lead to a better understanding – at least for me – of not only what a healthier gut microbiome might look like in a modern world, but also more importantly, what it shouldn’t look like. I will be collecting daily stool samples along the way for subsequent 16S rRNA analysis throughout the next 365 days.
On Jan 1 I started a high fat-protein diet with very, very little carbohydrates and near zero quantities of dietary fiber. In short, I’m attempting to starve my microbes of much-needed substrates for growth – such as dietary fiber, resistant starch, etc. I’m not arguing that anyone should do this on a regular basis, nor am I suggesting this is a good or bad dietary strategy, but I am trying to whack my microbiome around a bit to demonstrate that significant shifts in your gut microbiota can be achieved in very short periods of time with significant shifts in macronutrients.
I experienced this past summer how dramatically you can shift your gut bugs with diet when I traveled from New Orleans to West Texas where I was held up for a few months trying to finish a book (BLOOM will be out this year!). As I drove out of New Orleans, I left behind a diet heavy on meat, but with a quantity and diversity of dietary fiber that would make Michelle Obama smile. But once I landed in the parched landscape of West Texas near Big Bend National Park, the little writers shack I rented lacked some modern niceties – like a kitchen. So I ate most of my meals at the local watering hole(s). Below is a graph of what happened to my gut microbes.
As the pie charts below reveal, I look like an entirely different person – microbially-speaking. On the left my New Orleans microbiome were dominated by the phyla Firmicutes (74.80%). But after only 2-3 weeks of greatly reduced consumption of dietary fiber – remember, I still ate lots of meat – my Firmicutes dropped to 28.63%, while my Bacteroidetes shot up. In other words, my Firmicutes and Bacteroidetes traded places in my new desert belly.
Digging a little deeper in the data reveals that much of this dramatic shift can be attributed to a handful of genera. The bar graph below shows that my Bacteroides (in the phyla Bacteroidetes) seem to really like my no, to super low plant intake – going from a mere 15.91% relative abundance in New Orleans to a whopping 56.59% in my near plant less desert diet. Consequently, the relative abundance of the Family Ruminococcaceae took a hit along with the Family Lachnospiraceae and the Genus Ruminococcus. These three are known plant fermenters – that is, they metabolize dietary plant polysaccharides – that didn’t seem to compete very well as the fermentable substrates (fiber, resistant starch) dried up.
Also of interest are my Bifidobacterium levels which went from 5.46% in New Orleans, to 0.10% and my levels of Paraprevotella (kissing cousin of Prevotella) went from a paltry 0.40% to a monstrous 7.20% in the desert (red bar spiking on right-hand side of graph). In the case of Bifidobacterium levels taking a hit – note I like Bifidobacterium as they are often cited as being part of a healthy and balanced gut flora – I would go out on a limb and suggest they were suppressed due to my lack onions, garlic, leek etc. Though I suspect I could be wrong – but that’s my hunch at the moment. As for the increase Paraprevotella, I would again go out on a limb and suggest this spike is attributed to my modest intake of whole grains via Muesli-like cereal – essentially eaten dry every morning in my desert home. Something I didn’t do in New Orleans. Anyone that follows this blog knows I have something of a (Para)Prevotella fetish and attribute the increased relative abundance in many/some folks as a sign of “whole” grain consumption, not fiber intake per se as often argued. Strikingly, elevated levels of Prevotella have been noted among HIV-infected individuals who exhibit chronic gut inflammation. In this study, the researchers suggest that Prevotella may thrive under conditions of inflammation. In another study, researchers found that Prevotella strongly correlated with new-onset untreated rheumatoid arthritis. On the flipside, reduced rather than increased levels of Prevotella correlated with kids diagnosed with autism compared to symptom-free neurotypical children in a recent study. However, it’s interesting to note that many families will place ASD kids on a gluten and casein free diet following diagnosis. Therefore, if my “out on a limb” theory that Prevotella levels are associated with whole grain consumption is near the mark, then lower levels of Prevotella in these diagnosed youngsters is not completely unexpected. In other words, in diagnosed ASD kids the lower to no levels of Prevotella may have more to do with diet than the disease state. But we will wait and see how this shakes out over the coming years.
If you spend anytime reading the literature on Bacteroides – the genus that dominated my desert belly – you will quickly surmise that most researchers attribute it to a high fat western diet. It’s close to dogma. However, in my little New Orleans to desert diet experiment, my levels of meat and thus by extension, fat and protein, stayed more or less the same. The only thing that changed that much was my reduction in plants and the fermentable fibers they contain. So in my Sample Size of One, changes in my intake of meat can’t really explain the striking shifts seen in the graphs above. So rather then Bacteroides thriving in a fat-soaked environment of my desert gut, they likely gained a toehold in my increasing alkaline gut. Like many microbes, many strains of Bacteroides seem to be pH sensitive. And the main driver of the acidity of your colon is fermentation. Reduce the amount of dietary fiber and resistant starch reaching your colon (ie, no plants), the pH rises and becomes more alkaline due to a reduction of short chain fatty acids and other organic acids that are byproducts produced during fermentation. As pH rises, those microbes that are otherwise pH sensitive bloom. So, my “out on a limb” interpretation of the dramatic shift in my microbial community in the example/experiment above is not driven by increased meat consumption, but rather my shift in pH due to the lack of fermentation which ultimately provided fertile ground for Bacteroides to dominate. My increase in the phyla Proteobacteria from 0.03% in New Orleans to 2.63% in the desert, suggests this new, less acidic ecosystem may have favored some opportunistic pathogens. And in one final gut check – and most concerning of all to me, is the overall diversity of my gut microbiota was halved in the desert (as measured by species equivalent OTU’s). And as Ecosystems 101 teaches us, a less diverse microbiota is less resilient to perturbations and may tip one a tad closer to an unhealthy state. One recent study suggests that my reduction in gut microbial diversity – while not dramatically altering my sanitation and hygiene practices in the process – may have had a lot to do with my reduction in dietary fiber. This is also been seen in mice fed high versus low fiber diets (personal communication, Justin Sonnenburg, Stanford University)
My little experiment coupled with a steady flow of papers suggesting diet and lifestyle can dramatically impact your gut microbial composition in short period of time, has led me to my 2014 goal of acquiring and catching the healthiest gut microbiome in the world. By catching, I mean it’s not all about what you eat, but how and where you live – and whom you live with – and your interaction with the microbial world around us.
Throughout 2014 I will undertake a series of dramatic shifts in my diet and lifestyle in attempt to whack my microbiome around. For example, aside from the high fat/protein diet I just finished at the first of the this year (taking poo samples along the way), I will go on a raw food diet for a few weeks, followed by a juicing diet, possibly followed by a vegan diet, followed by an Atkins-like diet, followed by a Mediterranean diet, followed by a period of fasting, possibly a weeks of lots of fermented foods, followed by a Paleo diet, followed by Jenny Craig and Weight Watchers diets, followed by a Master Cleanse Diet, and so forth – repeating some diets several times. I will also go on the occasional drinking binge, exploring the impact of beer, wine and Jose Cuervo on my microbiota. Don’t tell John Boehner, but I will also explore the impact of copious amounts of weed as I wake and bake for a week while holding various diets constant. But perhaps the most interesting will be my hunter gatherer plunge I will take 2-3 times as I live and work among the Hadza hunter gatherers of Tanzania – where I started working in 2013 (Science did a nice 3-pager on our project recently if you want to learn more – see also tiny blurb in Nature). As a newly minted hunter-gatherer I will live in a grass hut, forage for plants and consume wild game (zebra, impala, kudu, baboons, wart hog, birds, etc.) and drink their water, all the while collecting my stool samples. It will be interesting to see if I can shift my western gut – which ever one I have at the time – to look more like the Hadza. I suspect my exposure to the microbes in the Hadza environment will dramatically alter my microbial composition and increase the overall diversity. But will it last when I return home?
I’m not sure what I will learn at this point, but will share my results with colleagues and ask them to weigh in on the microbial compositions generated by the various diets. I will ask them to do so without knowledge of the diet that produced the results in an effort to remove bias against any particular diet/strategy/lifestyle – such as the bias we see over at US News & World Report as they continue to deliver an ass whopping to the Paleo diet every year as they rank the healthiest diets on an annual basis. Will I nail down the diet and lifestyle that results in an optimal microbiome – whatever that is? Don’t know for sure but I’m pretty confident I will learn which diet and lifestyle choices yield less than optimal outcomes for my gut bugs. If anyone out there has any diets – crazy or mainstream – they would like me to consider, ping me. Let the games begin.