Fecal Microbiome Transplants: The way of the future, or a big pile of poop?

Coprophagia

Though many of us try to ignore it, the facts are clear; most of the animal kingdom isn’t nearly as concerned by poop as we humans are. In fact, numerous animals, from koalas and elephants, to rats and hippopotamus, all engage in the interesting behavior of poop eating – coprophagia. My dear old dog ‘Tess’ (rest her soul) had a particular penchant for bird poop. Although she knew it was a practice I did not approve of, her self-control would often break and I would have to scold her all over again. In hindsight, my admonishment might have been ill-founded – dear old Tess was just fulfilling her animal drives, and the process likely had an important functional consequence – to shape her microbial communities.

babykoalaIn many species, especially herbivores, poop is an essential part of the diet; it houses bacteria which animals need to digest their green food, but which they are not born with. For example, the Australian koala is a very fussy eater, consuming a diet that consists almost exclusively of leaves from select types of eucalyptus trees (and sometimes other Australian native plants, if they are feeling especially fun). Unfortunately, for the koala, the eucalypt leaves are particularly difficult to digest and are full of toxins. A cocktail of gastrointestinal microbes is needed to extract those nutrients and neutralize the toxins. Mother koalas help their infants to cultivate that microbial cocktail by creating and secreting a substance called ‘pap’ from their anus, which is laden with many of the microbes the infant needs to start their plant-based diet.

Interestingly, in humans, a similar sort of vertical microbial transmission, from mothers to infants occurs. Though in our case, the transfer is incidental, rather than purposeful. Specifically, as the baby passes through the birth canal and vagina, they are coated in their mothers’ microbial cocktail, which includes vaginal, fecal, and skin microbes. These bacteria make up the human baby’s ‘pioneer population’ of microbes, and will remain with that baby throughout much of their life, changing and adapting to their evolving diet and environment. Numerous researchers have begun to examine the importance of these initial communities in humans. They have found that the types of bacteria colonizing the gut in early life may predict the baby’s immune functioning and physical health. In both koalas and humans then, the act of digesting microbes, whether in pap, during birth, or through many other environmental sources, has important implications for digestion, immune function, and health.

Poop consumption for medicinal purposes – a human story

The story of coprophagia is an interesting one, as it shows that poop (or anal secretion) acts as the perfect storehouse for a pre-established, healthy community of microbes. It goes without saying then, that a good dose of healthy poop might be just what is needed when the community of microbes in our gut somehow goes awry. Indeed, the history of poop consumption for medicinal purposes appears to have been in use since at least the 4th century, where documented evidence suggests that stool-soup (from a healthy donor) was used to cure intractable diarrhea in a patient. Although it probably was not known at the time (bacteria were only discovered in the 1670s), the success of the soup was likely due to the replacement of the recipient’s resident bacterial community (diarrhea-causing) with that of the healthy donors (presumably diarrhea-free). In other words, the sick individual received a ‘fecal microbiome transplant’ (FMT). Today, FMTs (in non-soup mediums) are becoming a popular treatment for at least one particularly chronic and debilitating gastrointestinal disease – clostridium difficile. The idea of the FMT has caught both scientific and public imagination, and tests are underway to examine the effectiveness of this treatment across a range of disorders.

Clostridium Difficile – Breaking the Cycle

Clostridium Difficile (affectionately known as C.Diff) is a toxin-forming bacterium that can cause severe diarrhea, colon inflammation, and in some cases, can result in fatalities. The Centers for Disease Control and Prevention in the United States reported half a million new C.Diff infections in the year 2015, with around 15,000 cases resulting in deaths that were directly attributable to the infection, making C.Diff one of the most dangerous bacterial threats we face today.

c-diff

So where is C.Diff coming from, and how is it treated? Unfortunately the biggest risk factor for developing the infection is recent antibiotic use, which means that the sick and elderly are most at risk. Another big problem is that, until recently, the best treatment for C.Diff was further antibiotic treatment. However, even after aggressive antibiotic regimes, 10-20% of patients relapse within 1 week, and after one relapse the risk of further infections jumps to over 50%. For that reason, many patients with relapsing C.Diff were faced with the bleak prospect of long cycles of antibiotic use and recurrent symptoms. That was until FMTs stepped onto the scene. While FMTs have been infrequently used to treat various gastrointestinal illnesses since the 1950’s, the last 5-10 years has seen the popularity of FMT as a treatment for colitis skyrocket. The reason for this huge uptick in use seems to be a series of well-documented studies reporting its curative potential; 90% of chronically remitting cases are cured by FMT. While antibiotics indiscriminately killed all bacteria in the gut, leaving open new niches for C.Diff infection, FMT floods the gut with a pre-established, functioning community of microbes, filling all the niches and shouldering out infectious invaders like C.Diff. Hence, the FMT is now considered the gold standard treatment for many C.Diff presentations.

Unintended Consequences

When a new therapy is being tested, patients are asked to report all symptoms that occur during the treatment period, whether they think it is due to that therapy or not. This practice is designed to map the side effects of the new treatment, which is then reported to the drug manufacturer and is released to the public, such that informed decisions can be made regarding the use of the treatment. If you live in a country where medicines can be advertised on T.V., that list is reported at the end of the commercial and can be very long indeed. When FMTs were first being used to treat gastrointestinal distress and C.Diff, some very interesting unintended consequences emerged. Several patients noted changes in weight, mood, and even neurological disease symptoms. Interestingly, many researchers were already examining the role of the microbiome across those domains, providing a theoretical and empirically supported link between the FMT and the patient side effects.

Obesity

One of the most publicized unintended consequences reported after C.Diff treatment, involved a young woman with chronic C.Diff who received a FMT from her teenage daughter. While both mother and daughter were of normal, stable BMI at the time of the donation, the daughter rapidly gained weight after the donation, placing her in the obese range of the BMI. Following the FMT, which resolved the C.Diff symptoms, the mother also rapidly and unexplainably, gained a great deal of weight, placing her very close to the weight of her daughter, also in the obese category. Interestingly, this weight was incredibly hard for the mother to lose, despite being on a medically supervised liquid diet. The medical staff attributed the weight gain to the obese stool donor.

obese miceWhile the idea of ‘obese microbes’ may sound a little strange, there is now much work in rodents and in humans demonstrating how microbes seem to play a critical role in weight and body composition. In a particularly elegant study, one group took mice that were obese or slim and looked at the composition of their microbial communities. The obese and slim mice had a characteristically different microbial makeup – the lean mice had increased abundance of bacteria from the bacteroidetes phylum, whereas the obese mice were carrying relatively more firmicutes. What’s more, those bacterial profiles had a functional consequence – the obese makeup had a greater metabolic capacity to harvest energy from the diet. Perhaps most interestingly, the obese and slim phenotypes were transferable – obese mice given an FMT from a slim donor lost weight, suggesting a microbial basis for weight (when a relatively healthy diet is consumed). Other research in mice has shown that merely living with a slim cage mate can change the microbiome and weight of obese mice, an effect that ran in only one direction.

Malnutrition

Given the role of microbes in obesity, it is perhaps not surprising that they also seem to play an important role in diseases of malnutrition. FMT has been used as a research tool to understand the role microbes play in kwashiorkor, a disease of severe protein malnutrition especially affecting young children, and recognizable by the characteristic swelling of the abdomen and ankles. In one interesting study, stool samples were taken from sets of Malawian twins that were discordant for the disease and fed to mice that were consuming a typical Malawian diet. They found that the combination of the Kwashiorkor microbes and the Malawian diet were sufficient to cause significant weight loss, suggesting that a consideration of microbes in the disease is an important variable.

Anxiety and Depression

The role of the microbiome in anxiety and mood disorders has been recognized for some time. For example, the co-incidence of anxiety and irritable bowel syndrome is very high, and anxiety symptoms are often discussed with reference to the gastrointestinal system (e.g., “I was so nervous, I had butterflies in my stomach”). However, recent mouse models suggest that mood can be transferred between individuals via the microbiome. In one study, mice that are typically anxious were given an FMT from mice that are typically pretty relaxed, and vice versa. Incredibly, the behaviour of these mice also shifted – the anxious mice started to act more chilled out, and the relaxed mice became more nervous. In 2016, at The Society for Neuroscience, I heard about research that involved taking the stool of humans with anxiety disorders and administering them to germ free mice. The mice followed suit – those that received the bacteria of anxious humans also became anxious, whereas those that were given stool of the non-anxious individuals also remained so. Similar findings are reported for transfers from depressed humans to mice. Such findings are exciting, suggesting that the future of mental health treatment may include FMT, or even probiotics and nutrition interventions.

A panacea?

With its high success rates in treating chronic diarrhea and gastrointestinal disease, and great promise in addressing mental health, weight, and neurological disorders, it is no wonder that FMT is getting such attention. As researchers look, they continue to find that the microbiome seems to play at least some role in an ever-increasing list of human ailments. While this may sound unspecific and ‘messy’, we must remember that the field is still in its infancy, with the techniques to measure and quantify microbial differences still being developed and refined. What the future holds is anyone’s guess, but I imagine we are just at the very tip of the iceberg in our understanding of the way many peripheral factors, including the bacteria in our gut, interact with our central nervous system to affect behavioral and symptomatic change. With that in mind, our great excitement about FMT’s should be tempered by some of its unfavorable qualities.

probiotic

Some caveats of FMT

The microbiome isn’t always correlated with ‘disease states’. While some studies suggest microbiome differences between certain groups, others detect none. For example, phylum-level changes in the ratio of Firmicutes to Bacteroidetes reported in many studies of obese individuals, has been suggested to be an artifact of data collection, rather than a true group effect.

Rats aren’t mice, and mice aren’t humans. Like many fields in biology, our understanding of the microbiome and FMT in non-human animals is far ahead of the human research. We must therefore be extremely careful in extrapolating that research to humans. Laboratory rats and mice are often inbred (meaning that they are genetically homogenous) and have nearly identical life experiences (growing up in a box). Their diets are strictly controlled and their microbiome is often depleted before a FMT (through either antibiotic treatment, or being raised germ free; which is itself a very unique and completely non-human experience). While these models are essential for elucidating the basic mechanisms underlying FMT’s desirable outcomes, translating these findings to humans is going to be a complex business, requiring much more work.

There is a reason why we are revolted by poop. Though the apparent wide-reaching health benefits associated with FMT might get you thinking twice about our brown flushable friends, the fact stands, we find poop gross for a reason. In terms of the microbiome, human stool can house a Garden of Eden, or a cauldron of disease. Toxic microbes found in contaminated poop cause cholera, dysentery, and many other horrifying human diseases. Many great engineers, plumbers, and town planners have designed our cities precisely so that we do not come into contact with our own effluent. In addition, as discussed earlier, adverse unexpected outcomes have been associated with FMT’s, meaning that each stool and donor needs to be thoroughly screened. Thankfully, there are many institutions now open that do just that. However, unless you have a disease that has solid human evidence for the efficacy of FMT, it’s probably best to hold off until more of the data roll in.

The future of the FMT

Rodent and human research on FMT’s has shown how transplanting pre-established microbial communities into hosts can go a long way in reconfiguring a dysbiotic gut, back to a healthy state, with big consequences for physical, and perhaps even mental, health. However, FMT’s have a long way to go. Given the caveats stated above, what is in the future for this young and exciting treatment? Engineering of synthetic ‘human microbiomes’ with all of the gut microbes we see in healthy gut ecosystems, but none of the waste and pathogens, are currently under investigation. Effectiveness of current medications might be increased by a pre-drug survey of the microbiome and it’s metabolic potential, with dose and type of medication adjusted accordingly. On the horizon for future generations is the recognition that we are home to a whole world of helpful little critters, and an appreciation of the importance of diet and lifestyle in helping to keep those microbes alive. These approaches will bring another dimension to holistic medicine, helping us all appreciate that health and disease are whole body states, taking place in the context of the human-microbiome ecosystem.

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